Physiol Rev 85: 1205–1253, 2005;

doi:10.1152/physrev.00002.2005.

Molecular Physiology of Cardiac Repolarization

JEANNE M. NERBONNE AND ROBERT S. KASS

Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis,
Missouri; and Department of Pharmacology, College of Physicians and Surgeons,
Columbia University, New York, New York

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I. Introduction 1206
II. Myocardial Action Potentials and Voltage-Gated Inward Sodium and Calcium Currents 1208
A. Voltage-gated Na⫹(Nav) currents 1208
B. Voltage-gated Ca2⫹ (Cav) currents 1209
III. Myocardial Action Potentials and Repolarizing Voltage-Gated Potassium Currents 1211
A. Transient outward Kv currents 1211
B. Delayed rectifier Kv currents 1213
C. Regional differences in Kv current expression and properties 1214
IV. Other Myocardial Potassium Currents Contributing to Repolarization 1214
V. Molecular Components of Myocardial Nav and Cav Channels 1216
A. Nav channel pore-forming ␣-subunits 1216
B. Nav channel accessory subunits and other interacting proteins 1219
C. Cav channel pore-forming ␣-subunits 1222
D. Cav channel accessory subunits and other interacting proteins 1223
VI. Molecular Components of Myocardial Kv Channels 1225
A. Kv channel pore-forming ␣-subunits 1225
B. Kv channel accessory subunits 1227
C. Molecular correlates of cardiac transient outward Kv channels 1230
D. Molecular correlates of cardiac delayed rectifier Kv channels 1232
VII. Molecular Components of Other Cardiac Potassium Channels 1234
A. Inwardly rectifying cardiac K⫹ (Kir) channel pore-forming ␣-subunits 1234
B. Two-pore domain K⫹ (K2P) channel pore-forming ␣-subunits 1236
VIII. Myocardial Potassium Channels and the Actin Cytoskeleton 1237
IX. Summary and Conclusions 1238

Nerbonne, Jeanne M., and Robert S. Kass. Molecular Physiology of Cardiac Repolarization. Physiol Rev 85:
1205–1253, 2005; doi:10.1152/physrev.00002.2005.—The heart is a rhythmic electromechanical pump, the functioning of
which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until
the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward
(Na⫹ and Ca2⫹) and outward (K⫹) current carrying ion channels. In different regions of the heart, action potential
waveforms are distinct, owing to differences in Na⫹, Ca2⫹, and K⫹ channel expression, and these differences contribute
to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel
functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the
generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms
that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the
Na⫹, Ca2⫹, and K⫹ currents that generate cardiac action potentials, and molecular cloning has revealed a large number
of pore forming (␣) and accessory (␤, ␦, and ␥) subunits thought to contribute to the formation of these channels.
Considerable progress has been made in defining the functional roles of the various channels and in identifying the
␣-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits
and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function
as components of macromolecular complexes, comprising the ␣-subunits, one or more accessory subunit, and a variety
of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the
actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as
well as between cardiac structure and electrical functioning. Important areas of future research will be the identification
of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms
involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

www.prv.org 0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society 1205
1206 JEANNE M. NERBONNE AND ROBERT S. KASS

I. INTRODUCTION 67, 184, 365, 496, 501–503, 510), can lead to changes in
action potential waveforms, synchronization, and/or
The normal mechanical (pump) functioning of the propagation, thereby predisposing the heart to potentially
mammalian heart depends on proper electrical function- life-threatening arrhythmias (13, 14, 16, 24, 127, 259, 436).
ing (56, 173), reflected in the sequential activation of cells There is, therefore, considerable interest in delineating
in specialized, “pacemaker” regions of the heart and the the molecular, cellular, and systemic mechanisms con-
propagation of activity through the ventricles (Fig. 1). tributing to the generation and maintenance of normal
Myocardial electrical activity is attributed to the genera- cardiac rhythms, as well as in understanding how these
tion of action potentials in individual cardiac cells, and mechanisms are altered in the diseased myocardium.
the normal coordinated electrical functioning of the Myocardial electrical activity is initiated in the pace-
whole heart is readily detected in surface electrocardio- maker cells in the sinoatrial (SA) node and then propa-
grams (Fig. 1). The propagation of activity and the coor- gated through the atria to the atrioventricular (AV) node

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dination of the electromechanical functioning of the ven- (Fig. 1). Following a brief pause in the AV node, excitation
tricles also depend on electrical coupling between cells, spreads in the conducting Purkinje fibers to the apex of
mediated by gap junctions (251, 435). The generation of the heart and into the working, ventricular myocardium
myocardial action potentials reflects the sequential acti- (Fig. 1). In cells in each of these specialized regions,
vation and inactivation of ion channels that conduct de- excitation results in action potential generation, followed
polarizing, inward (Na⫹ and Ca2⫹), and repolarizing, out- by relaxation and a period of refractoriness until the next
ward (K⫹), currents (24, 375). The waveforms of action impulse is generated and propagated. The observed het-
potentials in different regions of the heart are distinct erogeneity in action potential waveforms in different cell
(Fig. 1), owing to differences in the expression and/or the types (Fig. 1) reflects differences in ion channel expres-
properties of the underlying ion channels (24, 374). These sion levels, and modeling studies suggest that small
differences contribute to the normal unidirectional prop- changes in the time- and/or voltage-dependent properties
agation of excitation through the myocardium and to the of cardiac sarcolemmal ion channels can have rather
generation of normal cardiac rhythms (23, 24, 259, 374, profound effects on action potential durations, as well as
375). Changes in the properties or the functional expres- impact refractoriness and rhythmicity (105, 127, 311, 312).
sion of myocardial ion channels, resulting from inherited In ventricular and atrial myocytes and in Purkinje fibers
mutations in the genes encoding these channels (23, 36, (Fig. 1), the upstroke of the action potential (phase 0) is
51, 102, 204, 243, 253) or from myocardial disease (34, 49, rapid, resulting from the activation of voltage-gated Na⫹

FIG. 1. Electrical activity in the myo-

cardium. Top: schematic of a human
heart with illustration of typical action
potential waveforms recorded in differ-
ent regions. Bottom: schematic of a sur-
face electrocardiogram; three sequential
beats are displayed.

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1207

(Nav) channels (172) (Fig. 2). In pacemaker cells in the SA play a role in automaticity (57, 394). As with cardiac Nav
node (SAN) and AV node (AVN), however, phase 0 is channels, however, the properties of the L- and T-type
markedly slower than in atria/ventricles (Fig. 1), suggest- cardiac Cav channels characterized electrophysiologi-
ing that Nav channels do not play a prominent role in cally in different cell types and in different species (Table
depolarization. Nevertheless, Nav currents have been de- 1) are quite similar, suggesting that the molecular corre-
scribed in subsets of rabbit and guinea pig AVN cells (361, lates of the underlying L- and T-type (Cav) channels are
579), as well as in rabbit SAN cells (173). The properties also similar throughout the myocardium (see sect. VC).
of the Nav currents expressed in cardiac cells from dif- The driving force for K⫹ efflux is high during the
ferent species, as well as in different cell types in the plateau phase of the action potential in ventricular and
same species (Table 1), are similar, an observation that atrial myocardium and, as the Cav channels inactivate, the
might be interpreted as suggesting that the molecular outward K⫹ currents predominate, resulting in (phase 3)
correlates of the underlying channels are the same (see repolarization, bringing the membrane voltage back to the

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sect. VA). resting potential (Fig. 2). In contrast to Nav and Cav
Phase 0 of the action potential in Purkinje fibers and currents, however, there are multiple types of voltage-
in atrial and ventricular myocytes is followed by a tran- gated K⫹ (Kv) currents, as well as non-voltage-gated,
sient repolarization (phase 1), reflecting Nav channel in- inwardly rectifying K⫹ (Kir) currents (Table 1), that con-
activation and the activation of the fast transient voltage- tribute to myocardial action potential repolarization. The
gated outward K⫹ current (Ito,f) (Fig. 2). This transient greatest functional diversity is among Kv channels (Table
repolarization or “notch,” which can be quite prominent in 1). At least two types of transient outward currents, Ito,f
Purkinje and ventricular cells (Fig. 1), influences the and Ito,s, and several components of delayed rectification,
height and duration of the action potential plateau (phase including IKr [IK(rapid)], IKs [IK(slow)], and IKur [IK(ultrarapid)],
2). Membrane depolarization also activates voltage-gated for example, have been distinguished (Table 1). The time-
Ca2⫹ (Cav) currents, and the influx of Ca2⫹ through L- and voltage-dependent properties of the various Kv cur-
type Cav channels during the phase 2 plateau is the main rents identified in myocytes isolated from different spe-
trigger for excitation-contraction coupling in the working cies and/or from different regions of the heart in the same
myocardium (57, 154). In SAN and AVN cells, activation of species, however, are remarkably similar, suggesting that
(L-type) Cav channels also contributes to action potential the same (or very similar) molecular entities contribute to
generation, particularly in cells expressing low levels of the generation of each of the various types of Kv channels
functional Nav channels (57). In some cardiac cells/spe- (Table 1) in different cells/species. The relative Kv chan-
cies, another class of Cav channels, the T-type Cav chan- nel expression levels vary in cardiac cells in different
nels (Table 1), has been distinguished and suggested to regions (i.e., atria, ventricles) of the heart, and this hetero-

FIG. 2. Action potential waveforms and

underlying ionic currents in adult human and
ventricular (left) and atrial (right) myocytes.
The time- and voltage-dependent properties
of the voltage-gated inward Na⫹ (Nav) and
Ca2⫹ (Cav) currents expressed in human
atrial and ventricular myocytes are similar.
In contrast, there are multiple types of K⫹
currents, particularly Kv currents, contribut-
ing to atrial and ventricular action potential
repolarization. The properties of the various
Kv currents are distinct, and in contrast to
the inward currents, there are multiple Kv
currents expressed in individual myocytes
throughout the myocardium.

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1208 JEANNE M. NERBONNE AND ROBERT S. KASS

TABLE 1. Cardiac currents contributing to action potential repolarization

Channel Type Current Name Activation Inactivation Recovery Species Tissue

Nav
INa Very fast Fast Fast Cat, dog, ferret, human, mouse, rat A, P, V, SAN†, AVN‡
Cav
ICa(L) Fast Moderate* Fast Cat, dog, ferret, human, mouse, rat A, P, V, SAN, AVN
ICa(T) Fast Fast Slow Cat, dog, guinea pig, rat A, P, SAN, AVN
Kv (Ito)
Ito, t Fast Fast Fast Cat, dog, ferret, human, mouse, rat A, P, V
Ito,s Fast Moderate Slow Ferret, human, mouse, rat, rabbit V (A, AVN, SAN)‡
Kv (Ik)
IKr Moderate Fast Slow Cat, dog, guinea pig, human, mouse, rabbit, rat A, P, V, SAN, AVN
IKs Very slow No Dog, guinea pig, human, rabbit A, P, V, SAN

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IKur Very fast Very slow Slow Dog, human A
IK,slow1 Very fast Slow Slow Mouse A, V
IKp Fast No Guinea pig V
IK,slow2 Fast Very slow Slow Mouse A, V
IK Slow Slow Slow Rat V
Iss Slow No Dog, human, mouse, rabbit, rat A, V, AVN
Kir
IKl Cat, dog, ferret, human, mouse, rabbit, rat A, P, V

A, atrial; P, Purkinje; V, ventricular; SAN, sinoatrial node; AVN, atrioventricular node. The dashed boxes are placed around currents given
different names in different species that likely are encoded by the same channel’s subunit genes. * Inactivation is Ca2⫹ and voltage dependent.
† Observed in some, but not all, AVN and SAN cells. ‡ Only in nonventricular cells in rabbit.

geneity contributes importantly to the observed regional to inherited and acquired disorders of the cardiovascular
differences in action potential waveforms (24, 127, 373, (and other) system will continue to increase, perhaps
374). Changes in the properties or the functional expres- dramatically, in the future. The densities and the func-
sion of Kv channels, as occurs in a variety of myocardial tional properties of myocardial Nav, Cav, Kv, and Kir
diseases (34, 49, 67, 365, 496, 503, 510), can, therefore, currents also change in a number of acquired myocardial
have dramatic effects on action potential waveforms, disease states (34, 49, 67, 365, 496, 503, 510), and these
propagation, and rhythmicity. changes can lead to the generation of potentially life-
A large number of pore-forming (␣) subunits, encod- threatening cardiac arrhythmias. At present, therefore,
ing Nav, Cav, Kv, and Kir channels, and a variety of there is considerable interest in understanding the de-
channel accessory (␤, ␦, and ␥) subunits have been iden- tailed molecular mechanisms controlling the properties
tified (Tables 2– 6), and considerable progress has been and the functional cell surface expression of the various
made in defining the expression patterns of these subunits ion channels controlling myocardial action potential re-
in the heart and the roles of the individual subunits in the polarization, as well as the impact of genetic and epige-
generation of functional cardiac (Nav, Cav, Kv, and Kir) netic factors, including cardiac and noncardiac disease,
channels (Tables 2– 6). These studies have demonstrated on the functioning of these channels.
that distinct molecular entities underlie the various car-
diac ion channels/currents that have been distinguished
II. MYOCARDIAL ACTION POTENTIALS AND
electrophysiologically and shown to contribute to myo-
VOLTAGE-GATED INWARD SODIUM AND
cardial action potential repolarization. It also has now
CALCIUM CURRENTS
been shown that mutations in the genes encoding the
subunits involved in the generation of functional cardiac
Nav, Kv, Cav, and Kir channels underlie several inherited A. Voltage-Gated Naⴙ(Nav) Currents
cardiac arrhythmias (23, 36, 51, 102, 204, 253, 479, 481).
Although inherited rhythm disorders are rare, these mu- Voltage-gated cardiac Na⫹ (Nav) channels open rap-
tations belong to an ever-increasing number of “chan- idly on membrane depolarization (Fig. 2) and underlie the
nelopathies,” i.e., diseases linked to genes encoding ion rapidly rising phases of the action potentials recorded in
channels (35, 123, 204, 220, 234, 243, 267, 309, 359, 403, mammalian ventricular and atrial myocytes and in cardiac
442, 459). Based on the rapid progression of this field Purkinje fibers (93, 375). Although not evident in all cells,
(249) and the growing molecular complexity of ion chan- Nav channels with similar properties are also expressed
nels, it seems certain that the number of genes encoding in subsets of mammalian SAN and AVN cells, and differ-
ion channels or ion channel regulatory molecules linked ences in functional Nav channel expression likely contrib-

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1209

ute to action potential heterogeneity in pacemaker cells membrane depolarizations. Although the persistent Nav
(262, 361, 579, 582). Although the properties of the Nav channel (“window”) current is small, this current could, in
channels expressed in different cardiac cells are similar, principle, contribute to determining action potential du-
the biophysical and pharmacological properties of these rations (438, 439). In this context, it is interesting to note
channels are distinct from Nav channels expressed in that it has been reported that the expression level of the
other excitable cells, such as neurons and skeletal muscle persistent Nav current component varies in different re-
(93, 573). Cardiac Nav channels, for example, are remark- gions of the ventricles (438), differences that could con-
ably insensitive to the Nav channel toxin tetrodotoxin tribute to the observed regional heterogeneities in ven-
(TTX), which binds with high (nM) affinity to neuronal tricular action potential durations (24, 374). The concept
and skeletal muscle Nav channels and blocks Na⫹ influx that small inward (Na⫹) currents could profoundly affect
(93, 573). This observation was probably the first indica- action potential waveforms and excitability in the myo-
tion that the molecular identities of the Nav channels in cardium was suggested more than 50 years ago in the

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cardiac myocytes, neurons, and skeletal muscle were dis- pioneering studies of Silvio Weidman (542). The impact of
tinct, and as detailed in section VA, this has now been alterations in the “persistent” Nav channel window cur-
demonstrated. rent on cardiac rhythms has now been definitively dem-
On membrane depolarization, cardiac Nav channels onstrated with the identification of mutations in the gene,
activate and inactivate rapidly (172, 174). The threshold SCN5A, encoding the TTX-insensitive cardiac Nav chan-
for Nav channel activation is quite negative (approxi- nels (see sect. VA) in patients with an inherited form of
mately ⫺55 mV), and the activation of these channels is long QT syndrome, LQT3 (52). A number of SCN5A mu-
steeply voltage dependent. Importantly, inactivation is tations in different affected individuals/families have been
also voltage dependent, and cardiac Nav channels can identified (Fig. 3A) and linked to Brugada syndrome and
undergo voltage-dependent inactivation without ever to conduction defects, in addition to LQT3 (23, 36, 51, 60,
opening (174). Nevertheless, persistent openings of car- 93, 102, 105, 204, 253, 422, 519, 525, 540). Interestingly,
diac Nav channels are occasionally observed, even at mutations in noncardiac Nav channel genes have also
depolarized membrane potentials (437, 591). At potentials been linked to familial paroxysmal dysfunction in the
corresponding to the action potential plateau in ventric- skeletal and nervous systems (123, 204, 220, 359).
ular myocytes, present estimates are that ⬃99% of the Nav
channels are in an inactivated, nonconducting state (423,
525). There is, therefore, a finite, albeit small (⬃1%), B. Voltage-Gated Ca2ⴙ (Cav) Currents
probability of Nav channels being open at potentials cor-
responding to the action potential plateau (525). A slow In contrast to skeletal muscle, it has long been rec-
component of Nav channel inactivation has indeed been ognized that Ca2⫹ entry from the extracellular space is
described in normal human ventricular myocytes (323). required for excitation-contraction coupling in the mam-
This current is modulated by lysolipids (501) and appears malian myocardium (56, 57, 154, 173). The pathway for
to be upregulated in failing myocardium (501–503). Im- plasmalemmal Ca2⫹ entry was first revealed in voltage-
portantly, the inward (Na⫹) current through open Nav clamp recordings from multicellular (frog) atrial prepara-
channels during the action potential plateau (phase 2) will tions and was termed the “slow inward” current pathway
counter the effects of the increased K⫹ efflux, thereby (416 – 418, 429). Subsequent studies revealed that this
slowing or delaying repolarization and increasing action “slow inward” current is carried by Ca2⫹ through a mem-
potential durations (23, 102). It follows, therefore, that brane conductance distinct from the voltage-dependent
changes in Nav channel open probability at voltages cor- (Nav channel) pathway for Na⫹ movement (45, 332, 386,
responding to the plateau (i.e., phase 2) could markedly 416 – 418, 429). Further studies detailed the time- and
affect action potential waveforms, particularly in ventric- voltage-dependent properties of voltage-gated cardiac
ular cells. Ca2⫹ (Cav) currents, first, in multicellular preparations
The probability of Nav channel opening at depolar- and later, in isolated single cardiac cells (45, 57, 172,
ized potentials (i.e., during phase 2) is determined by the 416 – 418).
overlap of the curves describing the voltage dependences Although the presence of two functionally distinct
of channel activation and inactivation (30). At the molec- types of Cav currents in single (starfish egg) cells was first
ular level, the fact that some channels are open over this reported in 1975 (201), it was not until the late 1980s that
voltage “window” implies that there is a finite probability the import and the generality of these observations be-
that inactivation is reversible, i.e., that inactivated chan- came clear. Two types of Cav currents/channels, for ex-
nels can reopen at depolarized potentials. Consistent with ample, were clearly distinguished in (chick and rat) sen-
these predictions, electrophysiological studies reveal the sory neurons, based primarily on differences in the
presence of a sustained component of inward Nav cur- thresholds for channel activation (85, 86). These channels
rent, i.e., a “persistent” Nav current, during prolonged were termed high voltage-activated (HVA) and low volt-

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1210 JEANNE M. NERBONNE AND ROBERT S. KASS

FIG. 3. Pore-forming (␣) subunits of

cardiac Nav (A) and Kv (B and C) chan-
nels linked to inherited arrhythmias. A:
membrane topology of the four domains
(I–IV) of SCN5A is illustrated with muta-
tions linked to LQT3 and Brugada syn-
dromes and to conduction disorders.

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Schematics illustrating the transmem-
brane topologies of KCNH2 (B) and
KCNQ1 (C) subunits with the mutations
linked to LQT2 and LQT1, respectively,
depicted by the open and closed circles.

age-activated (LVA) Cav channels. Cardiac HVA and LVA species, are quite similar, suggesting that the molecular
Cav channels were first described in isolated canine atrial compositions of the underlying channels and the molec-
cells (44). LVA Cav channels, also referred to as T-type ular mechanisms controlling the functional expression of
Ca2⫹ channels (394), activate at relatively hyperpolarized these channels are the same. Importantly, however, the
membrane potentials, i.e., approximately ⫺50 mV, and time- and voltage-dependent properties of cardiac L-type
these channels activate and inactivate rapidly (85, 86, HVA currents are distinct from the L-type HVA Cav cur-
382). HVA Cav channels, in contrast, open on depolariza- rents expressed in skeletal muscle and in neurons (44,
tion to membrane potentials positive to approximately 326, 340), suggesting that, similar to the Nav channels,
⫺20 mV, and these channels inactivate over a time course distinct molecular entities underlie the L-type HVA Cav
of several tens of milliseconds to seconds, depending on channels in different tissues (see sect. VC).
the preparation and the charge carrying ion (85, 326). The opening of cardiac L-type Cav channels in re-
Under physiological conditions, with Ca2⫹ as the charge sponse to membrane depolarization is delayed relative to
carrier, HVA channels in most cells inactivate in ⬍100 ms the Nav channels (Fig. 2), and these channels, therefore,
at depolarized voltages (44, 326). contribute little to phase 0 depolarization in Purkinje,
The detailed kinetic, pharmacological, and voltage- atrial and ventricular cells. Rather, the opening of HVA
dependent properties of HVA Cav channels in different L-type Cav channels and the Ca2⫹ entry through these
cell types are distinct, suggesting that HVA Cav channels channels underlies the action potential plateau (phase 2),
are heterogeneous, particularly compared with LVA Cav which is particularly prominent in ventricular and Pur-
channels. Consistent with this view, multiple types of kinje cells (Fig. 2). In addition, Ca2⫹ influx through the
HVA channels have now been identified in different cell L-type HVA Cav channels triggers Ca2⫹ release from in-
types, and these are referred to as L, N, P, Q, or R tracellular Ca2⫹ stores and underlies excitation-contrac-
channels (276, 382, 394). Although all HVA Cav channels tion coupling in the working (ventricular) myocardium
exhibit relatively large single-channel conductances (56, 57, 154, 173). L-type HVA Cav channels are also
(13–25 pS) and have similar permeation properties, the expressed in SAN and AVN cells, where they play a role in
detailed biophysical properties and the pharmacological action potential generation, as well as in regulating auto-
sensitivities of the various types of HVA Cav channels are maticity (49, 72, 262, 340, 361, 579). Cardiac L-type HVA
distinct. In the mammalian heart, L-type HVA Cav cur- Cav channels undergo rapid voltage- and Ca2⫹-dependent
rents appear to be ubiquitously expressed (44, 49, 326). In inactivation (166, 281, 326), processes that will also influ-
addition, the properties and the densities of L-type Cav ence action potential waveforms (Fig. 2) by affecting the
channel currents in cells isolated from different regions of duration of the plateau (phase 2) and the time course of
the myocardium, as well as in cardiac cells from different action potential repolarization.

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1211

In addition to the ubiquitously expressed HVA L-type that contribute to shaping action potential waveforms and
cardiac Cav currents, LVA or T-type Cav channel currents to regulating normal cardiac rhythms. Additional studies,
have also been identified in voltage-clamp recordings focused on further characterization of the properties of
from adult atrial myocytes and conducting tissues in sev- LVA Cav channels in SAN and AVN cells and determina-
eral different species (44, 200, 340, 394). Although not tion of the functional roles of these channels in regulating
evident in normal adult ventricular myocytes (394), T type pacemaking, will be needed to explore these possibilities
Cav currents have also been recorded in neonatal rat and directly.
rabbit ventricular myocytes (547, 548). In addition, it has
been demonstrated that T-type Cav currents are ex-
III. MYOCARDIAL ACTION POTENTIALS AND
pressed in ventricular myocytes in several animal models
REPOLARIZING VOLTAGE-GATED
of ventricular hypertrophy (328, 383), findings consistent
POTASSIUM CURRENTS
with the view that substantial remodeling occurs in the

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hypertrophied myocardium, reflecting a reversion to a
Voltage-gated K⫹ (Kv) channels are the primary de-
fetal/neonatal pattern of gene expression (486). It is cer-
terminants of action potential repolarization in the mam-
tainly possible that similar remodeling occurs in the hy-
malian myocardium, and compared with cardiac Nav and
pertrophied human heart (49). Nevertheless, it is impor-
Cav channels, there is considerable electrophysiological
tant to note that, to date, T-type LVA Cav channels have
and functional cardiac Kv channel diversity (42, 373, 375).
not been detected in normal or diseased human myocar-
Based primarily on differences in time- and voltage-de-
dial cells (49, 394).
pendent properties and pharmacological sensitivities (42,
In addition to marked differences in biophysical
373, 375), two broad classes of repolarizing cardiac Kv
properties, the physiological role(s) of cardiac T-type LVA
currents have been distinguished (42): transient outward
Cav channels appears to be quite different from the L-type
K⫹ currents (Ito) and delayed, outwardly rectifying K⫹
HVA Cav channels. As noted previously, for example,
currents (IK) (Table 1). The transient currents (Ito) acti-
Ca2⫹ entry through L-type channels in cardiac cells re-
vate and inactivate rapidly on membrane depolarizations
sults in Ca2⫹-induced Ca2⫹ release from intracellular
to potentials positive to approximately ⫺30 mV and un-
(Ca2⫹) stores and is the main trigger for excitation-con-
derlie the early phase (phase 1) of repolarization in ven-
traction coupling (57, 154). Although Ca2⫹ entry through
tricular and atrial cells (Fig. 2). Cardiac delayed rectifiers
T-type channels also triggers Ca2⫹ release from intracel-
(IK) activate at similar membrane potentials and with
lular stores, the coupling is less efficient (589), and it
variable kinetics, and these currents determine the latter
seems unlikely that T channels contribute importantly to
phase (phase 3) of repolarization back to the diastolic
excitation-contraction coupling. This may simply reflect
potential (Fig. 2). Multiple types of myocardial Ito and IK
the fact that LVA channel densities are low and that,
channels with distinct time- and voltage-dependent prop-
owing to rapid inactivation, very little Ca2⫹ actually en-
erties (Table 1), however, have been identified, and dif-
ters cells on depolarization. Alternatively, these func-
ferences in the densities and the biophysical properties of
tional differences may reflect the fact that HVA and LVA
these channels contribute to variations in the waveforms
cardiac Cav channels are differentially localized, i.e., L-
of action potentials recorded in different cardiac cell
type, but not T-type, Cav channels are highly localized in
types (Fig. 1), as well as in different species (24, 374, 375,
the t tubules near the storage sites for intracellular Ca2⫹
436). The detailed pharmacological, time- and voltage-
sequestration/release (394, 589). Further experiments will
dependent properties of each of the various repolarizing
be necessary to determine the mechanistic basis for the
Kv currents characterized in different cardiac cell types
distinct functional roles of L- and T-type Ca2⫹ channels in
and species are quite similar, thereby allowing Kv chan-
regulating excitation-contraction coupling.
nels to be classified based on these biophysical properties
The finding that T-type LVA Cav currents activate at
(Table 1). The observed similarities in Kv channel prop-
relatively hyperpolarized potentials and that these chan-
erties also suggest that the molecular correlates of the
nels are expressed preferentially in pacemaker and con-
underlying Kv channels are also similar (42, 373), and
ducting cells in the heart suggests the interesting possi-
considerable experimental evidence has now been pro-
bility that there is a role for LVA channels in pacemaking
vided to support this hypothesis (see sect. VI).
(200). Although some experimental support for this hy-
pothesis has been provided, rigorous testing is compli-
cated by the paucity of highly selective LVA Cav channel A. Transient Outward Kv Currents
blockers (394). In addition, it has been reported that
(rabbit) SAN cells express rapidly activating Na⫹-depen- Although cardiac transient outward currents were
dent inward currents that are blocked by Ca2⫹ channel first described in (sheep) Purkinje fibers and thought to
blockers (582). These observations suggest that pace- reflect Cl⫺ conductances (143, 175), subsequent work
maker cells may express additional novel inward currents demonstrated the presence of two transient outward cur-

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1212 JEANNE M. NERBONNE AND ROBERT S. KASS

rents with distinct properties and referred to as Ito1 and different cells/species (15). These observations suggest
Ito2 (112). Pharmacological studies revealed that Ito1 is that there may well be subtle, albeit potentially important,
blocked by 4-aminopyridine (4-AP) and unaffected by molecular heterogeneity among Ito,f and Ito,s channels in
changes in extracellular Ca2⫹, whereas Ito2 is not blocked different cell types and/or in different species (see
by 4-AP and is Ca2⫹ dependent (257, 256). In further sect. VIC).
studies, it was shown that the Ca2⫹-dependent Ito2 in Although originally identified in Purkinje fibers, Ito,f
Purkinje fibers and ventricular cells is a Cl⫺ (not a K⫹) is a prominent repolarizing current in atrial and ventric-
current (593, 594). In contrast, the Ca2⫹-independent ular myocytes in most species (26, 58, 65, 69, 75, 79, 160,
component, Ito1, was shown to be K⫹ selective (594), and 178, 264, 294, 297, 500, 530, 545, 546, 578), including
transient outward K⫹ currents, referred to variably by humans. Nevertheless, there are exceptions. In guinea pig
different laboratories as Ito, Ito1, or It (42, 83, 436), have ventricular cells, for example, Ito,f has not been detected
now been described in many cardiac cell types and in except when extracellular Ca2⫹ is removed (224). In ad-

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most species. Comparison of the detailed biophysical dition, Ito,f is not detected in rabbit atrial or ventricular
properties of the transient outward K⫹ currents described cells (156, 160, 183, 530). Nevertheless, there are transient
in various cell types/species, however, suggested there Kv currents in rabbit myocytes (typically referred to as It),
might actually be two types of transient outward K⫹ which inactivate slowly and recover from (steady-state)
currents (42), and electrophysiological and pharmacolog- inactivation very slowly (160, 530). The properties of
ical studies have now provided considerable support for these currents, therefore, more closely resemble mouse
this hypothesis. In adult mouse ventricular myocytes, for ventricular Ito,s than Ito,f (562). Similar to the mouse,
example, two transient K⫹ currents, termed Ito,fast (Ito,f) however, two distinct transient outward Kv currents have
and Ito,slow (Ito,s), have been distinguished (562). On mem- been described in the ventricles of other mammals (77,
brane depolarization, mouse ventricular Ito,f channels ac- 178, 294, 500), including humans (225, 264, 545, 546), and
tivate and inactivate rapidly, and on membrane repolar- the properties of these currents are quite similar to those
ization, these (Ito,f) channels recover rapidly from steady- of mouse ventricular Ito,f and Ito,s (79, 196, 562), permit-
state inactivation (562). In the adult mouse, Ito,f channels ting their classification as such (Table 1). In ferret, the
contribute importantly to the rapid repolarization of ac- rates of inactivation and recovery (from steady-state in-
tion potentials (194, 562) that is likely necessary to main- activation) of the transient Kv currents in myocytes iso-
tain the very high resting heart rates (⬃700 beats/min) in lated from the left ventricular (LV) endocardium are sig-
these animals. In humans and other larger mammals, Ito,f nificantly slower than the currents in cells from the epi-
underlies the early phase (phase 1) of repolarization in cardial surface of the LV, suggesting the presence of two
ventricular and atrial cells (Fig. 2) and likely also contrib- distinct transient Kv currents that are differentially ex-
utes to determining the plateau (phase 2). pressed (77). Examination of the reported biophysical
Similar to Ito,f, mouse ventricular Ito,s channels acti- properties (77) suggests that the endocardial and epicar-
vate and inactivate rapidly (562). In contrast to Ito,f, how- dial LV currents can be classified as Ito,s and Ito,f, respec-
ever, Ito,s channels recover very slowly (time constants of tively (Table 1). The distinct transient Kv currents in the
seconds) from (steady-state) inactivation and are func- epicardial, midmyocardial, and endocardial layers of ca-
tionally distinct from Ito,f channels (196, 562). In addition, nine (294, 500) and human (264, 545, 546) ventricles can
Ito,f is readily distinguished from other Kv currents, in- also be appropriately referred to as Ito,f or Ito,s (Table 1).
cluding Ito,s, (562), using the spider K⫹ channel toxins Transient Kv currents that can be classified as Ito,f
Heteropoda toxin-2 or -3 (449). The distinct properties of (Table 1) have also been shown to be expressed in (rab-
Ito,f and Ito,s suggested that these currents reflect the bit) SAN cells, although, similar to Nav currents, Ito,f
functioning of two molecularly distinct Kv channels, and densities vary markedly among (SAN) cells (213, 283). Ito,f
considerable evidence has now been provided to support densities are higher, for example, in the larger cells iso-
this hypothesis (see sect. VIC). Detailed comparisons of lated from the periphery, compared with the smaller cells
the properties of the transient outward K⫹ currents ex- in the center, of the SAN (213, 283). In addition, when
pressed in other species, whether termed Ito, Ito1, or It, expressed, Ito,f appears to play a role in shaping action
suggest that, in each case, these currents could also be potential waveforms and in regulating automaticity in
classified as Ito,s or Ito,f, based on the kinetics of current SAN cells (72, 213, 283). Cells isolated from the (rabbit)
inactivation and recovery from steady-state inactivation, AVN also express Ito,f (349, 361, 371), and detailed kinetic
as well as by the differential sensitivities of the channels analysis of the currents reveals the presence of two com-
to the Heteropoda toxins. Although the properties of the ponents with distinct rates of inactivation and recovery
transient K⫹ currents in different cell types and species (349). It is unclear whether these findings reflect differ-
are similar and are amenable to classification as either Ito,f ences in the kinetic properties of a single type of Ito,f
or Ito,s (Table 1), there are differences in the detailed channel or if two distinct types of Ito channels are ex-
biophysical properties of the (Ito,f and Ito,s) currents in pressed in (rabbit) AVN cells. Similar to the (rabbit) SAN,

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1213

there is considerable heterogeneity in Ito densities among although, in general, IKr and IKs densities are highest in
(rabbit) AVN cells (349). In contrast to SAN cells (213, the larger cells found at the periphery of the node (284).
283), however, the differences in Ito,f densities are not It may be that the densities of IKr and/or IKs in some cells
correlated with cell size in AVN cells (349). Interestingly, are too low to be resolved reliably or, alternatively, that
and similar to findings in guinea pig atrial and ventricular the properties of IKs and IKr in each of these cell types are
cells, Ito,f is not detected in guinea pig AVN cells (579). It distinct from guinea pig ventricular and atrial IKs and IKr.
is presently unclear, however, whether currents with The apparent absence of IKr and IKs in some cells, as well
properties similar to ventricular Ito,s are expressed in as the observation that IKr and IKs expression is hetero-
conducting tissues in guinea pig heart. Owing to the geneous and variable, might also reflect the fact that
marked differences in inactivation and recovery kinetics functional cardiac Kv channel expression is labile and
of Ito,f and Ito,s channels, however, the differential expres- might well be affected by the isolation methods, which
sion of these two channel types would be expected to typically involve the use of enzymes (578). Detailed stud-

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have profound functional effects on the regulation of ies focused on current characterizations in intact prepa-
rhythmicity in the normal heart, effects that will be aug- rations, as well as on examining the effects of specific
mented in the diseased myocardium. enzymes and cell isolation methods on Kv current densi-
ties and properties, will be needed to explore these vari-
ous possibilities further.
B. Delayed Rectifier Kv Currents Although IKr and IKs are not prominent repolarizing
Kv currents in rodent atria or ventricles, there are other
Myocardial delayed rectifier Kv currents, IK, also first components of delayed rectification with time- and volt-
described in (sheep) Purkinje fibers (379), have been age-dependent properties distinct from IKs and IKr (Table
characterized in atrial and ventricular myocytes, as well 1) in myocytes from these (and other) species. In rat
as in pacemaker cells, isolated from a variety of different ventricular myocytes, for example, there are multiple de-
species, and, in most cases, multiple components of IK are layed rectifier Kv currents that are coexpressed, and these
coexpressed (Table 1). In guinea pig ventricular and atrial are referred to as IK, IKlate, and Iss (26, 210, 561). In adult
myocytes, for example, two prominent components of IK, mouse ventricular myocytes, three distinct delayed recti-
IKr (IK,rapid) and IKs (IK,slow), were first distinguished, fier Kv currents have also been separated and character-
based on marked differences in time- and voltage-depen- ized (168, 196, 263, 291, 303, 560, 562, 586, 587), and these
dent properties (216, 445, 446). Both IKr and IKs are also are referred to as IK,slow1, IK,slow2, and Iss (Table 1). Mul-
coexpressed in guinea pig AVN cells (579). Although IKr tiple components of delayed rectification have also been
activates rapidly, inactivates very rapidly, and displays described in rodent atrial myocytes (68, 69, 74, 75, 497). In
marked inward rectification, no inward rectification is both rat and mouse, it has been demonstrated that all the
evident for the slowly activating IKs (445, 446). These various delayed rectifier Kv current components contrib-
channels can also be distinguished at the microscopic ute, together with Ito,f channels, to (ventricular and atrial)
level, as well as by their unique pharmacological profiles action potential repolarization (291, 303, 560, 586, 587).
(37, 524). Similar to guinea pig, IKr and IKs are also report- It is interesting to note that a steady-state, noninacti-
edly coexpressed in human atrial and ventricular myo- vating K⫹ current, which resembles Iss in rodent atria
cytes (290, 514, 532, 533), as well as in canine (296, 297, and ventricles, has also been described in human atrial
513, 522, 578) and rabbit (440, 518) ventricles and in myocytes (58).
canine Purkinje fibers (513) and, in each case, are prom- In rat (74, 75), canine (577), and human (531–533)
inent repolarizing currents. In adult rodent ventricles, in atrial myocytes, a novel, very rapidly activating, and
contrast, IKr and IKs densities are very low (104) or the largely noninactivating, outward Kv current, now typi-
currents are undetectable (562). cally referred to as IKultrarapid or IKur (479), has been
The unique time- and voltage-dependent properties described (Table 1). In most species, IKur is not detected
of IKr and IKs suggest that these currents play prominent in ventricular cells, and it seems likely that the expression
roles in action potential repolarization, particularly in and the properties of IKur, together with Ito,f, contribute to
ventricular myocytes and Purkinje fibers. Nevertheless, in determining the more rapid repolarization evident in
some cardiac cells, only IKr or IKs appears to be ex- atrial, compared with ventricular, myocytes (Fig. 2). Im-
pressed. In isolated human (225), feline (171), and rat portantly, as in most other species, IKur is not expressed
(404) ventricular myocytes and in rat atrial (404), mouse in human ventricular myocytes or in Purkinje fibers, sug-
SAN (108), rabbit AVN and SAN (218, 233, 467) cells, for gesting that IKur channels might represent a therapeutic
example, only IKr is detected. It has also been reported, target for the treatment of atrial arrhythmias without
however, that both IKr and IKs are coexpressed in rabbit complicating effects on impulse propagation, ventricular
SAN cells (284). In this study, the measured densities of functioning, or cardiac output (444). The potential of this
IKr and IKs (in rabbit SAN cells) were quite variable, pharmacological strategy, however, will have to be deter-

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1214 JEANNE M. NERBONNE AND ROBERT S. KASS

mined by the atrial specificity/selectivity of the drugs that Ito,s or both Ito,f and Ito,s (79, 196, 562). Even when ex-
are developed. In contrast to rat, canine, and human, Kv pressed, however, Ito,f density is significantly lower in
currents have been described in guinea pig (576) and septum, compared with ventricular (or atrial), cells (79,
mouse (168, 291, 587) ventricular myocytes that have 562). The densities of the delayed rectifier Kv currents,
biophysical properties very similar to human (rat or ca- IK,slow1, IK,slow2, and Iss, in contrast, are similar throughout
nine) atrial IKur. Indeed, the properties of the rapidly adult mouse ventricles (79, 196, 562). The main deter-
activating, IKur-like, current in guinea pig ventricular myo- minant of action potential heterogeneity in the mouse,
cytes, referred to as IKp (576), and the micromolar 4-AP- therefore, appears to be the differential expression of
sensitive component of mouse ventricular IK,slow, referred Ito,f (79, 196).
to as IK,slow1 (69, 291, 302, 587), are indistinguishable from In larger mammals, including humans, the differen-
human (canine and rat) atrial IKur. These currents should, tial expression of Ito,f is also a primary determinant of
therefore, probably be renamed IKur (Table 1) to reflect action potential heterogeneity (24, 374). In human heart,

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the similarities in properties, as well as molecular identi- however, it is clear that differences in the expression
ties of the channels underlying IKp and IK,slow1 and IKur levels of the various delayed rectifier Kv currents, as well
(see sect. VID). as the persistent component of the Nav current (see sect.
IIA), also play important roles in regulating action poten-
tial heterogeneity (24, 374). In canine heart, for example,
C. Regional Differences in Kv Current Expression IKs density is higher in cells in the RV, compared with the
and Properties LV, whereas IKr densities are similar in both chambers
(24, 522). IKs density is also higher in canine LV epicardial
Although the properties of Ito,f in different cardiac and endocardial cells than in M cells (24, 296). In guinea
cells are similar (Table 1), there are marked regional pig heart, IKr and IKs densities are approximately twofold
differences in current densities. In humans (160, 367, 527, higher in atrial, than in ventricular, myocytes (37, 216,
542, 543) and in rats (26, 74, 75), for example, Ito,f densi- 442, 524). There are also regional differences in functional
ties are significantly higher in atrial, compared with ven- IKr and IKs expression within the ventricles (80, 316). In
tricular, myocytes. Similarly, in the rabbit, Ito,s densities cells isolated from the (guinea pig) LV free wall, for
are higher in atrial myocytes and Purkinje fibers than in example, IKr density is higher in subepicardial, than in
ventricular cells (75, 514). In the mouse, however, Ito,f either midmyocardial or subendocardial, myocytes (316).
density is significantly higher in ventricular (79, 562), than At the base of the LV, however, the densities of both IKr
in atrial (69), myocytes. The density of Ito,f is also quite and IKs are significantly lower in endocardial, than in
variable in sheep Purkinje fibers (520) and in different either epicardial or midmyocardial, cells (80). These dif-
regions of the ventricles in canine (294, 297, 522), cat ferences clearly contribute to the marked differences in
(178), ferret (77), human (367, 545, 546), mouse (79, 196, action potential waveforms and frequency-dependent
562), and rat (107, 545) hearts. In canine (522) and mouse properties in cells through the thickness of the ventricular
(79, 196, 562) heart, for example, Ito,f density is higher in wall (24). In addition to having a major impact on action
the right ventricle (RV), compared with the left ventricle potential repolarization, it is now very clear that differ-
(LV), and Ito,f densities are lower in the base of the LV ences in functional IKr and IKs densities are also expected
than in the LV apex (79). In addition, in canine and in to influence the maintenance of normal cardiac rhythms
human heart, Ito,f density varies throughout the thickness and the susceptibility to rhythm disturbances (24).
of the ventricular walls, being severalfold higher in the
epicardial and midmyocardial, than in the endocardial,
layers (297, 546). In large mammals, the regional and IV. OTHER MYOCARDIAL POTASSIUM
cellular heterogeneities in Ito,f densities are directly re- CURRENTS CONTRIBUTING
flected in the differences in action potential waveforms in TO REPOLARIZATION
Purkinje, ventricular, and atrial cells (75, 107, 366, 520,
551). Within the ventricles, for example, the differences in In addition to the depolarization-activated Kv cur-
Ito,f densities are revealed by the presence and the appear- rents, non-voltage-gated inwardly rectifying K⫹ (Kir) cur-
ance and depth of the “notch” in the initial phase rents, through IK1 channels, also contribute to myocardial
(phase 1) of action potential repolarization (24, 364, 374; action potential repolarization, particularly in ventricular
see Fig. 2). cells (232, 306, 377, 380). There are also other types of Kir
There are also marked regional differences in the channels that are expressed and are important in the
expression/distribution of Ito,s in adult rat, mouse, human, normal functioning of the heart, although these do not
and canine ventricles (77, 79, 196, 366, 367, 551, 562). In seem to play important roles in action potential repolar-
mouse RV and LV, for example, Ito,s is undetectable, ization under normal physiological conditions (306, 377).
whereas cells in the interventricular septum express only One example of a functionally important class of myocar-

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1215

dial Kir channels is the IKATP channels, which are inhib- Mg2⫹ (506), Ca2⫹ (335), and polyamines (164, 307, 308).
ited by intracellular ATP, activated by nucleotide diphos- Removal/depletion of intracellular polyamines, Mg2⫹
phates, and thought to provide a link between cellular and/or Ca2⫹, eliminates the steep inward rectification of
metabolism and membrane potential (232, 380). In the (cardiac) IK1 channels and converts to a linear current-
ventricular myocardium, the opening of IKATP channels is voltage relation (164, 307, 308, 335, 506).
thought to be important under conditions of metabolic The expression of IK1 is clearly reflected in the neg-
stress, as occurs during ischemia or hypoxia, and to result ative slope region (between approximately ⫺50 and ⫺10
in shortening action potential durations and minimizing mV) of the (total steady-state) myocyte conductance-volt-
K⫹ efflux (165, 232). The opening of IKATP channels has age relation, which is prominent in ventricular myocytes,
also been suggested to contribute to the cardioprotection but is small or undetectable in atrial cells (183). The fact
resulting from ischemic preconditioning (141, 188). Al- that the strongly inwardly rectifying IK1 channels conduct
though IKATP channels appear to be distributed uni- at negative membrane potentials suggests that these chan-

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formly in the RV and LV and through the thickness of nels will play a role in establishing the resting membrane
the ventricular wall, these channels are expressed at potentials of Purkinje fibers, as well as of atrial and
much higher density than other sarcolemmal K⫹ chan- ventricular myocytes. Direct experimental support for
nels, suggesting that action potentials could be short- this hypothesis was provided with the demonstration that
ened markedly when only very small numbers of IKATP ventricular membrane potentials are depolarized in the
channels are activated (463). presence of Ba2⫹ (377), which blocks IK1 channels. In
Another important cardiac Kir channel type is the addition, action potentials are prolonged, and phase 3
IK(ACh) channels, which are gated through a G protein- repolarization is slowed in the presence of extracellular
2⫹
coupled mechanism mediated by muscarinic acetylcho- Ba (306), suggesting that IK1 channels also contribute to
line receptor activation (275, 564). Physiologically, IK(ACh) repolarization, particularly in the ventricular myocar-
channels are activated by the binding of G protein ␤␥- dium. The voltage-dependent properties of IK1 channels
subunits in response to the acetylcholine released on (306, 377), however, are such that the conductance is low
vagal stimulation (414). Although IK(ACh) channels are at potentials positive to approximately ⫺40 mV. Never-
expressed in AVN, SAN, atrial, and Purkinje cells, and are theless, because the driving force on K⫹ is markedly
activated by acetylcholine released on vagal stimulation, increased at depolarized potentials, these channels
these channels are not thought to contribute appreciably should contribute outward K⫹ current during the phase 2
to action potential repolarization under normal physiolog- plateau and during phase 3 repolarization (Fig. 2). In
ical conditions. Consistent with this hypothesis, targeted contrast to atrial, ventricular, and Purkinje cells, IK1 den-
deletion of one of the Kir subunits (Table 6) encoding sity is low or undetectable in SAN and AVN cells (244, 381,
IK(ACh) channels, Kir3.4, does not measurably affect rest- 468). These observations, as well as the fact that pace-
ing heart rates (552). Interestingly, however, atrial fibril- maker currents are expressed and functional in SAN and
lation is not evident in Kir3.4 null mice exposed to the AVN cells, likely explain the findings that resting mem-
acetylcholine receptor agonist carbachol, suggesting that brane potentials in these (SAN/AVN) cells are depolarized
activation of IK(ACh) channels is involved in the cholin- (significantly) and that the rising phases of the action
ergic induction of atrial fibrillation (269). potentials in these cells are less steep, relative to resting
As the “inward rectifier” terminology implies, Kir membrane potentials/action potentials in atrial and ven-
channels
⫹
carry inward K⫹ currents better than outward tricular cells (Fig. 1).
K currents (306, 377). Nevertheless, it is the outward K⫹ Similar to the Kv channels, IK1 densities and the
currents through these channels that are important phys- detailed biophysical properties of the currents do vary in
iologically because myocardial membrane potentials different myocardial cell types. In human heart, for exam-
never reach values more negative than the K⫹ reversal ple, IK1 density is more than twofold higher in ventricular,
potential (approximately ⫺90 mV). As a result, there is than in atrial, cells (514). In guinea pig, the properties of
never an opportunity for the inward movement of K⫹ the atrial and ventricular IK1 currents are also distinct in
currents through Kir (or any other K⫹ selective) channels. that ventricular IK1 inactivates during maintained depo-
At the macroscopic level, IK1 channels have been charac- larizations, whereas atrial IK1 does not (133, 223). In
terized in human (206, 514), guinea pig (133, 514), and addition, changes in extracellular K⫹ modulate the mag-
rabbit (183, 381, 468) atrial and ventricular myocytes and nitude of ventricular IK1, but have little effect on atrial IK1
in rabbit SAN cells (381). The properties of the IK1 chan- (223). At the microscopic level, (guinea pig) atrial and
nels in each of these preparations are similar in that all ventricular IK1 channels are also distinct. Mean channel
are K⫹ selective, blocked by extracellular Ba2⫹ and intra- open times of ventricular IK1 channels, for example, are
cellular Cs⫹ and strongly inwardly rectifying (183, 206, approximately five times longer than those of atrial IK1
223, 514). The strong inward rectification evident in car- channels, whereas the single atrial and ventricular IK1
diac IK1 channels is attributed to block by intracellular channel conductances are indistinguishable (223). Taken

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1216 JEANNE M. NERBONNE AND ROBERT S. KASS

together, these observations suggested the interesting data, solution NMR analysis of this cytoplasmic linker
possibility that distinct molecular entities underlie ven- peptide revealed a rigid helical structure positioned to
tricular and atrial IK1 channels, and experimental support block the pore (427).
for this hypothesis has now been provided (133). Although there are a number of homologous Nav
␣-subunits (Table 2), Nav1.5 (SCN5A) is the prominent
Nav ␣-subunit expressed in the mammalian myocardium,
V. MOLECULAR COMPONENTS OF
and this subunit encodes the rapidly activating and inac-
MYOCARDIAL NAV AND CAV CHANNELS
tivating, tetrodotoxin (TTX)-insensitive Nav channels that
underlie rapid (phase 0) depolarization in atrial and ven-
A. Nav Channel Pore-Forming ␣-Subunits tricular myocytes and in Purkinje fibers (Fig. 1). Never-
theless, several studies have demonstrated that mRNAs
Voltage-gated Na⫹ (Nav) channel pore-forming (␣) encoding other Nav ␣-subunits, notably Nav1.1, Nav1.3

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subunits (Fig. 3A) belong to the “S4” superfamily of volt- (120, 426, 471), and Nav1.4 (590), which are typically
age-gated ion channel genes (93, 172, 174, 573). Nav ␣-sub- considered the Nav ␣-subunits encoding brain and skele-
units have four homologous domains (I to IV), each of tal muscle Nav channels, respectively, are also expressed
which contains six transmembrane-spanning regions (S1- in the myocardium. In contrast to the Nav channels
S6), and these four domains come together to form the formed by Nav1.5, however, Nav1.1-, Nav1.3- and Nav1.4-
Na⫹-selective pore. Structure-function studies have re- encoded Nav channels are blocked by nanomolar concen-
vealed many of the important features of voltage-depen- trations of TTX (120, 426, 471, 590). In addition, although
dent Nav channel gating (91, 93). The cytoplasmic linker cardiac Nav currents are generally considered relatively
between domains III and IV, for example, has been shown TTX insensitive (174, 573), application of nanomolar con-
to play a pivotal role in voltage-dependent Nav channel centrations of TTX has been reported to shorten canine
inactivation (392), and a critical isoleucine, phenylala- Purkinje fiber action potential durations (113). These find-
nine, methionine (IFM) motif within this linker (91, 444) ings suggest a possible role for TTX-sensitive Nav chan-
has been identified as an important molecular component nels in the generation of the persistent component of
of the inactivation gate (516, 517, 544). Voltage-dependent cardiac Nav currents, at least in canine Purkinje fibers.
inactivation of Nav channels is attributed to the rapid Nevertheless, there have been very few reports docu-
block of the inner mouth of the channel pore by the menting the presence of TTX-sensitive inward Nav cur-
cytoplasmic linker between domains III and IV that oc- rent components in cardiac cells, raising some concern
curs within milliseconds of membrane depolarization about the functional significance of the expression data,
(483). Consistent with the functional electrophysiological in spite of the fact that the (message) expression levels of

TABLE 2. Diversity of voltage-gated Na⫹ (Nav) channel ␣- and ␤-subunits

Subfamily Protein Gene Human Mouse Cardiac Current

Nav␣1 Nav1.1 SCN1A 2q24 2C1.3 INa (TTX)†??

Nav1.2 SCN2A 2q23
Nav1.3 SCN3A 2q24 2C1.3 INa (TTX)†??
Nav1.4 SCN4A 17q21 11E1 INa (TTX)??
Nav1.5 SCN5A 3p21 9F3 INa (TTX-resistant)*
Nav1.6 SCN8A 2q13 15F2 INa (TTX)†??
Nav1.7 SCN9A 2q24
Nav1.8 SCN10A 3p22 9F3
Nav1.9 SCN11A 3p21 9F3
Nav␣X Nav2.1 SCN6A 2q21-23
SCN7A
Nav␤ ␤1 SCN1B 19p11 7A3 ??
␤2 SCN2B 11q24 INa (TTX-resistant)*
␤3 SCN3B 11q26 9F3 INa (TTX-resistant)*
␤4 SCN4B 11q24

Boxes denote cardiac expression. * Major cardiac (TTX-resistant) Nav current in atria, ventricles, Purkinje fibers, and nodal cells. † TTX-
sensitive, neuronal-like, Nav current.

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1217

Nav1.1, Nav1.3, and Nav1.4 in the myocardium appear to SCN5A, linked to the LQT3 syndrome (Fig. 3A), disrupt
be quite high (120, 426, 471, 590). Nav channel inactivation (52, 346). These “gain of func-
It has also been reported that there are several Nav1 tion” mutations lead to an increase in the amplitude of the
␣-subunit proteins in addition to Nav1.5 in adult (mouse) sustained component of the Na⫹ current (Fig. 4B) and to
myocardium (314). These include Nav1.1, Nav1.3, and action potential prolongation (Fig. 4A). The enhanced
Nav1.6 (314). The immunolocalization data also suggest
that the Nav1.1, Nav1.3, and Nav1.6 ␣-subunits are local-
ized in the t tubules in adult mouse ventricles (314),
whereas Nav1.5 appears to be localized preferentially to
intercalated disks in mouse, as well as in rabbit and rat,
hearts (270, 315, 400). The subcellular localization of
Nav1.5-encoded myocardial Nav channels at the interca-

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lated disks has been interpreted as suggesting that these
(Nav) channels play a major role in regulating conduction
(270). Although the functional role(s) of t-tubular Nav
channels in cardiac functioning has not been established,
voltage-clamp studies have clearly demonstrated that
TTX-sensitive Nav currents can be measured in whole cell
recordings from adult mouse ventricular myocytes
treated with ␤-scorpion toxin, which shifts the voltage
dependence of activation of brain Nav channels, but does
not affect cardiac (i.e., SCN5A-encoded) Nav channels
(314). These observations have been interpreted as sug-
gesting a distinct role for the neuronal Nav channels
localized to the t tubules, i.e., linking depolarization of the
sarcolemmal membrane with the t tubules, thereby cou-
pling depolarization with excitation-contraction coupling
(314). This hypothesis has important functional implica-
tions and certainly warrants further direct experimental
testing.
Immunohistochemical studies have also provided ev-
idence suggesting that Nav1.1 and Nav1.3, but not Nav1.5,
are expressed in rat and mouse SAN (314). These findings
suggest a substantive molecular difference between the
SAN and the remainder of the myocardium in terms of
Nav channel expression. Given the primary role of the
SAN in regulating heart rate, it would seem certain that
modulating the (TTX-sensitive) Na⫹ current in the SAN
should impact heart rate. Nevertheless, exposure to TTX
reportedly has no effect on heart rate in the mouse (314).
In mice in which one copy of the SCN5A gene has been
disrupted, however, conduction defects, as well as ven-
tricular dysfunction, are evident (389), suggesting that FIG. 4. Simulated human ventricular action potentials reveal the

SCN5A encodes most, if not all, of the cardiac Nav cur- impact of gain of function (LQT3) and loss of function (Brugada) mu-
tations in SCN5A. Steady-state action potential waveforms (A and C)
rent. It seems reasonable to suggest, therefore, that addi- and inward Nav1.5 currents (B and D) were simulated (103, 105). Con-
tional studies focused on exploring the functioning of trol action potential and current waveforms simulated for wild-type
Nav1.1-, Nav1.3- and Nav1.6-encoded channels in the SCN5A-encoded Nav1.5 currents are depicted by the solid black lines in
A–D. The corresponding voltage and current waveforms resulting from
heart are warranted. LQT3 and Brugada mutations in SCN5A (Fig. 3A) are represented by the
During the plateau phase of the action potential in dashed purple (LQT3) and red (Brugada) lines in A–D. “Gain of function”
human ventricular myocytes, ⬃99% of the Nav channels LQT3 mutations in SCN5A, resulting in an increase in the persistent
component of the Nav current (B), lead to marked action potential
are in an inactivated, nonconducting state with the inac- prolongation (A). “Loss of function” Brugada mutations in SCN5A, in
tivation gate occluding the inner mouth of the conducting contrast, result in reduced Nav current (D) and changes in the action
pore through specific interactions with sites on either the potential upstroke velocity (C). The impact of the loss of function
Brugada mutations are more readily illustrated in the insets of C and D,
S6 segment (345) or the S4-S5 loop (346) of domain IV. in which the voltage (C) and current (D) deflections are displayed on an
Mutations in the linker between domains III and IV in expanded time scale.

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1218 JEANNE M. NERBONNE AND ROBERT S. KASS

inward current can be measured during sustained depo- the COOH terminus of Nav1.5 and other components of
larizations and appears to reflect a change in (Nav chan- the channel protein complex and that these interactions
nel) gating that results in channel “bursting” (52). As stabilize channels in the inactivated state (114). In addi-
illustrated in Figure 4A, the increase in late inward Na⫹ tion, biochemical studies provide strong support for a
current (due to Nav channel bursting) prolongs “mod- model in which there is a direct physical interaction be-
eled” cardiac action potentials (103, 105). Interestingly, tween the III-IV linker of Nav1.5 and the proximal, struc-
action potential prolongation is also evident in genetically tured portion of the COOH terminus (358). Taken to-
modified mice expressing human LQT3-associated mutant gether, these findings suggest the formation of a molecu-
SCN5A Nav channels (384). In mice heterozygous for an lar complex between these domains that is pivotal for
SCN5A deletion at residues (KPQ) 1505–1507, a modifica- channel inactivation and further that mutations in either
tion linked to LQT3, premature ventricular beats and the III-IV linker or the COOH-terminal tail disrupt this
pacing-induced ventricular tachycardia are also evident interaction and destabilize inactivation. In addition, the

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(384). Mutations in SCN5A are also linked to another homology with calmodulin suggests that there may be
(rare) inherited rhythm disorder, the Brugada syndrome structural similarities in the control of Nav and Cav chan-
(23, 41) and, similar to LQT3 mutations, a number of nel gating, a hypothesis that clearly warrants direct ex-
Brugada mutations in SCN5A have been identified (Fig. perimental testing.
4A). In contrast to long QT3, however, Brugada syndrome Analyses of additional mutations in SCN5A linked to
mutations are “loss of function” mutations in Nav1.5 and LQT3, Brugada, and conduction system defects have pro-
result in reduced Nav current (Fig. 4D) and lead to slow- vided further molecular insights into Nav channel func-
ing of the action potential upstroke (Fig. 4C). Reductions tioning and arrhythmia mechanisms. One of the well-
in Nav current can also influence action potential ampli- described LQT3 mutations, I1768V, for example, does not
tudes (Fig. 4C), as well as phase 1 repolarization. In result in increased channel bursting, but rather, acceler-
addition, owing to intrinsic electrical heterogeneity of the ates the rate of recovery of Nav channels from inactiva-
heart (Fig. 1), the impact of Brugada and LQT3 mutations tion at diastolic membrane potentials (106). Computa-
in SCN5A would be expected to be variable in different tional analysis predicted that this mutation would have a
regions/cell types, an effect which may contribute further substantial effect under nonequilibrium conditions, e.g.,
to arrhythmogenesis. during action potential repolarization (106). Subsequent
Other identified SCN5A mutations, linked to both the experiments confirmed this prediction, revealing a novel
LQT3 and Brugada syndromes, are found in several other mechanism by which mutation-altered Nav channel gating
regions of SCN5A, most notably in the COOH terminus can prolong cardiac action potentials (7). Interestingly, it
(Fig. 3A), that also lead to altered channel inactivation has also been demonstrated that a common polymor-
(60, 105, 358, 422, 519, 540). These findings should prob- phism (that results in an S/Y switch) at residue 1102 in
ably have been expected, given that structure-function SCN5A is associated with elevated arrhythmia risk in
studies suggest that multiple domains in Nav ␣-subunits African Americans (481). Expression studies revealed
contribute to the regulation of channel gating (8, 48, 91, that this variant results in very subtle changes in Nav1.5
105, 114, 174, 248, 254, 299, 357, 358, 521). A role for the channel activation and inactivation. Modeling studies sug-
COOH-terminal tail of Nav1.5 in the regulation of channel gest, however, that these changes are not likely to alter
inactivation, for example, has been demonstrated (36, 51, cellular electrical activity in carriers unless they are
248, 251, 521). In addition, point mutations in the COOH treated with drugs that block (cardiac) Kv channels (481).
terminus affect the kinetics and the voltage dependence Additional polymorphisms in SCN5A have also been iden-
of channel inactivation and recovery from inactivation tified that affect, at least in heterologous expression sys-
and promote sustained channel activity (8, 48, 254, 299, tems, the trafficking of functional cell surface Nav chan-
357). Single-channel studies have also demonstrated that nels (318, 570). In principle, the presence of these poly-
the proximal portion of the COOH terminus has pro- morphisms could, like the S1102Y polymorphism (481),
nounced effects on repetitive channel openings during impact arrhythmia susceptibility in the context of other
prolonged depolarization (114). Modeling studies of the factors (e.g., disease or drugs) that affect membrane ex-
COOH terminus of Nav1.5, assuming homology with the citability, action potential durations, and rhythmicity
NH2 terminus of calmodulin, predict that the proximal (318). Mutations in SCN5A and changes in Nav1.5-channel
region (of the COOH terminus) adopts an ␣-helical struc- gating have also been linked to sudden infant death syn-
ture, a prediction verified in circular dichroism studies on drome (538). In addition, mutations in two of the neuronal
a purified COOH-terminal protein (114). The distal region Nav channel ␣-subunits, SCN1A and SCN2A, are associ-
of the COOH-terminal tail, in contrast, is largely unstruc- ated with epilepsies (204, 220, 249, 359). It will be inter-
tured and does not appear to affect channel gating mea- esting to determine if the molecular mechanisms linking
surably (114). These observations suggest that interac- these mutations, as well as the mutations in the skeletal
tions occur between the structured (proximal) region of muscle Nav channel SCN4A, to disorders in membrane

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1219

excitability are similar to those evident for SCN5A in the (20). Expression studies suggest that SCN2b plays a role
LQT3 and Brugada syndromes. in controlling the Ca2⫹ permeability of Nav channels
(450). The targeted deletion of SCN2b (in Nav␤2 ⫺/⫺
mice) markedly affects neuronal Nav channel expression
B. Nav Channel Accessory Subunits and Other
and properties and has profound neurological conse-
Interacting Proteins
quences (95). No cardiac phenotype, however, has been
Although molecular and functional studies of cardiac described in Nav␤2 ⫺/⫺ mice (95), suggesting that Nav␤1
Nav channels have focused primarily on the pore-forming or Nav␤3 more likely contributes to the formation of the
Nav1.5 ␣-subunit, it is now quite clear that functional Nav SCN5A-encoded cardiac Nav channels. Consistent with
channels in cardiac (and other) cells reflect the assembly this hypothesis, heterologous coexpression of Nav␤1,
of multimeric protein complexes comprising accessory which markedly affects Nav1.4-encoded skeletal muscle
subunits, as well as a variety of other auxiliary, interacting Nav channels (319), alters the inactivation kinetics and

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and regulatory proteins. All available evidence suggests, the densities of Nav1.5-encoded (cardiac) Nav channels
for example, that functional Nav channels in cardiac (and (20, 134, 155). Heterologous coexpression of SCN3b with
other) cells are multisubunit proteins consisting of a cen- SCN5A also reportedly increases the cell surface density
tral pore-forming Nav ␣-subunit (Fig. 5) and one to two and modifies the inactivation kinetics of Nav1.5-encoded
auxiliary Nav ␤-subunits (229). In brain, the functional currents (155).
stoichiometry appears to be one Nav ␣- to two Nav ␤-sub- In addition to modifying the cell surface expression
units (229); the ␣/␤-subunit composition of cardiac Nav and the kinetic properties of Nav channels, Nav ␤-sub-
changes is probably similar. Three different Nav ␤-subunit units also appear to be multifunctional cell adhesion mol-
genes, SCN1b (230, 320), SCN2b (231, 241), and SCN3b ecules of the IgG superfamily (228) that target channels to
(354) encoding Nav␤1, Nav␤2 and Nav␤3 proteins, re- the plasma membrane and mediate channel interactions
spectively, have been identified, and it appears that all with a variety of signaling molecules. It has been demon-
three Nav ␤-subunits are expressed in heart (Table 2). The strated, for example, that Nav ␤-subunits interact with
functional role(s) of the Nav ␤-subunits in the generation cell adhesion molecules (252, 413), components of the
of cardiac Nav currents, however, is not well understood extracellular matrix (413, 481, 559), and mediate the re-

FIG. 5. Molecular assembly of car-

diac Cav (Nav), Kv, and Kir channels.
Top: the four domains (I–IV) of individual
Cav (and Nav) ␣-subunits contribute to
the formation of individual Cav (Nav)
channels, whereas four Kv (or Kir) ␣-sub-
units combine to form tetrameric Kv (or
Kir) channels. Bottom: schematic illus-
trating functional cardiac Nav, Cav, and
Kv channels, composed of the pore-form-
ing ␣-subunits and a variety of channel
accessory subunits.

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1220 JEANNE M. NERBONNE AND ROBERT S. KASS

cruitment of the actin-binding protein ankyrin to the in mediating Nav channel gating in the normal and in the
plasma membrane at points of cell-cell contact (321). The diseased myocardium.
ankyrins are (cytosolic) cytoskeletal proteins that have An important functional role for the actin cytoskele-
been suggested to function in regulating the trafficking of ton in the regulation of Nav channel gating was directly
a variety of plasma membrane proteins (53, 54, 350). It has revealed with the demonstration that mice heterozygous
been demonstrated directly that the intracellular COOH for a targeted deletion of ankyrin B, ankyrin B ⫹/⫺, have
terminus of Nav␤1 mediates the interaction with ankyrin abnormal cardiac electrical activity attributed to altered
and that Nav␤1 and ankyrin B associate in transfected Nav channel gating and cell surface expression levels
cells and in rat brain membranes (135, 322). Interestingly, (40). Single-channel studies on ankyrin B ⫹/⫺ ventricular
the intracellular COOH-terminal domain of Nav␤1 has cells revealed increased channel bursting, consistent with
also been shown to be required for interaction with Nav1, a LQT channel phenotype (94). These observations were
specifically Nav1.2, ␣-subunits (347). Taken together, interpreted as suggesting that mutations in ankyrin, which

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these observations suggest an important functional role would lead to Nav channel dysfunction, might well be
for the cytosolic COOH-terminal domain of Nav␤1 in the important in familial LQT syndromes or other inherited
regulation of Nav channel trafficking and/or Nav channel cardiac rhythm disturbances (50). Consistent with this
localization, perhaps through ankyrin B (Fig. 6) and/or hypothesis, molecular genetic studies subsequently re-
interactions with other components of the actin cytoskel- vealed a loss-of-function mutation in ankyrin B (E1425G)
eton (135). that is causally linked to variant 4 of familial long QT
It has long been recognized that the proper function- syndrome, LQT4 (351). In addition to providing funda-
ing of myocardial Nav channels requires an intact actin mentally important new insights into the molecular defect
cytoskeleton (324, 504). Disruption of actin polymeriza- underlying LQT4 (351), these findings demonstrate a
tion on treatment with cytochalasin D, for example, re- novel, physiologically important, mechanism for regulat-
sults in marked (⬃20%) reductions in peak Nav current ing Nav functioning involving interactions between chan-
densities in isolated rat and rabbit ventricular myocytes nel proteins and the cytoskeleton that are coordinated by
(504). Single-channel recordings from excised membrane the adaptor protein ankyrin B. It is possible that the
patches from cytochalasin D-treated cells, however, re- ankyrin B mutations interfere directly with Nav␤1-Nav␣1
vealed that, in addition to reduced open probability, chan- interactions, or perhaps indirectly, through other regula-
nel “bursting” is increased (504). The latter effect is at- tory and/or signaling molecules. In this context, it is also
tributed to a change in Nav channel gating and is func- interesting to note that the cell surface expression of the
tionally similar to the alterations in channel activity seen Na⫹-K⫹-ATPase, the Na⫹/Ca2⫹ exchanger, and inositol
with some long QT3 mutations (52, 60, 105, 346, 358, 419, 1,4,5-trisphosphate (IP3) receptors, each of which also
519, 540). These results suggest the interesting possibility interacts with ankyrin B, are all affected in ankyrin B ⫹/⫺
that multiple pathways (mechanisms) may be important ventricular myocytes (351). It seems certain that the

FIG. 6. Schematic illustrating the

complexity of protein-protein interac-
tions that likely are involved in regulat-
ing/modulating the expression, distribu-
tion, and functioning of myocardial ion
channels. The ␣- and ␤-subunits of Nav
channels interact with the actin cytoskel-
eton through syntrophin-dystrophin and
ankyrin B and with the extracellular ma-
trix through the sarcoglycan complex.
Interactions between Kv channel ␣
(and/or ␤) subunits and the actin cy-
toskeleton are mediated by the actin
binding proteins filamin and ␣-actinin
and through PDZ domain-containing
scaffolding proteins.

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1221

ankyrin B-mediated interactions between each of these syntrophin and, therefore, to Nav1.5 channels (Fig. 6).
molecules and the actin cytoskeleton are important for Nitric oxide synthase (NOS), for example, which is also
the normal functioning of each of these ion transport part of the dystrophin-proteoglycan complex (189), and
proteins, as well as the intracellular pathways coupled to thought to play a role in myocardial ischemia (466), ap-
these proteins. The physiological import of these interac- pears to bind directly to syntrophin, as well as to caveo-
tions and the impact of the disruption of each of these lin-3 (115, 207, 265), the muscle-specific caveolin in plas-
interactions on the generation of normal cardiac rhythms malemmal caveoli. Nearly all of the endothelial NOS ac-
is potentially staggering. tivity can be coimmunoprecipitated from cardiac muscle
Extrapolating this concept further, it is interesting to using an anti-caveolin-3 antibody (161, 162). The caveo-
note that there is now a growing body of evidence in the lins are also important regulators of NOS activity (161,
cardiovascular (and other) system that functional Nav 415), and it is of interest to note that overexpression of
(and other) channels interact directly and/or indirectly
caveolin-3 results in cardiomyopathy and the downregu-

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with the actin cytoskeleton and with a variety of regula-
lation of NOS and other components of the dystrophin-
tory and signaling molecules (Fig. 6) which might well
dystroglycan complex (27). Given that it has also been
play a role in the regulation of channel trafficking and
demonstrated that caveolin-3 binds directly to the cyto-
channel expression and/or in the modulation of channel
plasmic tail of ␤-dystroglycan (477), these observations
properties and functioning (418). It has, for example, been
reported that syntrophins, proteins thought to provide a suggest additional links between cardiac Nav channels,
link between the actin cytoskeleton and other membrane- the actin cytoskeleton, and the extracellular matrix (Fig.
associated proteins, interact directly with Nav ␣-subunits, 6). Caveolin-3 is thought to play a direct role in regulating
including Nav1.5 and the skeletal muscle Nav channel the interaction of caveoli with the sarcolemmal mem-
␣-subunit Nav1.4 (182, 212). Because the syntrophins also brane and, therefore, to function to facilitate the transfer
interact directly with dystrophin and dystrobrevin (117) of (Nav or other) channels to the cell surface membrane
and, therefore, with the entire dystrophin-associated com- from the intracellular compartment (161). It seems rea-
plex (151) in cardiac and skeletal muscle, it seems rea- sonable to suggest here that alterations in the interactions
sonable to suggest further that alterations in the proper- between any of the individual components of the pro-
ties of any of the protein components of this macromo- posed functional Nav channel complex (Fig. 6), through
lecular complex (Fig. 5) could alter myocardial Nav acquired or inherited disease, could have profound effects
channel functioning or expression. It is of further interest on the properties and/or the functional cell surface ex-
to note that cardiomyopathy is often evident in patients pression of Nav channels, effects that in turn will impact
with congenital (skeletal) muscular dystrophies, attrib- the generation of normal cardiac rhythms and the likeli-
uted to mutations in the dystrophin gene (343), as well as hood that rhythm disturbances will occur.
to mutations in other genes that are part of the dystro- In cardiac myocytes, functional cell surface Nav
phin-sarcoglycan protein complex (144). With the as- channel expression is also regulated directly by ␤-adren-
sumption that the model of functional cardiac Nav chan- ergic receptor occupancy and the activation of the stim-
nels proposed in Figure 6 is at least qualitatively correct, ulatory G protein (Gs) pathway (310, 334). In addition, it
it would seem reasonable to speculate that the mutations has now been demonstrated that Gs␣ functions through
in any of the genes encoding any of the components of the binding to caveolin-3, increasing the presentation of
depicted macromolecular complex could lead to altered
caveoli to the sarcolemmal membrane which could lead
Nav channel functioning and cardiac arrhythmias alone or
to increased cell surface expression of Nav channels
in the background of other myocardial disease, particu-
(569). It has also been reported that caveolin-3 expression
larly structural heart disease. If complexes such as those
is increased and that nitric oxide signaling is augmented
illustrated in Figure 6 are indeed shown to be the physi-
ologically important units of cardiac Nav functioning, ex- in a (canine) pacing-induced model of heart failure (203).
ploring the molecular mechanisms involved in mediating The relationship between these biochemical changes and
the many protein-protein interactions important in con- the observed structural and electrical changes evident in
trolling the assembly, trafficking and functioning of these this model and the relevance of this model and these
macromolecular channel protein complexes might well changes to human heart failure remain to be established.
provide insights into the link between structural heart As for heterologously expressed Nav channels, there may
disease and the electrophysiological abnormalities that well also be additional regulatory molecules, including
are linked to the generation of life-threatening cardiac growth factors (295, 555) and membrane lipid-anchoring
arrhythmias in a wide variety of myocardial disease proteins (460), that play a role in regulating the properties
states. and the functional cell surface density of cardiac Nav
Other potentially important signaling molecules in channels. Clearly, this possibility warrants direct experi-
cardiac physiology and pathophysiology are also linked to mental testing.

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1222 JEANNE M. NERBONNE AND ROBERT S. KASS

C. Cav Channel Pore-Forming ␣-Subunits one of the four members of the Cav1 subfamily, Cav1.1,
Cav1.2, Cav1.3, or Cav1.4 (Table 3), for example, re-
Similar to Nav channels, voltage-gated Ca2⫹ (Cav) veals L-type HVA Cav channel currents (92, 395),
channel pore-forming ␣-subunits belong to the “S4” whereas heterologous expression of Cav3 ␣-subunits
superfamily of voltage-gated ion channel genes (92, produces T-type LVA Cav channel currents (92, 395).
395), and functional voltage-gated Ca2⫹ (Cav) channels Numerous studies, exploiting both heterologous ex-
reflect the multimeric assembly of one Cav ␣-subunit pression systems in vitro and transgenic strategies in vivo
(␣1) and auxiliary Cav␤ and Cav␣2␦, as well, at least in (363), have provided important (and new) molecular in-
some cases, as Cav␥, subunits (Fig. 5). Also similar to sights into Cav channel composition and functioning in
Nav channels, Cav ␣-subunits comprise four homolo- cardiac (and other) cells. In the past decade, a number of
gous domains (domains I–IV), each of which is com- mutations in Cav channel ␣- and ␤-subunit genes have
posed of six transmembrane segments (S1–S6), with an also been identified in both humans and mice that result

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“S4” voltage-sensing domain and a Ca2⫹-selective pore in disorders of excitability, such as epilepsy, ataxia, peri-
region between S5 and S6 (92, 395). Four distinct sub- odic paralysis, and migraine (153, 245, 388, 402, 410). Until
families of Cav channel pore-forming ␣1-subunits, Cav1, very recently, there have been no established links be-
Cav2, Cav3, and Cav4 (47), each with many subfamily tween inherited disorders of myocardial membrane excit-
members (Table 3), and alternately spliced transcripts ability and mutations in the subunits encoding cardiac
(476) have been identified. The Cav ␣1-subunits are Cav channels. It has now been demonstrated, however,
differentially expressed, and studies in heterologous that a de novo point mutation in the CACNA1C gene,
expression systems have revealed that the various Cav which encodes the Cav1.2 channel ␣-subunit, underlies
␣1-subunit genes encode Cav channels with distinct Timothy syndrome, a multisystem disorder with sporatic
time- and voltage-dependent properties and pharmaco- inheritance (479). Individuals with Timothy syndrome
logical sensitivities. Heterologous expression of any have profound cardiac arrhythmias, as well as dysfunc-

TABLE 3. Diversity of voltage-gated Ca2⫹ (Cav) channel ␣- and ␤-subunits

Locus Locus
Cardiac Cardiac
Subfamily Protein Gene Human Mouse Current Subfamily Protein Gene Human Mouse Current

Cav␣1 Cav1.1 (␣11.1) (␣1S) CACNA 1S 1q31-32 1E4 Cav ␤ ␤1 CACNB1 17q11.2 11D
␤2 CACNB2 10p12 2A1 ICa(L)
Cav1.2 (␣11.2) (␣1C) CACNA1C 12p13.3 6E3 ICa(L) ␤3 CACNB3 12q12 15F1
␤4 CACNB4 2q23 2C1.1
Cav1.3 (␣11.3) (␣1D) CACNA1D 3p14.3 14A3 Cav␣2␦ ␣2␦ ⫺1 CACNA2D1 7q11.2 5A1 ICa(L)
Cav1.4 (␣11.4) (␣1F) CACNA1F Xp11.23 XA1.1 ␣2␦ ⫺2 CACNA2D2 3p14 9F1 ??
␣2␦ ⫺3 CACNA2D3 3p13 14A3
␣2␦ ⫺4 CACNA2D4 12p13
Cav␣2
Cav2.1 (␣12.1) (␣1A) CACNA1A 19p13 8C3
Cav␥ ␥1 CACNG1 17q26 11E1
␥2 CACNG2 22q13 15D3
Cav2.2 (␣12.2) (␣1B) CACNA1B 9q34 2A3 ␥3 CACNG3 16p12 7F2
␥4 CACNG4 17q26 11E1
␥5 CACNG5 17q26 11E1
Cav2.3 (␣12.3) (␣1E) CACNA1E 1q25-31 1G1 ?? ␥6 CACNG6 19q13.4 7A1
␥7 CACNG7 19q13.4 7A1
␥8 CACNG8 19q13.4 7A1
Cav␣3
Cav3.1 (␣13.1) (␣1G) CACNA1G 17q21 11D ICa(T)?
Cav3.2 (␣13.2) (␣1H) CACNA1H 16p13.3 17A3.3 ICa(T)?
Cav3.3 (␣13.3) (␣1I) CACNA1I 22q13

Boxes denote cardiac expression.

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1223

tion in multiple organ systems, including the immune and D. Cav Channel Accessory Subunits and Other
nervous systems (479). Interacting Proteins
All available molecular and biochemical evidence
suggests that Cav1.2, which encodes the ␣1C-subunit, is There are a number of Cav accessory subunits that
the prominent Cav ␣-subunit expressed in the mammalian coassemble with Cav␣1 (Fig. 5) and play a role in the
myocardium. The CACNA1C gene is large, comprising 44 generation of functional Cav channels in cardiac, as well
invariant and 6 alternative exons (474), and the Cav1.2 as in other, cells. Three distinct types of Cav channel
message is widely expressed. From the many possible accessory subunits, Cav␤, Cav␣2␦, and Cav␥ (Table 3), for
splice sites, a number of different variants of the ␣1C example, have been identified (28, 110). Of these subunits,
protein, including Cav1.2a, Cav1.2b, and Cav1.2c, are gen- only the accessory Cav␤ and Cav␣2␦ subunits appear to
erated (6, 348, 474, 475). Interestingly, although nearly be expressed in the myocardium (Table 3) and to contrib-
identical (⬎95%) in amino acid sequence, the various ␣1C ute to the formation of functional cardiac Cav channels
(110). The accessory Cav ␤-subunits are cytosolic pro-

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splice variants appear to be expressed in different cells/
tissues, and the cardiac specific isoform is Cav1.2a, which teins that assemble with Cav1 ␣-subunits and regulate the
encodes cardiac L-type HVA Cav channels (6, 92). Thus expression of functional cell surface HVA Cav channels,
similar to cardiac Nav channels and consistent with the including cardiac L-type Cav channels. Four different
similarities in the properties of the L-type cardiac Cav Cav␤ subunit-encoding genes, CACNB1, CACNB2,
channel currents, it appears that a single pore-forming CACNB3, and CACNB4, which encode the Cav␤1 (408,
␣1-subunit (Cav1.2a) is responsible for the generation of 434), Cav␤2 (222, 396), Cav␤3 (89, 222, 396), and Cav␤4
HVA channels throughout the myocardium (92, 395). In- (89, 505) proteins, respectively, have been identified (Ta-
terestingly, however, it has been reported that sinus node ble 3). It appears, however, that Cav␤2 is most promi-
dysfunction is seen in mice with a targeted disruption nently expressed in the heart (222, 396). In each Cav␤
(363) of the Cav1.3 ␣-subunit gene, CACNAID (585), sug- subunit, there are three variable regions flanking two
highly conserved domains (89, 222, 396, 408, 434, 505).
gesting that SA nodal HVA Cav channels are encoded by
The variable regions are in the COOH termini, the NH2
Cav1.3, rather than by Cav1.2 (585). These observations
termini, and a small (⬃100 amino acids) region in the
raise the interesting possibility that, with the right tools,
center of the linear protein sequence between the two
one would be able to manipulate selectively the function-
conserved domains (89, 222, 396, 408, 434, 505). The con-
ing of atrial/ventricular (Cav1.2) and/or nodal (Cav1.3)-
served domains of the Cav ␤-subunits mediate interac-
encoded myocardial Cav channels.
tions with the pore-forming Cav ␣1-subunits, whereas the
The recently identified linkage between Timothy syn-
variable domains influence the functional effects of Cav
drome and a point mutation in the CACNA1C gene encod-
␤-subunit coexpression on the properties of the resulting
ing Cav1.2a (479) demonstrates, as likely would have been Cav channels (407). In heterologous expression systems,
expected, that defective Cav channel (like defective Na coexpression of Cav ␤-subunits with Cav ␣1-subunits
and Kv channel) functioning can lead to cardiac arrhyth- markedly increases Cav channel current amplitudes and
mias. The Timothy syndrome mutation is a missense mu- densities (59, 187, 541, 565), effects which could reflect
tation that results in a single amino acid change, glycine increased cell surface channel expression, increased
(G) to arginine (R), at residue 406 (479), which is in the channel open probability, and/or the stabilization of the
cytoplasmic loop between domains I and II, immediately Cav␣1-Cav␤ channel complexes in the cell membrane (98,
C terminal to S6 transmembrane segment in domain I 99, 565). In addition to increasing current amplitudes,
(Fig. 3). Heterologous expression studies reveal that the coexpression of Cav ␤-subunits also modifies the kinetics
G406R mutation in Cav1.2a markedly reduces voltage- and the voltage dependences of Cav current activation
dependent channel inactivation, resulting in increased and inactivation (70, 242, 279, 353).
persistent inward Ca2⫹ current (479). The biophysical A highly conserved sequence motif in Cav ␣1-sub-
consequence of the Timothy syndrome mutation in units, called the alpha subunit interaction domain, ap-
Cav1.2a, therefore, is highly reminiscent of several Nav1.5 pears to mediate ␣-subunit interaction(s) with accessory
channel mutations associated with long QT and Brugada Cav ␤-subunits (407). The Cav␣1 interaction domain (Qqx-
syndromes that result in increased persistent inward Na⫹ ExxLxGYxxWIxxxE) is located in the cytoplasmic loop
currents (and in action potential prolongation). Interest- between domains I and II, exactly 24 amino acids from the
ingly, however, in contrast to the LQT and Brugada syn- S6 transmembrane region of domain I (63, 64, 132, 211).
dromes, Timothy syndrome is a multisystem disorder Interestingly, the Timothy syndrome mutation, G406R, is
(479). This latter observation is consistent with the hy- close to this subunit interaction domain (479), suggesting
pothesis that Cav1.2a, unlike Nav1.5, is expressed widely that the (G406R) mutations might disrupt Cav␣1-Cav␤
and that mutations in Cav1.2a result in phenotypic con- subunit-subunit interactions. Regions outside of this in-
sequences in many different organ systems. teraction domain, including low-affinity binding sites in

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1224 JEANNE M. NERBONNE AND ROBERT S. KASS

the COOH termini of the Cav ␣1-subunits, however, have rents (250). In addition, the Cav ␥-subunits that are ex-
also been suggested to participate in Cav␤-Cav␣1 subunit- pressed in the nervous system, Cav␥2, Cav␥3, Cav␥4, and
subunit interactions (412, 493, 523). Indeed, it now ap- Cav␥8, all have COOH-terminal PDZ-binding domain mo-
pears that these COOH-terminal regions in Cav ␣1-sub- tifs (250). These observations suggest the interesting pos-
units also interact specifically with a second, highly con- sibility that the Cav ␥-subunits play a role in controlling
served domain in the Cav ␤-subunits to produce the the localization and/or trafficking of functional Cav chan-
observed modulatory effects of accessory Cav ␤-subunit nels (250). Interestingly, it has also been reported that
coexpression (131, 181). Cav␥2 interacts with the AMPA subtype of neuronal glu-
In addition to the Cav ␤-subunits, another type of tamate receptors, suggesting that the Cav ␥-subunits may,
accessory subunit, referred to as Cav␣2␦, has also been like other channel accessory subunits, be multifunctional
shown to be part of functional Cav channel complexes proteins (96). Although Cav ␥-subunits appear to be
(146). Unlike Cav␤, the Cav␣2␦ subunits are transmem- widely expressed in the nervous system (250), it is not

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brane accessory subunits (Fig. 5), the first of which, clear at present whether one or more of the CACNG genes
Cav␣2␦-1, was cloned from skeletal muscle (146). At least is expressed in the heart and/or if these subunits play a
four different Cav␣2␦-1 subunit-encoding genes, functional role(s) in the generation of cardiac L-type Cav
CACNA2D1, CACNA2D2, CACNA2D3, and CACNA2D4, channels. Clearly, further studies focused on exploring
have been identified (Table 3), and all produce heavily this topic and determining directly the role(s) of the var-
glycosylated proteins that are cleaved posttranslationally ious Cav channel accessory subunits in the generation of
to yield ␣2 and ␦ proteins that then become linked via cardiac Cav channels are warranted.
disulfide bridges (Fig. 5). In each of the Cav␣2␦-1 com- As noted in section IIB, it is now very well docu-
plexes, the Cav␣2 domain is located extracellularly, mented that HVA myocardial Cav channels undergo rapid
whereas the Cav␦ domain, which has a large hydrophobic Ca2⫹- and voltage-dependent inactivation (44, 166, 281,
region, inserts into the membrane (Fig. 5) and serves as 326). Fundamentally important insights into the likely
an anchor to secure the entire (Cav␣2␦) complex (197, molecular mechanism underlying the Ca2⫹-dependent
198, 554). In contrast to the accessory Cav␤ subunits, the component of inactivation were revealed with the dem-
functional roles of accessory Cav␣2␦ subunits are variable onstration that the EF-hand domain containing protein,
and appear to depend, at least in part, on the identities of calmodulin, that binds Ca2⫹ and modulates a variety of
the coexpressed Cav␣1 and Cav␤ subunits, as well as on Ca2⫹-dependent processes, is associated with the COOH-
the expression environment. In general, however, coex- terminal cytoplasmic domain of L-type HVA channels
pression of Cav␣2␦-1 shifts the voltage dependence of (398). Several subsequent studies have provided many of
activation of Cav␣/Cav␤-encoded channels, accelerates the molecular details of the calmodulin:Cav channel ␣1-
current activation and inactivation, and increases current subunit association and interaction domains (17, 149, 293,
amplitudes, compared with the channels/currents pro- 355, 428). In addition, the generality of the calmodulin-
duced on expression of the Cav␣1 and Cav␤ subunits mediated mechanism of Ca2⫹-dependent inactivation of
alone (38, 158, 197, 198, 260, 472). The increase in func- Cav channels was documented with the demonstration
tional cell surface Cav current densities on coexpression that P/Q-type neuronal HVA channels are also regulated
of Cav␣2␦-1 (and Cav␤) subunits appears to reflect im- by calmodulin binding (128).
proved targeting of Cav ␣1-subunits to the plasma mem- In addition to the regulation of channel gating by
brane (469). This effect (improved targeting) is produced Ca2⫹ and calmodulin, the properties and the functional
through interactions with Cav␣2, whereas the changes in expression of myocardial Cav channels are also regulated
channel kinetics are attributed to the presence of the by a variety of extracellular signals and intracellular sig-
Cav␦ protein (469). naling pathways. Prominent among these are the rather
A distinct type of Cav channel accessory subunit was well studied ␤-adrenergic G protein-coupled receptor-me-
revealed with the identification of the Cav␥ subunit, diated augmentation of cardiac L-type Cav channel cur-
Cav␥1, that is expressed in mammalian skeletal muscle, rents, increased Ca2⫹ entry, and positive inotropy (255,
and that contributes to the formation of functioning of 509). Considerable experimental evidence suggests that
skeletal muscle Cav channels (462). A number (seven) of the pore-forming Cav1.2 ␣-subunit and Cav ␤-subunits are
additional Cav␥-encoding genes, CACNG1-CACNG8 (Ta- targets of posttranslational modifications by a variety of
ble 3), have now been identified in skeletal muscle and in protein kinases that impact the functional cell surface
brain (250). All Cav␥ subunits have four transmembrane expression and the properties of cardiac L-type Cav chan-
spanning domains with the COOH and NH2 termini pre- nels (255, 509). It has also been reported that cardiac HVA
dicted to be intracellular (462). Coexpression of ␥-sub- Cav channels are actually associated with ␤-adrenergic
units with various combinations of Cav␣ and Cav␤ sub- receptors in macromolecular complexes that likely also
units has been shown to affect both the time- and the include heterotrimeric G proteins, adenylate cyclase, pro-
voltage-dependent properties of the resulting Cav cur- tein kinases, phosphatases and protein kinase A binding

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1225

proteins, or AKAPs (18, 122), which appear to subserve a Further functional Kv channel diversity in cardiac
scaffolding function (18). Unlike Nav channels, however, and other cells could, in principle, arise through alterna-
no direct links between cardiac Cav channel subunits and tive splicing of transcripts (29), as well as through the
actin or actin-binding proteins have been demonstrated to formation of heteromultimeric channels (116) between
date. Nevertheless, a number of Ca2⫹-binding proteins, two or more Kv ␣-subunit proteins in the same Kv sub-
including calmodulin, have been shown to be linked both family. Kv channel assembly, as well as the properties of
directly and indirectly to the actin cytoskeleton (452). In the resulting channels, are largely determined by the in-
addition, it has been reported that the time- and voltage- tracellular NH2- and COOH-terminal ␣-subunit domains
dependent properties of L-type HVA channels are altered (100). Molecular and biochemical studies have revealed
in skeletal muscle from dystrophin-deficient animals, an that, of the many Kv1-Kv9 ␣-subunits identified, only a
effect interpreted as resulting from remodeling of the small subset is expressed in the heart (Table 4). Although
subcellular actin cytoskeleton (111). Similarly, neuronal many studies have characterized the detailed time- and
voltage-dependent properties of the various Kv ␣-subunit-

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HVA Cav channel inactivation is differentially affected by
agents that stabilize and destabilize the actin cytoskeleton encoded Kv channels in heterologous expression systems,
(239). In retinal ganglion neurons, for example, stabiliza- these studies have provided little insight into the molec-
tion or disruption of the actin cytoskeleton affects func- ular correlates of functional cardiac Kv channels. The
tional cell surface Cav channel expression (454). It seems difficulties encountered in these studies probably reflect
reasonable to suggest, therefore, that Cav channels inter- the fact that Kv channel properties depend on the expres-
act directly or indirectly with the actin cytoskeleton (556) sion environment (397), likely owing to cell-type specific
and that, similar to cardiac Nav channels, the functioning differences in posttranslational processing of the Kv
of myocardial Cav channels likely also depends impor- channel ␣-subunit proteins and/or the expression of Kv
tantly on interactions with the actin cytoskeleton. In sup- channel accessory subunits or other Kv channel interact-
port of this hypothesis, targeted deletion of endothelial ing, regulatory proteins (397).
NOS eliminates the muscarinic modulation of myocardial Additional subfamilies of Kv ␣-subunit genes in the
L-type Cav channels (202). Further investigations focused KCNQ and KCNH subfamilies (Table 4) have been iden-
on delineating the molecular mechanism controlling func- tified, and one member of each of these subfamilies,
tional Cav channel expression will be needed to define the KCNQ1 and KCNH2, has been shown to be the loci of
role of the cytoskeleton in regulating myocardial Cav (and mutations leading to congenital long QT syndromes, LQT1
Nav) channel expression and functioning. (Fig. 3C) and LQT2 (Fig. 3B), respectively (40, 119, 447,
448, 499, 528). Heterologous expression of human
KCNH2, which encodes the ether-a-go-go-related protein
VI. MOLECULAR COMPONENTS OF
ERG1, reveals Kv currents (448, 499) that are similar to
MYOCARDIAL KV CHANNELS
cardiac IKr (Table 4). Similar to SCN5A mutations linked
to the LQT3 and Brugada syndromes (Fig. 3A), LQT2
A. Kv Channel Pore-Forming ␣-Subunits mutations in KCNH2 are found throughout the ERG1
protein sequence (Fig. 3B). These (LQT2) mutations are
Similar to Nav and Cav ␣-subunits, voltage-gated K⫹ all “loss of function” and result in reduced functional IKr
channel (Kv) pore-forming (␣) subunits (Fig. 3) belong to channel expression owing to dominant negative effects or
the “S4” superfamily of voltage-gated channels (405). In to alterations in channel processing or trafficking (23, 126,
contrast to Nav and Cav channel ␣-subunits, however, Kv 220, 246, 253, 273, 584). Interestingly, a novel “gain of
␣-subunits are six transmembrane-spanning domain pro- function” mutation in KCNH2, which results in increased
teins (Fig. 3, B and C), and functional Kv channels com- IKr channel densities, has recently been identified and
prise four ␣-subunits (Fig. 5). A very large number of Kv linked to one form of short QT syndrome (78).
␣-subunit genes have been identified, and a systematic There are six additional members of the KCNH sub-
terminology for naming these subunits (Table 4) has been family, KCNH3-KCNH8 (Table 4). Two of these, KCNH3
developed (199). Heterologous expression of Kv ␣-sub- and KCNH4, appear to be nervous system specific (465),
units in the Kv1-Kv4 subfamilies reveals functional Kv and it is presently unclear whether any of the others are
channels with distinct time- and voltage-dependent prop- present in the myocardium. Alternatively processed forms
erties (116), whereas Kv ␣-subunits of the Kv5–9 subfam- of KCNH2, with unique NH2 and COOH termini, however,
ilies (Table 4) are electrically silent (88, 142, 221, 441). have been cloned from both mouse and human heart
Coexpression of Kv5-Kv9 subunits with Kv2 ␣-subunits, cDNA libraries and postulated to contribute to the gener-
however, attenuates the amplitudes of the Kv2-encoded ation of functional cardiac IKr channels (272, 282, 304).
K⫹ currents (441). Nevertheless, the functional roles of Indeed, coexpression of the NH2-terminal splice variant
the “silent” Kv ␣-subunits in the generation of myocardial ERG1b with the full-length ERG1a produces Kv currents
Kv channels remains to be determined. that more closely resemble cardiac IKr than the currents

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1226 JEANNE M. NERBONNE AND ROBERT S. KASS

TABLE 4. Diversity of voltage-gated K⫹ (Kv) channel ␣-subunits

Locus Locus
Cardiac Cardiac
Subfamily Protein Gene Human Mouse Current Subfamily Protein Gene Human Mouse Current

Kv1 Kv8
Kv1.1 KCNA1 12p13 6F2 Kv8.1 KCNV1 8q21.1
Kv1.2 KCNA2 1p11 3F2.2 IK,slow Kv8.2 KCNV2 9p24
Kv9
(IK,DTX)

Kv1.3 KCNA3 1p21 3F2.2 Kv9.1 KCNS1 20q12 2H3

Kv9.2 KCNS2
Kv1.4 KCNA4 11p14 2E2 Ito,s Kv9.3 KCNS3 2p25 15B3.1

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Kv1.5 KCNA5 12p13 6F2 IKur
IK,slow1 eag
Kv1.6 KCNA6 12p13 6F2 eag KCNH1 1q32 1H6
Kv1.7 KCNA7 19q13 7B3 erg1 KCNH2 7q36 5A3 IKr
Kv1.10 KCNA10 1p11 erg2 KCNH3 15
erg3 KCNH4 17q21
Kv2 erg4 KCNH5 14q22
Kv2.1 KCNB1 20q13.1 2H3 IK,slow2 erg5 KCNH5 17q24
Kv2.2 KCNB2 8q13 ?? erg6 KCNH7 2 2C1.1
erg7 KCNH8 3p24
Kv3 KvLQT
Kv3.1 KCNC1 11p15 7B3 IKs
Kv3.2 KCNC2 12q21 KvLQT1 KCNQ1 11p15 7F6
Kv3.3 KCNC3 19q13.4 7B2 KCNQ2 KCNQ2 20p11.1 2H4
Kv3.4 KCNC4 1p11 3F2.2 KCNQ3 KCNQ3 8q24.3 15D1
Kv4 KCNQ4 KCNQ4 1p34.3
Kv4.1 KCND1 Xp11.2 ?? KCNQ5 KCNQ5 6q11
Kv4.2 KCND2 7q32 6A2 Ito,f
Kv4.3 KCND3 1p11 3F2.2 Ito,f
Kv5
Kv5.1 KCNF1 2p25 ??
Kv6
Kv6.1 KCNG1 20q13.1
Kv6.2 KCNG2 18q23
Kv6.3 KCNG3 2p21 17E3
Kv6.4 KCNG4 16q24

Boxes denote cardiac expression.

produced on expression of ERG1a alone (304). Although was also demonstrated that ERG1a and ERG1b coimmu-
it has been reported that only the full-length ERG1 pro- noprecipitate from heart, suggesting that functional car-
tein(s) are detected in adult rat, mouse, and human hearts diac IKr channels reflect the heteromeric assembly of
(404), raising some doubts about the functional signifi- ERG1a and ERG1b subunits (240). The expression, distri-
cance of alternative splicing of KCNH2 transcripts, more bution, and functioning of the COOH-terminal variant of
recent studies have identified ERG1b protein in adult rat, ERG, ERG-USO (272), in contrast, remains to be explored.
human, and canine heart (240). Presumably, these dispar- As noted previously, mutations in the KCNQ1 gene
ate results reflect the fact that different anti-ERG1 anti- have been linked to LQT1 (253, 329). Heterologous ex-
bodies were used (240, 404). Further studies will be pression of KvLQT1 (KCNQ1) alone yields rapidly acti-
needed to explore this and other possible explanations. vating and noninactivating outward Kv currents, whereas
Using antibodies targeting the specific ERG1 isoforms, it coexpression with the Kv channel accessory subunit,

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1227

minK (see sect. VB), produces slowly activating K⫹ cur-

rents that resemble the slow component of cardiac de-
layed rectification, IKs (40, 447). Similar to the SCN5A
mutations linked to the LQT3 and Brugada syndromes
(Fig. 3A) and KCNH2 mutations linked to LQT2 (Fig. 3B),
KCNQ1 mutations linked to LQT1 have been identified
throughout the protein sequence (Fig. 3C). Expression
studies suggest that the various LQT1-associated muta-
tions in KCNQ1 are all loss of function, resulting in re-
ductions in functional IKs cell surface channel expression.
Simulations demonstrate that reductions in IKs density
(Fig. 7B) result in markedly prolonged ventricular action

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potential waveforms (Fig. 7A). Given the intrinsic heter-
ogeneities in IKs (and other) channel densities and action
potential waveforms throughout the myocardium (Fig. 1),
the effects of LQT1 mutations in KCNQ1 might also be
heterogeneous, further impacting the arrhythmogenic po-
tential of these mutations. Importantly, a novel “gain of
function” mutation in KCNQ1 (V307L) was identified and
linked to short QT interval syndrome (46). Heterologous
expression studies revealed that expression of KCNQ1
V307L, alone or with wild-type KCNQ1, in the presence of
KCNE1, produces IKs-like currents with markedly altered
activation kinetics and voltage-dependent properties (46)
relative to the channels produced by wild-type KCNQ1
and KCNE1. A gain of function mutation (S140G) in
KCNQ1 has also been identified in a family with heredi-
tary persistent atrial fibrillation (97). Computer simula-
tions incorporating the KCNQ1 short QT mutant channels
reveal that IKs densities are increased (Fig. 7D) and that
action potentials are shortened markedly (Fig. 7C). As
noted above for LQT1 mutations, the impact of gain of
function mutations in KCNQ1 on different cell types and
regions of the heart will likely be heterogeneous, owing to
the existing heterogeneity in IKs (and other current) den-
sities and action potential waveforms, an effect which
may acerbate the arrhythmogenic potential of alterations FIG. 7. Simulations reveal the effects of loss of function (LQT1) and
in IKs densities. gain of function (short QT) mutations in KCNQ1. Steady-state action
potential waveforms (A and C) and outward IKs currents (B and D) were
Similar to the multiplicity of ␣-subunits in the Kv and simulated (103, 105). Control action potential and current waveforms
the KCNH subfamilies, there are a number (four) of ad- simulated for wild-type KCNQ1-encoded IKs currents are depicted as the
ditional members of the KCNQ subfamily (Table 4), al- solid black lines in A–D. The corresponding simulated voltage and
current waveforms depicting the effects of KCNQ1 mutations are illus-
though none of these appears to be expressed in heart. trated by the dashed purple (LQT1) and red (short QT) lines in A–D.
Two of the KCNQ subfamily members, KCNQ2 and “Loss of function” LQT1 mutations (Fig. 3C), resulting in a decrease in
the maximum amplitude and a slowing of the time to peak of IKs (B),
KCNQ3, however, are expressed in the nervous system lead to marked action potential prolongation (A). In contrast, “gain of
and have been identified as loci of mutations leading to function” short QT mutations in KCNQ1 increase the maximal amplitude
benign familial neonatal convulsions (65, 329, 453, 526). of IKs (D) and shorten action potential durations.
Heterologous expression of KCNQ2 or KCNQ3 results in
the generation of slowly activating, noninactivating K⫹-
selective channels that also deactivate very slowly on B. Kv Channel Accessory Subunits
membrane repolarization (329, 453, 526). Interestingly,
the properties of the heteromeric KCNQ2/KCNQ3 chan- Similar to the Nav and Cav channels, a number of
nels closely resemble neuronal muscarinic acetylcholine different types of Kv channel accessory subunits have
receptor regulated ion channel currents, typically referred been identified (Table 5) and postulated to contribute to
to as “M” currents/channels (329, 526). the generation of functional myocardial Kv channels. The

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1228 JEANNE M. NERBONNE AND ROBERT S. KASS

TABLE 5. Auxiliary Kv channel subunits both cardiac IKs and IKr (and other Kv?) channels. Bio-
chemical studies focused on exploring these questions
Family Subunit Gene Human Mouse Current are clearly warranted. Although the details of minK func-
Kv␤ tioning remain to be clarified, it is important to emphasize
Kv␤1 KCNAB1 3q25 3D ??
that the physiological significance of this subunit in the
generation of cardiac membrane currents was clearly
Kv␤2 KCNAB2 1p36.3 4E2 ??
demonstrated with the identification of mutations in
Kv␤3 KCNAB3 17p13 11B3
KCNE1 that are associated with one type of inherited long
KCNE
QT syndrome, LQT5 (62, 478, 481).
Mink KCNE1 21q22 16C4 IKs Several additional members of the minK-related pep-
MiRP1 KCNE2 21q22 16C4 IKr??, Ito,f?? tide, MiRP (KCNE), subfamily (Table 5) have also been
MiRP2 KCNE3 11q13 7E1 ?? identified and characterized in coexpression studies with
Kv ␣-subunits (1–3, 339). One of these, MiRP1 (KCNE2),

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MiRP3 KCNE4 2q36.3
MiRP4 KCNE5 Xq22 XF1 has been suggested to function as an accessory subunit of
KChAP ERG1 (KCNH2) to generate cardiac IKr (1, 5). As noted
KChAP PIAS3 1q12 3F1 Ito,f??, IK?? above, however, it has previously also been suggested
KChIP that minK associates with ERG1 to produce IKr channels
KChIP1 KCNIP1 5q35 11A4
(341). Although the resolution of this seeming contro-
versy must await further experimentation, particularly
KChIP2 KCNIP2 10q25 19C3 Ito,f, others??
biochemical studies, it is reasonable to conclude that
KChIP3 KCNIP3
MiRP1 (KCNE2) is functionally important in the regula-
KChIP4.2 CSEN 2q11.1 2F1
tion of myocardial membrane excitability, as evidenced
KChIP4.3 KCNIP4 4p15.3 by the fact that KCNE2 variants are associated with spo-
NCS radic and drug-induced long QT syndromes (5, 227, 457,
NCS-1 FREQ 9q34 2A3 Ito,f, others?? 478). It is also interesting to note that studies in heterol-
ogous systems have revealed that the MiRP subfamily of
Boxes denote cardiac expression.
Kv channel accessory subunits can assemble with Kv
␣-subunits in several different subfamilies (4, 583) to
first of these was cloned from human (362), and later from modify the properties and/or the cell surface expression
rat (170), heart and was referred to as minK, i.e., “minimal of Kv ␣-subunit-encoded channels. Heterologous expres-
K⫹” channel subunit. MinK, which is encoded by the sion studies, for example, have shown that MiRP1 also
KCNE1 gene on chromosome 21 in human (Table 5), is a interacts with Kv4 ␣-subunits (583). In addition, it has
small (130 amino acids) protein with a single transmem- been demonstrated that MiRP2 (KCNE3) forms Kv chan-
brane spanning domain (170, 288, 362). Although initial nels with Kv3.4 ␣-subunits in skeletal muscle and that
characterizations of minK in Xenopus oocytes suggested mutations in MiRP2 result in reduced Kv3.4-encoded Kv
that this small protein could produce functional Kv chan- current densities, membrane depolarization, and periodic
nels when expressed alone (170, 362), subsequent studies paralysis (4). Biochemical and coexpression studies have
demonstrated the presence of a KCNQ1 homolog in oo- also suggested that MiRP1 can associate with hyperpolar-
cytes that combines with the heterologously expressed ization-activated cyclic nucleotide-gated (HCN) cation
minK to generate Kv channels that very closely resemble channels, suggesting a distinct function for the MiRP1
cardiac IKs (447). As noted above, these observations have subunit in the regulation of myocardial pacemaker cur-
led to suggestions that minK coassembles with the Kv- rents, rather than, or in addition to, the regulation of
LQT1 protein to produce functional cardiac IKs channels myocardial Kv channels (574). Taken together, these ob-
(40, 447). It has also been reported, however, that minK servations suggest the interesting possibility that mem-
coassembles with the ERG1 protein in heterologous ex- bers of the KCNE subfamily might be multifunctional
pression systems, observations interpreted as suggesting proteins, coassembling with several different Kv (3)
a role for minK in the generation of cardiac IKr channels and/or other (e.g., HCN) ion channel pore-forming ␣-sub-
(341). It has become increasingly clear, however, that units and contributing to the formation of multiple types
accessory Kv subunits, such as minK, can, at least in of cardiac Kv (and other) channels. Experiments focused
heterologous expression systems, associate with multiple on testing this hypothesis and on defining the functional
different Kv␣ subunits. It is not a given, however, that roles of the various MiRP (KCNE) subunits in the gener-
these interactions occur in intact tissues. As a result, it is ation of myocardial Kv (and other) channels will be of
presently unclear whether minK subunits actually associ- considerable interest.
ate with both KvLQT1 and ERG1 (and other Kv?) ␣-sub- Another type of Kv channel accessory subunit was
units in the myocardium and contribute to the function of revealed with the biochemical identification (360) and

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1229

subsequent cloning (419) of low molecular mass (⬍45 Coexpression of Kv␤1 subunits has also been reported to
kDa) cytosolic Kv ␤-subunits from brain. Three distinct, modulate the cell surface expression of Kv4.3-encoded
but homologous, Kv ␤-subunits, Kv ␤1, Kv ␤2, and Kv ␤3, currents, an effect attributed to Kv␤1 binding to the
encoded on three different (KCNAB) genes (Table 5), as COOH terminus of Kv4.3 (566). In addition, although with-
well as alternatively spliced transcripts (337), have now out any detectable effect on current properties or densi-
been identified (90, 124, 147, 148, 317, 352). Of these, ties, coexpression (in Xenopus oocytes) of Kv␤1.2 with
Kv␤1.1, Kv␤1.2, Kv␤1.3, and Kv␤2 have been shown to be Kv4.2 ␣-subunits modulates the redox sensitivity of Kv4.2-
expressed in the heart (12, 90, 124, 147, 148, 278, 317, 352). encoded channels (393).
The Kv ␤-subunits share a conserved COOH-terminal Similar to the KCNE subfamily of Kv accessory sub-
“core” region, related in amino acid sequence to aldo- units, therefore, the functional roles assigned to the Kv
ketone reductases, members of the triose phosphate ␤-subunits in the generation of myocardial Kv channels
isomerase enzyme family (101, 338). The NH2-terminal have been largely a matter of speculation. Interestingly,
domains of the Kv ␤-subunits are unique, and members of

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however, recent studies, completed on ventricular myo-
the Kv␤1 subfamily, as well as Kv␤3.1, have long NH2- cytes isolated from mice with a targeted disruption in the
terminal sequences that are structurally similar to the Kv␤1 locus, reveal that the loss of Kv␤1 affects the func-
Shaker (Kv1) channel inactivation gate that functions in a tional cell surface densities of Kv4- and Kv2-encoded, but
“ball and chain”-like mechanism (217) to accelerate Kv1 not Kv1-encoded, Kv channels (12). It has also been re-
channel inactivation (300 301). Although the core region ported that Kv ␤-subunits associate with ␣-subunits of the
of the Kv ␤-subunits contains an NAPH/NADPH binding eag (KCNH) subfamily (553). On the basis of all the
site (101, 338) and Kv ␤-subunits crystallize with NADPH available data, therefore, it seems reasonable to suggest
bound (191), the role of this binding in regulating the that the Kv ␤-subunits subserve multiple functions in the
functional interactions between Kv ␤- and Kv ␣-subunits generation of myocardial Kv channels. Further studies
and/or in controlling the expression/properties of the re- focused on providing the molecular details of Kv ␤-func-
sulting Kv channels has not been defined. tioning are clearly warranted.
Previous studies have demonstrated that the Kv A novel Kv channel accessory protein, KChAP (K⫹
␤-subunits interact with the intracellular T1 tetrameriza- channel accessory protein) (Table 5), was identified in a
tion domain of the Kv ␣-subunits of the Kv1 subfamily, yeast two-hybrid screen using the NH2 terminus of Kv4.2
combining in a 1:1 stoichiometric ratio (190, 192). Heter- as the bait (550). Sequence analysis of KChAP revealed a
ologous coexpression studies have revealed that Kv 574-amino acid protein with no transmembrane domains
␤-subunits affect the functional properties and the cell and no homology to Kv ␣- or Kv ␤-subunits (550). Coex-
surface expression of Kv1 ␣-subunit-encoded channels (9, pression of KChAP with Kv2.1 (or Kv2.2) in Xenopus
10, 90, 147, 148, 317, 352, 464). In some cases, the func- oocytes, however, markedly increases functional Kv2.x-
tional consequences of Kv␤ coexpression have been induced current densities without measurably affecting
shown to be Kv1 ␣-subunit specific (10). Coexpression of the time- and/or voltage-dependent properties of the cur-
Kv␤2, for example, increases the expression of Kv1.2- rents (550), suggesting that KChAP functions as a chap-
encoded channels and decreases the expression of Kv1.5- erone protein (277). Yeast two-hybrid assays also re-
encoded channels (9, 10). Because Kv1␣ and Kv␤ sub- vealed that KChAP interacts with the NH2 termini of
units coassemble in the endoplasmic reticulum (369), the ␣-subunits in the Kv1 subfamily and with the COOH ter-
observed increases in functional cell surface Kv1-encoded mini of Kv ␤1-subunits (278, 550). Interestingly, it was
channel expression suggest that the Kv␤ subunits affect subsequently demonstrated that KChAP belongs to the
Kv1 channel assembly, processing or stability or, possibly, protein inhibitor of the activated STAT family of proteins
function as chaperone proteins. that interact with a variety of transcription factors and
The facts that the Kv ␤-subunits were originally iden- play a role in programmed cell death (549). The relation-
tified in association with Kv1 ␣-subunits (360) and that ship between the apoptotic and chaperone functions of
heterologous expression studies suggest that Kv␤1 and KChAP, as well as the functional role of KChAP in the
Kv␤2 interact only with the Kv1 ␣-subunits (370, 458) generation/regulation of Kv channels in the normal and
have been interpreted as suggesting that the Kv ␤-sub- the diseased myocardium, however, remain to be deter-
units function as specific accessory subunits in the gen- mined.
eration of Kv channels encoded by Kv1 ␣-subunits. In With the use of the intracellular NH2 terminus (amino
expression systems, however, Kv␤3 has also been shown acids 1–180) of Kv4.2 as the “bait” in a yeast two-hybrid
to interact specifically with Kv2 subunits (167). Biochem- screen, three novel Kv channel interacting proteins,
ical studies also suggest that Kv ␤-subunits might well be KChIP1, KChIP2, and KChIP3 (Table 5), were identified
functionally more diverse (370, 393, 458). Both Kv␤1.1 and (21). The KChIPs belong to the recoverin family of neu-
Kv␤1.2, for example, coimmunoprecipitate with Kv4 ronal Ca2⫹-sensing (NCS) proteins, particularly in the
␣-subunits following coexpression in COS-1 cells (370). “core” regions, which contain multiple EF-hand domains

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1230 JEANNE M. NERBONNE AND ROBERT S. KASS

(81). Unlike other NCS-1 proteins, however, KChIP2 and revealed that Kv4␣ and KChIP accessory subunits assem-
KChIP3 lack NH2-terminal myristoylation sites, and the NH2 ble in a 4:4 stoichiometry and provide new insights into
termini of each of the KChIP proteins are unique (21). Nev- the intracellular interactions between the NH2 termini of
ertheless, KChIP2 and KChIP3 have several potential palmi- Kv4 subunits and the EF hand domains of the KChIPs
toylation (on cysteine residues) sites, and metabolic labeling (258, 588). In addition, it had been shown that myristoyl-
studies suggest that these sites are palmitoylated in situ ation of KChIP1 appears necessary for the normal traf-
(491). It is now clear that KChIP3 is identical to the previ- ficking of newly synthesized (KChIP1) protein to the en-
ously identified protein calsenilin, which is a Ca2⫹-binding doplasmic reticulum where the association with Kv4
protein that interacts with presenilin-1 and presenilin-2 and ␣-subunits occurs (385). It may be that palmitoylation of
regulates the proteolytic processing of these two proteins KChIP2 and KChIP3 plays a similar functional role. Mu-
(82). In addition, however, KChIP3 is also identical to an- tagenesis and structural studies have also revealed that
other previously identified protein called DREAM, which is two regions in the NH2 termini of Kv4 subunits are nec-

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a Ca2⫹-regulated transcriptional repressor (87). The DREAM essary for KChIPx interaction with (and modulation of)
protein has been shown to bind to the downstream regula- Kv4-encoded channels and that residues 71–90 (in Kv4.x)
tory elements (DRE) of several genes in the absence of Ca2⫹ form a “contact loop” that mediates the interaction with
and to dissociate from the DRE sequence when Ca2⫹ is the KChIP protein(s) (451).
elevated (87). Thus DREAM is thought to act as an activity- Biochemical methods were exploited in efforts that
dependent regulator of gene expression (87). An additional led to the identification of another Kv channel accessory
member of the KChIP family, KChIP4, also referred to as subunit, DPPX or DPP6, that also appears to interact
calsenilin-like-protein or CALP, was subsequently identified specifically with Kv4 ␣-subunits (368). A novel protein of
in biochemical studies focused on identifying the binding previously unknown function, DPP6 is structurally related
partners of the presenilin proteins (356). The interactions to CD26, which is a dipeptidyl aminotransferase and a cell
between KChIP3 (calsenilin) and KChIP4 (CALP) and the adhesion protein (368). Interestingly, DPP6 actually be-
presenilin proteins are also Ca2⫹ dependent (356). longs to a family of nonclassical serine proteases, al-
Of the four KChIP genes, only KChIP2 appears to be though DPP6 itself has no enzymatic activity (368). In
expressed in the heart (21, 431). There are, however, contrast to the KChIPs, DPP6 is an integral membrane
numerous splice variants of KChIP2 that have now been glycoprotein with a rather large extracellular COOH-ter-
identified (33, 125, 129, 390, 391, 430, 431). Studies in minal domain (368). Coexpression of DPP6 with Kv4
heterologous systems have revealed that coexpression of ␣-subunits affects the trafficking and the membrane tar-
any one of the (full-length) KChIP proteins with Kv4 geting of Kv4 ␣-subunits and modifies the kinetic proper-
␣-subunits increases the functional cell surface expres- ties of expressed cell surface Kv4-encoded channels
sion of Kv4.x-encoded Kv channels, slows current inacti- (368). Although expressed in brain and thought to func-
vation, speeds recovery from inactivation and shifts the tion in the generation of neuronal Kv4-encoded transient
voltage dependence of channel activation (21, 193, 195). outward Kv currents, DPP6 does not appear to be ex-
In contrast, KChIP expression reportedly does not affect pressed in heart and, therefore, cannot contribute to the
the properties or the densities of the K⫹ currents pro- formation of functional cardiac Kv channels. Another
duced on expression of other Kv ␣-subunits, including member of the dipeptidyl transferase family, DPP10, has
Kv1.4 and Kv2.1 (21). These observations were inter- also been shown to associate with Kv4 ␣-subunits in
preted as suggesting that the modulatory effects of the heterologous expression systems and to modify the bio-
KChIP proteins are specific for ␣-subunits of the Kv4 physical properties of Kv4.x-encoded channels (235). The
subfamily (21). In addition, although the binding of the effects of DPP10 on Kv4 channels are qualitatively similar
KChIP proteins to Kv4 ␣-subunits is not Ca2⫹ dependent, to the effects of DPP6 (235), although, like DPP6, DPP10
mutations in EF hand domains 2, 3, and 4 of KChIP1 also appears to be expressed predominantly in the brain
reportedly eliminate the modulatory effects of KChIP1 on (235). It also seems unlikely, therefore, that DPP10 plays
Kv4.2-encoded K⫹ currents in CHO cells (21). It has, a role in the generation of cardiac Kv channels. It is
however, also been reported that a splice variant of certainly possible, however, that there are additional
KChIP2, KChIP2d, which lacks three of the four EF hand members of this family that are expressed in the myocar-
domains of full-length KChIP2, modifies the inactivation dium and that remain to be identified and characterized.
kinetics of heterologously expressed Kv4.3-encoded K⫹
currents, but does not alter the kinetics of channel recov-
ery from steady-state inactivation (390). Taken together, C. Molecular Correlates of Cardiac Transient
these findings suggest that distinct regions of the (full- Outward Kv Channels
length) KChIP proteins underlie the various modulatory
effects of KChIPs on the properties and cell surface ex- All available evidence suggests that Kv ␣-subunits of
pression of Kv4-encoded channels. Structural analysis has the Kv4 subfamily encode rapidly activating, inactivating,

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1231

and recovering cardiac transient outward Kv channels (193, 431), and it appears that differences in Kv4.2 expres-
referred to as Ito,f (Table 1). In rat and mouse ventricular sion underlie the regional variations in Ito,f densities in
myocytes exposed to antisense oligodeoxynucleotides rodents (137, 193). Thus there seem to be two potentially
(AsODNs) targeted against Kv4.2 or Kv4.3, for example, important differences between Ito,f in rodents and Ito,f in
Ito,f density is reduced by ⬃50% (169, 193). Significant large mammals, including humans. In rat and mouse, Ito,f
reductions in rat ventricular Ito,f density are also seen in channels reflect the heteromeric assembly of Kv4.2,
cells exposed to an adenoviral construct encoding a trun- Kv4.3, and KChIP2, and differences in Kv4.2 expression
cated Kv4.2 subunit (Kv4.2ST) that functions as a domi- underlie regional differences in Ito,f densities. In large
nant negative (238). In addition, it has been reported that mammals, however, Ito,f channels appear to be produced
Ito,f is eliminated in ventricular myocytes isolated from by the coassembly of Kv4.3 and KChIP2, and KChIP2
transgenic mice expressing a pore mutant of Kv4.2, appears to be the primary determinant of the observed
Kv4.2W362F, that functions as a dominant negative, regional differences in Ito,f densities.
Although the Kv␤ accessory subunits were originally

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Kv4.2DN (43). Taken together, these results demonstrate
that members of the Kv4 subfamily underlie Ito,f in mouse identified based on association with Kv1 ␣-subunits and
and rat ventricles. Biochemical studies have also shown have been considered to be Kv1 ␣-subunit specific, recent
that Kv4.2 and Kv4.3 are associated in adult mouse ven- studies suggest a functional role for Kv␤1 subunits in the
tricles, suggesting that functional mouse ventricular Ito,f generation of cardiac Ito,f channels (12). Electrophysio-
channels reflect the heteromeric assembly of the Kv4.2 logical studies, for example, have revealed that Ito,f den-
and Kv4.3 ␣-subunits (193). Given that the properties of sities are decreased in ventricular myocytes isolated from
the currents classified as Ito,f in other species (Table 1) mice bearing a targeted deletion of the KCNAB1 gene,
are very similar to mouse (and rat) Ito,f, it seems reason- which encodes Kv␤1 subunits (12). In addition, biochem-
able to suggest that Kv4 ␣-subunits also underlie Ito,f in ical studies revealed that Kv4.2 and Kv4.3 coimmunopre-
other species. In dog and human myocardium, however, cipitate with the Kv␤1 splice variants, Kv␤1.1 and Kv␤1.2,
Kv4.2 appears not to be expressed (266), suggesting that from adult mouse ventricles (12). Taken together, these
only Kv4.3 contributes to Ito,f in larger mammals. Direct observations suggest that (mouse) ventricular Ito,f chan-
biochemical and/or molecular evidence to support this nels function as multimeric protein complexes compris-
hypothesis, however, has not been provided to date. In ing the Kv4.2 and Kv4.3 pore-forming ␣-subunits and the
addition, multiple splice variants of Kv4.3 have been iden- accessory Kv␤1.1, Kv␤1.2, and KChIP2 subunits (Fig. 5).
tified in human (387) and rat (490) heart, although the The targeted disruption of Kv␤1 reduces the cell surface
functional roles of these variants in the generation of membrane expression of Kv4 ␣-subunits (12), further sug-
cardiac Ito,f channels remain to be determined. gesting that Kv␤1 functions to regulate the assembly
It has been demonstrated that KChIP2 coimmunopre- and/or the trafficking of mouse ventricular Ito,f channels
cipitates with Kv4.2 and Kv4.3 ␣-subunits from adult from the endoplasmic reticulum to the cell surface (12).
mouse ventricles, consistent with a role for this subunit in The Kv␤1 COOH-terminal “core” domain has been
the generation of functional Kv4-encoded mouse ventric- shown to interact with NH2-terminal tetramerization (T1)
ular Ito,f channels (193). An important structural role of domains in Kv1 ␣-subunits (191), and recent studies sug-
KChIP2 in the generation of myocardial Ito,f channels is gest that Kv4 ␣-subunit NH2-terminal domains structurally
suggested by the observation that Ito,f is eliminated in resemble Kv1 T1 domains (451). It seems reasonable to
ventricular myocytes isolated from mice with a targeted suggest, therefore, that Kv4 NH2 termini are likely in-
disruption of the KChIP2 locus (271). In both canine and volved in mediating the interaction with Kv␤1 subunits.
human heart, it has been demonstrated that there is a As noted above, however, it has also previously been
gradient in KChIP2 message expression across the thick- demonstrated that Kv4 ␣-subunit NH2-terminal domains
ness of the (left and right) ventricular walls (429, 431), are also important in mediating the interactions with
observations interpreted as suggesting that KChIP2 un- KChIPs (21, 451). Taken together, these observations sug-
derlies the observed differences in Ito,f densities in myo- gest that Kv4 NH2-terminal domains are multifunctional,
cytes isolated from the epicardial, midmyocardial, and mediating ␣-subunit/␣-subunit interactions, as well as the
endocardial layers of the (human and canine) ventricles associations with the accessory KChIP2 and Kv␤1 sub-
(429, 431). Although this point remains somewhat contro- units. It has also been reported, however, that Kv␤1 sub-
versial (129), it has been reported that KChIP2 protein units regulate the cell surface expression of Kv4.3 sub-
expression in canine ventricles parallels KChIP2 message units in heterologous expression systems through inter-
expression (429), lending further support to the hypothe- actions with the COOH, not the NH2, terminus (566). It is
sis that KChIP2, not Kv4.3, underlies the gradient in ca- not clear if Kv␤1 subunits play a role in the generation of
nine (and human) ventricular Ito,f densities. In rat and Ito,f (and/or other) channels in large mammals, including
mouse, however, there is no detectable gradient in humans, primarily because this possibility has not been
KChIP2 message or protein expression in the ventricles explored directly. Given the heterogeneity of subunits

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1232 JEANNE M. NERBONNE AND ROBERT S. KASS

that can affect Kv4 channel properties in heterologous ventricles of Kv4.2DN-expressing transgenic animals (43,
expression systems (130), it seems reasonable to suggest 194, 196), suggesting that electrical remodeling occurs in
that additional accessory subunits or regulatory proteins the myocardium when Ito,f is eliminated. When the
might be involved in mediating the interaction(s) between Kv4.2DN transgene is expressed in the Kv1.4 ⫺/⫺ null
Kv4␣ and Kv␤1 subunits. It is certainly also possible that background, however, both Ito,f and Ito,s are eliminated
the interactions between Kv4␣ and Kv␤1 subunits are and, interestingly, no further electrical remodeling is evi-
indirect, mediated, for example, by other accessory sub- dent (194). Indeed, electrophysiological recordings from
units, such as KChIP2 or KChAP (278) or through scaf- Kv4.2DN-expressing Kv1.4 ⫺/⫺ cells revealed that the
folding proteins (39) or components of the actin cytoskel- waveforms of the Kv currents in RV, LV, and interventric-
eton (401, 529). In addition, there could well be further ular septum cells are indistinguishable (194). Although
complexity in the subunit composition of Ito,f channels, as these observations suggest that the molecular mecha-
well as in Ito,f channel regulation and posttranslational nisms underlying the observed electrical remodeling in

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processing in some cell types/species. Further studies Kv4.2DN ventricles is highly specific for Kv1.4, it is pres-
focused on defining all of the molecular components of ently unclear which of the many possible transcriptional,
functional myocardial Ito,f (and other) channels are translational, and/or posttranslational mechanisms (430)
needed to provide insights into the detailed molecular might be operative. Future studies focused on delineating
mechanisms involved in the regulation and modulation of the molecular mechanisms involved in the regulation of
these channels in the normal and in the diseased myocar- ion channel remodeling in this and other mouse models
dium. will likely provide important new mechanistic insights.
Electrophysiological studies on atrial myocytes iso-
lated from Kv4.2DN mice revealed that, similar to the
findings in ventricular cells (43), Ito,f is eliminated (563). D. Molecular Correlates of Cardiac Delayed
There are some differences, however, in the properties of Rectifier Kv Channels
mouse (and rat) ventricular and atrial Ito,f (26, 43, 68, 69,
75, 79, 194, 562, 563), differences that may reflect varia- As noted above, KCNH2 has been identified as the
tions in the subunit composition of the channels and/or in locus of mutations underlying one form of familial long
posttranslational processing of these subunits. Further QT syndrome, LQT2 (119). Heterologous expression of
studies focused on detailing the molecular compositions KCNH2 cRNA in Xenopus oocytes reveals voltage-gated,
and the mechanisms controlling the expression and func- inwardly rectifying K⫹-selective channels with properties
tioning of Ito,f channels in other cell types, particularly similar to cardiac IKr channels (448, 499), observations
atrial, nodal, and Purkinje cells, in rodents and in large interpreted as suggesting that KCNH2 encodes IKr (448).
animals, are needed to define definitively the similarities/ Subsequent studies identified NH2- and COOH-terminal
differences in the molecular compositions of Ito,f channels splice variants of the ERG1 protein (272, 282, 304), and
in different cell types/species. recent biochemical studies suggest that an NH2-terminal
The kinetic and pharmacological properties of slow ERG1 splice variant, ERG1b, coassembles with the full-
transient outward myocardial Kv currents, referred to as length ERG1a protein to form heteromeric IKr channels in
Ito,s (Table 1), are different from Ito,f, observations inter- rat, human, and canine heart (240). The role of the COOH-
preted as suggesting that the molecular correlates of Ito,s terminal variants of ERG1, ERG1-USO (272) in the gener-
and Ito,f channels are also distinct. Direct support for this ation of functional cardiac IKr channels, however, is pres-
hypothesis was provided in studies (196) completed on ently unclear. It has been reported that heterologously
myocytes isolated from (Kv1.4 ⫺/⫺) mice with a targeted expressed KCNH2 and minK (KCNE1) coimmunoprecipi-
disruption in the KCNA4 (Kv1.4) locus (305). The wave- tate (341) and that antisense oligodeoxynucleotides tar-
forms of the outward currents in cells isolated from the geted against minK attenuate IKr amplitudes in AT-1 (an
ventricles of Kv1.4 ⫺/⫺ animals are indistinguishable atrial tumor line) cells (567). It has also been reported
from those recorded in wild-type ventricular cells (196). that heterologous coexpression of another member of the
In cells isolated from the interventricular septum of Kv1.4 KCNE subfamily of accessory subunits, MiRP1 (KCNE2),
⫺/⫺ animals, however, Ito,s is undetectable, thereby dem- modifies the properties of KCNH2-encoded Kv currents
onstrating directly that Kv1.4 underlies Ito,s (196). Given (5). It is presently unclear, however, whether the minK or
the similarities in the time- and voltage-dependent prop- MiRP1 (or both) accessory subunits associate with
erties of Ito,s (Table 1) in other species (77, 83, 178, 294, ERG1a and/or ERG1b in adult human heart and contrib-
545, 546), it seems reasonable to suggest that Kv1.4 also ute to the generation of functional cardiac IKr channels.
encodes Ito,s in ferret, rabbit, canine, and human atrial and The availability of specific anti-ERG1 antibodies that can
ventricular myocytes. be exploited to immunoprecipitate ERG1 proteins from
Interestingly, it has also been reported that Ito,s and heart (240) should make it possible to explore directly the
the Kv1.4 protein are upregulated in the right and left association between the minK/MiRP accessory subunits

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1233

and the pore-forming ERG1 subunits and the functional of the KvLQT1 protein with minK, with fh12 and/or with
roles of these interactions in the generation of myocardial any other Kv channel accessory subunits (Table 5) in the
IKr channels. myocardium has not been provided, and the subunit stoi-
Biochemical studies have now revealed that the heat chiometry of functional myocardial IKs channels remains
shock proteins, Hsp70 and Hsp90, coimmunoprecipitate to be determined. Similar to KCNH2, splice variants of
with heterologously expressed ERG1 and that geldanamy- KCNQ1, which exert a dominant negative effect when
cin, a specific inhibitor of Hsp90, prevents the maturation coexpressed with the full-length KvLQT1 protein (236),
(posttranslational processing) and increases the proteo- have also been described, although the roles of these
somal degradation of the ERG1 protein (163). Interest- variants in the generation of IKs channels in vivo remain to
ingly, the interactions between the ERG1 protein and be determined.
Hsp70/Hsp90 are increased in LQT2 trafficking deficient A variety of experimental strategies, primarily in
KCNH2 mutants, such as ERG1G601S (180). In addition, mice, have been exploited in studies focused on defining

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the mutant ERG1G601S protein is retained in the endo- the molecular correlates of several of the other types of
plasmic reticulum (163). Importantly, it has also been cardiac delayed rectifier Kv currents (Table 1). A role for
demonstrated that inhibition of Hsp90 decreases func- Kv1 ␣-subunits in the generation of mouse ventricular
tional IKr densities in isolated ventricular myocytes (163). IK,slow, for example, was revealed with the demonstration
Taken together, these results suggest that Hsp70 and that IK,slow is selectively attenuated in ventricular myo-
Hsp90 function as chaperone proteins, bringing mature cytes isolated from transgenic mice expressing a trun-
ERG1 protein complexes to the cell surface to generate cated Kv1.1 ␣-subunit, Kv1.1N206Tag, that functions as a
functional IKr channels (163). It is certainly possible that dominant negative (303). It was subsequently shown,
there are additional components of myocardial IKr chan- however, that IK,slow is also reduced in ventricular myo-
nels that influence the properties and/or the functional cytes expressing a dominant negative mutant of Kv 2.1,
cell surface expression of these channels, and further Kv2.1N216 (560). Further analyses revealed that there are
studies are needed to test these hypotheses directly. actually two distinct components of wild-type mouse ven-
Heterologous expression of KCNQ1, the locus of mu- tricular IK,slow: one that is sensitive to micromolar con-
tations in LQT1 (522), reveals rapidly activating, noninac- centrations of 4-AP and encoded by Kv1 ␣-subunits, and
tivating Kv currents, whereas coexpression with KCNE1 another that is sensitive to TEA and encoded by Kv2
(minK) produces slowly activating Kv currents similar to ␣-subunits (263, 560, 587). These currents are now re-
cardiac IKs (40, 447). These observations, together with ferred to as IK,slow1 and IK,slow2, respectively (263, 291,
biochemical data demonstrating that heterologously ex- 587). Subsequent studies revealed that IK,slow1 is selec-
pressed KvLQT1 and minK proteins associate (447), have tively eliminated in ventricular myocytes isolated from
been interpreted as suggesting that minK coassembles mice in which Kv1.5 has been deleted, suggesting that
with KvLQT1 to form functional cardiac IKs channels (40, Kv1.5 encodes the micromolar 4-AP-sensitive mouse ven-
447). In addition, the finding that mutations in the trans- tricular IK,slow1 (302). These findings, together with the
membrane domain of minK alter the properties of the previous results obtained on cells isolated from Kv1.4
KCNQ-1 encoded Kv channels was interpreted as suggest- ⫺/⫺ animals (305), in which Ito,s is eliminated (196),
ing that the transmembrane segment of minK contributes suggest that, in contrast to the Kv4 ␣-subunits (193), the
to the channel pore (185, 487, 492, 527). Nevertheless, and Kv1 ␣-subunits, Kv1.4 and Kv1.5, do not associate in adult
similar to the suggested interaction between ERG1 and mouse ventricles in situ. Rather, functional Kv1 ␣-subunit-
MiRP1 (and/or minK), there is presently no direct bio- encoded Kv channels in mouse ventricular myocytes ap-
chemical/molecular evidence demonstrating a functional pear to be homomeric, composed of Kv1.4 ␣-subunits
interaction between the minK and KvLQT1 proteins (Ito,s) or Kv1.5 ␣-subunits (IK,slow1). The roles of Kv chan-
and/or that minK/KvLQT1 interactions play a role in the nel accessory subunits in the generation of these myocar-
generation of cardiac IKs channels. dial Kv1 ␣-subunit-encoded Kv channels, however, remain
A yeast two-hybrid screen, using the intracellular to be defined.
cytoplasmic COOH terminus of minK as the bait, led to Electrophysiological studies completed on isolated
the identification of a novel LIM-domain-containing pro- rat atrial myocytes (74, 75), and later on canine (577),
tein, fh12 (274). Heterologous expression studies further human (19, 531), and mouse (69) atrial myocytes, demon-
suggest that fh12 is required for the generation of func- strated the presence of a novel component of delayed
tional cell surface KvLQT1/minK (IKs) channels (274). rectification, referred to as IKur (IKultrarapid), with time-
These observations suggest that fh12 is required for the and voltage-dependent properties that are quite distinct
proper assembly of the KvLQT1 and minK subunits, the from IKr and IKs (479). Although IKur appears to be an
trafficking of assembled channels, and/or the cell surface atrial specific current in large mammals, the properties of
expression of functional KvLQT1/minK (IKs) channels. IK,slow1 in mouse ventricular myocytes are indistinguish-
Nevertheless, direct biochemical evidence for coassembly able from (rat, human, and canine) atrial IKur (168, 562,

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1234 JEANNE M. NERBONNE AND ROBERT S. KASS

586). Human, rat, and canine atrial IKur, like mouse ven- has been developed for naming the Kir ␣-subunit proteins
tricular IK,slow1, activates rapidly and undergoes little or (Kir1.x–Kir6.x) and the genes (KCNJ1–KCNJ15) encod-
no inactivation during brief depolarizations, properties ing these proteins (199). In contrast to the Kv ␣-subunits,
similar to those seen on heterologous expression of sev- however, the Kir ␣-subunits have two (not six) transmem-
eral different Kv ␣-subunits, including Kv1.2, Kv1.5, Kv3.1, brane domains (Fig. 5).
and others. In addition, IKur, like IK,slow1, is sensitive to Based on the properties of heterologously expressed
micromolar concentrations of 4-AP (168, 562, 586). The Kir subunits, it was suggested that ␣-subunits of the Kir2
later finding led to the hypothesis that Kv1.5 likely en- subfamily likely encode the strongly inwardly rectifying
codes human and rat atrial IKur (75, 533). Direct experi- Kir channels, IK1, in cardiac cells (140, 378), and all
mental support for this hypothesis was provided with the (three) members of the Kir2 subfamily (Table 6) are ex-
demonstration that exposure to antisense oligode- pressed in the myocardium (298, 488). Interestingly, the
oxynucleotides targeted against Kv1.5 selectively attenu- KCNJ2 gene, which encodes Kir2.1, has been identified as

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ates IKur in isolated adult human (159) and rat (68) atrial the locus of mutations in Andersen’s syndrome (243, 403),
myocytes. The important physiological role for Kv1.5 in an inherited disorder that is often life-threatening owing
human atria is suggested by the finding that IKur densities to QT prolongation and cardiac (ventricular) arrhythmias.
and Kv1.5 protein expression are reduced markedly in the Similar to Timothy’s syndrome (479), however, Ander-
atria of patients with chronic atrial fibrillation (511). sen’s syndrome is actually a multisystem disorder involv-
Although it was reported that Kv3.1, rather than ing the cardiovascular, skeletomuscular, and other sys-
Kv1.5, functions in canine atria to encode IKur (479), tems, and typically, Andersen’s syndrome patients
subsequent work demonstrated that Kv3.1 is not detect- present initially with developmental abnormalities (494).
able in canine atria, whereas Kv1.5 (message and protein) The mutations in KCNJ2 that are associated with Ander-
is robustly expressed (157). It seems reasonable to con- sen’s syndrome that have been described to date appear
clude, therefore, that, similar to other Kv channels, the to result in mutant Kir2.1 proteins that function in a
molecular correlate of cardiac IKur (Kv1.5) is similar dominant negative fashion to suppress Kv2.x-encoded IK1
across species. At present, it is unclear if Kv accessory currents (11, 280, 409). Individuals carrying Andersen’s
subunits play a role in the generation of atrial (mouse, rat, syndrome mutations in KCNJ2 can display QT prolonga-
canine, or human) IKur. Unexpectedly, however, it has tion (Long QT7), periodic paralysis, as well as craniofacial
now been demonstrated that Kv␤1 subunits do not asso- malformations (11, 22, 494, 498), alone or in combination.
ciate with Kv1.5 in adult mouse ventricles and that the Because only the KCNJ2 gene appears to be affected in
targeted deletion of Kv␤1 has no detectable effect on Andersen’s syndrome, the multisystem nature of this dis-
mouse ventricular IKur (IK,slow1) (12). It may well be, order likely reflects the fact that Kir2.x-encoded channels
however, that other Kv channel accessory subunits con- are expressed and are functional in a variety of cells/
tribute to the generation of IKur channels. Further studies, tissues. Myocardial IK1 (and other K⫹ channels) have been
focused on defining the molecular composition of IKur shown to be regulated directly by phosphatidylinositol
channels and the roles of accessory subunits, are needed bisphosphate (PIP2) (209, 219, 470, 489). Interestingly,
to define the underlying molecular mechanisms involved many of the Andersen’s mutations are in the PIP2 binding
in the regulation of IKur channels in the normal and dis- region of Kir2.1 (139), suggesting that the regulation/mod-
eased myocardium. ulation of IK1 channels by PIP2 is altered and that it is the
alterations in the modulatory effects of PIP2 that underlie
the phenotypic consequences of the Andersen’s syndrome
VII. MOLECULAR COMPONENTS OF OTHER
mutations.
CARDIAC POTASSIUM CHANNELS
The first direct molecular evidence that Kir2 ␣-sub-
units encode cardiac IK1 channels was provided in studies
A. Inwardly Rectifying Cardiac Kⴙ (Kir) Channel completed on myocytes isolated from mice bearing a
Pore-Forming ␣-Subunits targeted disruption of the coding region of Kir2.1 (Kir2.1
⫺/⫺) or Kir 2.2 (Kir2.2 ⫺/⫺) (580, 581). Although the
Similar to the Kv channels, functionally distinct types Kir2.1 ⫺/⫺ mice have cleft palate and die shortly after
of myocardial inwardly rectifying K⫹ channels (378) are birth, thereby precluding electrophysiological studies on
formed by the association of diverse inward rectifier K⫹ adult cells (580), experiments completed on isolated new-
(Kir) channel pore-forming ␣-subunit genes (140). Several born Kir2.1 ⫺/⫺ ventricular myocytes revealed that IK1 is
Kir subunit subfamilies, Kir1 through Kir6, most with absent (581). Interestingly, however, an inwardly rectify-
several members, have been identified (Table 6) and, like ing current, with properties distinct from the wild-type
Kv ␣-subunits, Kir ␣-subunits also assemble as tetramers IK1, is evident in Kir2.1 ⫺/⫺ myocytes (581), suggesting
to form functional K⫹ selective channels (Fig. 5). Also either that an additional Kir current component is
similar to Kv channel ␣-subunits, a unifying terminology present, but difficult to resolve in wild-type cells in the

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1235

TABLE 6. Diversity of inwardly rectifying K⫹ (Kir) and two-pore domain K⫹ (K2P) channel ␣-subunits

Location Location
Cardiac Cardiac
Family Subfamily Protein Gene Human Mouse Current Family Subfamily Protein Gene Human Mouse Current

Kir1 K2P
Kir1 TWIK
Kir1.1 KCNJ1 11q25 9A4 ?? TWIK-1 KCNK1 1q42 8E2 ??
TWIK-2 KCNK6 19q11 ??
Kir2
Kir2.1 KCNJ2 17q23 11E1 IK1 TWIK-3 KCNK7 11q12 19A
TWIK-4 KCNK8 11q12

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Kir2.2 KCNJ12 17p11.2 11B1.3 IK1 TREK
Kir2.3 KCNJ4 22U ?? TREK-1 KCNK2 1q41 1H6 Iss??
TREK-2 KCNK10 14q32
Kir2.4 KCNJ14 19q13.4 7B3 ?? TASK
Kir3 TASK-1 KCNK3 2p24 ??
Kir3.1 KCNJ3 2C1.1 IKACh TASK-2 KCNK5 6p21.1 14A1
Kir3.2 KCNJ6 21q22 16C4 TASK-3 KCNK9 8q24.3
KCNJ7 TASK-4 KCNK14
Kir3.3 KCNJ9 1q21 1H2.3 TASK-5 KCNK15 20q12
TRAAK
Kir3.4 KCNJ5 11q25 9A4 IKACh TRAAK-1 KCNK-4 11q12 19A
Kir4 THIK
Kir4.1 KCNJ10 1q21 1H2.3 THIK-1 KCNK13 14q32 12E
Kir4.2 KCNJ15 21q22 16C4 THIK-2 KCNK12 2p21 ??
Kir5 TALK
Kir5.1 KCNJ16 17q25
Kir6 TALK-1 KCNK16 6p21
Kir6.1 KCNJ8 12p11.1 6G2 ?? TALK-2 KCNK17 6p21 ??
Kir6.2 KCNJ11 11p15 783 IKATP

Boxes denote cardiac expression.

presence of IK1 or, alternatively, that a novel IK1 is up- suggests marked regional and cell type specific differ-
regulated in Kir2.1 ⫺/⫺ hearts. In contrast to the findings ences in the molecular composition of IK1 channels (133).
in Kir2.1 ⫺/⫺ cells, voltage-clamp recordings from adult Further studies focused on defining the molecular com-
Kir2.2 ⫺/⫺ ventricular myocytes revealed that IK1 densi- positions of myocardial IK1 channels in different cell types
ties are reduced, compared with IK1 densities in wild-type and in different species, including humans, are needed to
cells, and that the properties of the residual IK1 currents define the molecular diversity and the functioning of these
(in Kir2.2 ⫺/⫺ cells) are indistinguishable from wild-type channels.
IK1 (581). These results were interpreted as suggesting In the heart, weakly inwardly rectifying IKATP chan-
that both Kir2.1 and Kir2.2 contribute to (mouse) ventric- nels are thought to play a role in both myocardial isch-
ular IK1 channels, and subsequent studies provided bio- emia and preconditioning (232, 377, 380). In heterologous
chemical and molecular evidence to support this hypoth- systems, IKATP channels can be reconstituted by coex-
esis (342, 592). The observation that the inwardly rectify- pression of Kir6.x subunits with ATP-binding cassette
ing channels remaining in the absence of Kir2.1 have proteins that encode the sulfonylurea receptors, SURx
properties distinct from the endogenous IK1 channels fur- (31, 456). Although previous pharmacological and molec-
ther suggests that functional cardiac IK1 channels are ular studies suggest that cardiac sarcolemmal IKATP chan-
heteromeric. Consistent with this hypothesis, detailed nels reflect the heteromeric assembly of Kir6.2 and
comparisons of the properties of heterologously ex- SUR2A subunits, Kir6.1 is also expressed in the heart
pressed Kir2.1, Kir2.2, and Kir2.3 ␣-subunits and endoge- (406), and exposure of isolated (rat neonatal) ventricular
nous guinea pig and sheep atrial and ventricular myocytes myocytes to antisense oligodeoxynucleotides against

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1236 JEANNE M. NERBONNE AND ROBERT S. KASS

SUR1 reduces IKATP channel densities (572). These obser- ological conditions, particularly those involving metabolic
vations suggest the interesting possibility that there may stress (74, 577). Interestingly, however, it has been dem-
be some molecular heterogeneity among cardiac IKATP onstrated that action potential durations are also largely
channels. The absolute requirement for the Kir6.2 subunit unaffected in transgenic animals expressing mutant IKATP
in the generation of cardiac IKATP channels, however, was channels with markedly (40-fold) reduced ATP sensitivity
unequivocally demonstrated in studies completed on (268). The mutant IKATP channels would be expected to be
mice in which the Kir6.2 gene was disrupted by homolo- open (owing to the reduced sensitivity to closure by ATP)
gous recombination (292, 456, 484). Voltage-clamp record- at rest and to markedly affect cardiac membrane excit-
ings from ventricular myocytes isolated from these ability. The fact that action potentials are unaffected in
(Kir6.2 ⫺/⫺) animals revealed no detectable IKATP chan- ventricular myocytes expressing mutant IKATP channels
nel activity (292, 484). These findings clearly suggest that clearly suggests that additional inhibitory regulatory
Kir6.1 alone (i.e., in the absence of Kir6.2) cannot gener- mechanisms play a role in the physiological control of

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ate functional myocardial IKATP channels. Nevertheless, it cardiac IKATP channel activity in vivo (268). Further stud-
is certainly still possible that Kir6.1 coassembles with ies focused on defining and characterizing these regula-
Kir6.2 to form Kir6.1/Kir 6.2 heteromeric cardiac IKATP tory mechanisms will be of considerable interest.
channels.
The suggestion that SUR2 plays a pivotal role in the
generation of cardiac IKATP channels is supported by the B. Two-Pore Domain Kⴙ (K2P) Channel
finding that IKATP channel density is reduced in myocytes Pore-Forming ␣-Subunits
from animals (SUR2 ⫺/⫺) in which SUR2 has been de-
leted (411). In contrast, there are no measurable cardiac In addition to the many Kv (Table 4) and Kir (Table 6)
effects of the targeted disruption of SUR1 (455, 456). channel ␣-subunits, a novel type of K⫹ pore-forming
Nevertheless, it is interesting to note that IKATP channel ␣-subunit with four transmembrane spanning regions and
density is reduced, i.e., the channels are not eliminated, in two pore domains (K2P) was identified with the cloning of
SUR2 ⫺/⫺ ventricular myocytes, and the properties of the TWIK-1 (289), now referred to as KCNK1 (199). Studies in
residual IKATP channels in SUR2 ⫺/⫺ ventricular myo- heterologous systems suggest that functional K2P chan-
cytes are similar to those of the channels produced on nels, unlike Kv and Kir channels that assemble as tetra-
heterologous coexpression of Kir6.2 and SUR1 (411). mers, reflect the dimeric assembly of (two) K2P ␣-sub-
These findings strongly suggest that SUR1 likely also units and that each of the (two) pore domains in each
coassembles with Kir 6.2 in ventricular myocytes to pro- ␣-subunit contributes to the formation of the K⫹-selective
duce functional IKATP channels (at least in the absence of pore (286). Subsequent to the identification of TWIK-1, a
SUR2). Immunohistochemical studies suggest that Kir6.2 rather large number of K2P ␣-subunit genes, KCNK1–
and SUR2A assemble to form plasmalemmal cardiac IKATP KCNK17, were identified, and a subset of these appears to
channels, whereas Kir6.1, Kir6.2 and SUR2A are ex- be expressed in the myocardium (Table 6). Similar to the
pressed in mitochondria, observations interpreted as sug- Kv and Kir channels, a systematic terminology has been
gesting that the molecular compositions of functional IKr developed for naming the (KCNK) genes encoding K2P
channels in different cellular compartments are distinct ␣-subunits.
(473). Similar to IK1 channels, myocardial IKATP channels Heterologous expression studies have demonstrated
are also modulated by the binding of PIP2 and other that the members of various K2P subunit subfamilies give
membrane lipids (209, 470). rise to K⫹-selective currents with distinct time- and volt-
The waveforms of action potentials recorded from age-dependent properties and differential sensitivities to
isolated Kir6.2 ⫺/⫺ ventricular myocytes are indistin- a variety of modulators, including pH, fatty acids, and
guishable from those recorded from wild-type cells (484). anesthetics (286, 287). It seems likely, therefore, that K2P
These observations clearly suggest that IKATP channels do subunit-encoded K⫹ channels could be important in reg-
not play a role in shaping action potential waveforms (in ulating the normal physiological functioning of the adult
mouse ventricles) under normal physiological conditions. mammalian heart, as well, perhaps, as influencing myo-
The action potential shortening typically observed in cardial responses to pathophysiological stimuli. Direct
wild-type ventricular cells during ischemia or metabolic experimental support for this hypothesis was provided
blockade, however, is abolished in Kir6.2 ⫺/⫺ ventricular with the demonstration that the pathophysiological ef-
cells (484). In addition, the protective effect of ischemic fects of platelet activating factor on the myocardium are
preconditioning is abolished in Kir6.2 ⫺/⫺ hearts (456, directly linked to inhibition of KCNK3 (TASK-1)-encoded
485), and infarct size in Kir6.2 ⫺/⫺ animals, with and (or closely related) K⫹ channels in ventricular myocytes
without preconditioning, is the same (485). These obser- (39). Interestingly, the effect of platelet activating factor is
vations are consistent with the hypothesis that cardiac dependent on protein kinase C (39), although the under-
IKATP channels play an important role under pathophysi- lying molecular mechanisms have not been detailed. Al-

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1237

though it has been demonstrated that different KCNK- myocardial IKATP channels likely are linked to, and regu-
encoded K2P ␣-subunits coassemble to form heteromeric lated by, the actin cytoskeleton (179, 336). Exposure to
channels (55), it is presently unclear whether heteromeric cytochalasin D, which disrupts/destabilizes actin fila-
K2P ␣-subunit assembly is physiologically relevant in the ments, for example, accelerates the rundown of cardiac
myocardium. Similarly, there is very little information IKATP channels, whereas actin filament stabilizers inhibit
presently available about the role(s) of accessory sub- channel rundown (179). It appears that cytochalasin D
units and/or other regulatory molecules in the generation exerts its effects by interfering with the interaction be-
of K2P ␣-subunit-encoded myocardial channels. tween SUR2A and Kir6.2 subunits, thereby modifying
The facts that there are so many K2P ␣-subunits SUR-mediated regulation of the IKATP channels (76, 571).
(Table 6), that many of them are ubiquitously expressed, These observations suggest that the biophysical proper-
and that the properties of K2P ␣-subunit-encoded chan- ties, as well as the cell surface expression of IKATP chan-
nels are regulated by a variety of potentially relevant nels, are affected by cytoskeletal interactions. Similarly,

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physiological (and pathophysiological) stimuli suggest the biophysical properties, including rectification and
that channels encoded by K2P ␣-subunits likely subserve Ca2⫹ (but not Mg2⫹) sensitivity, of myocardial IK1 chan-
a variety of important physiological functions. Experi- nels are affected by treatment with cytochalasin D (336).
mental support for this hypothesis was provided with the There is also experimental evidence suggesting that
demonstration that mice bearing a targeted disruption of the functioning of Kv channels in myocardial (and other)
the KCNK2 gene (which encodes TREK-1, Table 6) dis- cells is regulated and/or modulated through interactions
play increased sensitivity to epilepsy and ischemia (208). with the actin cytoskeleton. It has been demonstrated, for
It is unclear, however, whether there is a cardiac pheno- example, that exposure to phalloidin, which stabilizes
type in the KCNK2 ⫺/⫺ mice, primarily because this actin filaments, markedly reduces action potential dura-
possibility appears not to have been addressed (208). The tions, whereas treatment with cytochalasin D (or cytocha-
physiological roles of TREK-1 and of each of the other lasin B) prolongs action potential durations, in hypertro-
K2P channel ␣-subunits expressed in the myocardium, as phied rat ventricular myocytes (568). Voltage-clamp stud-
well as in other cell types, therefore, remain largely un- ies revealed that the cytochalasin- and phalloidin-
known. Both TREK-1 and TASK-1 are expressed in the mediated effects on action potentials reflect the specific
heart, and heterologous expression of either of these attenuation or augmentation, respectively, of Ito,f (568).
subunits alone gives rise to instantaneous, noninactivat- These observations suggest that functional cardiac Kv4
ing K⫹ currents that display little or no voltage depen- ␣-subunit-encoded Ito,f channels are regulated/modulated
dence (286). These observations have led to suggestions directly or indirectly through interactions with the ac-
that these subunits contribute to myocardial “back- tin cytoskeleton. Interestingly, experiments in heterol-
ground” or “leak” K⫹ currents (32), although presently, ogous expression systems also suggest that the modu-
there is no direct experimental evidence to support this lation of Kv1.5, which encodes cardiac IKur channels, by
hypothesis. Interestingly, however, the properties of the protein kinases and phosphatases, requires an intact
currents produced on expression of TREK-1 or TASK-1 cytoskeleton (333).
are similar to those of the current referred to as IKp Similar to cardiac Nav channels, the interactions be-
identified in guinea pig ventricular myocytes (576), as well tween functional myocardial Kir and Kv channels and the
as to Iss in mouse ventricular myocytes (79, 562). Further actin cytoskeleton are assumed to be mediated through
studies focused on defining the roles of each of the K2P association with actin-binding proteins and/or other scaf-
␣-subunits in the generation of myocardial K⫹ channels, folding proteins, suggesting that Kir and Kv channels also
and the roles of these channels in the physiological, as function as multimeric protein complexes (Fig. 6). Con-
well as the pathophysiological, functioning of the heart, sistent with this hypothesis, it was recently demonstrated
are needed to clarify these issues. that Kir2.x ␣-subunits associate with several scaffolding
proteins, including CASK, veli-3, mint-1, and SAP-97 (285).
Interestingly, Kir subunits in brain also interact with a
VIII. MYOCARDIAL POTASSIUM CHANNELS very large number and variety of PDZ domain-containing
AND THE ACTIN CYTOSKELETON proteins (285, 372). In addition, it has been reported that
Kir6.x subunits interact directly with the 14 –3-3 protein
Similar to myocardial Nav channels, considerable ev- and that this interaction is requisite for the functional cell
idence has now accumulated to suggest that several dif- surface expression of assembled Kir6.x-SUR-encoded
ferent types of plasmalemmal K⫹ channels in cardiac cells IKATP channels (575). It has also been reported that Kv
also interact with components of the actin cytoskeleton ␣-subunits in several subfamilies bind to PDZ-containing
and that these interactions play important roles in regu- proteins, including PSD-95 and SAP-97 (145, 237, 557,
lating the properties, the trafficking, and/or the anchoring 558), although the physiological significance of these ob-
of these channels. It has been shown, for example, that servations in terms of the expression and/or the function-

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1238 JEANNE M. NERBONNE AND ROBERT S. KASS

ing of cardiac Kv channels has not been determined. The and functioning, as well as those focused on probing the
interactions between Kv1 and Kv4 ␣-subunits and PSD-95 underlying molecular mechanisms, will likely provide im-
impact the recruitment of Kv1- and Kv4-encoded channels portant new insights into the physiological and patho-
into lipid rafts (558). This finding may explain early ob- physiological roles of these interactions.
servations suggesting that the expression of Kv4 ␣-sub-
units alone fails to reveal targeting to lipid rafts (327).
More importantly, these observations suggest that spe- IX. SUMMARY AND CONCLUSIONS
cific associations between Kv ␣-subunits and PDZ-con-
taining scaffolding proteins play an important role in the Electrophysiological studies have identified multiple
targeting of functional Kv channels to specific subcellular types of voltage-gated inward and outward currents ex-
domains. The targeting of Kv channels to specific subcel- pressed in cardiac cells (Table 1). The outward K⫹ cur-
lular compartments would be expected to have rather rents are more numerous and more diverse than the in-
ward (Na⫹ and Ca2⫹) currents, and most cardiac myo-

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profound effects on the regulation of membrane excitabil-
ity and conduction through the myocardium (270, 463). In cytes express multiple voltage-gated, as well as inwardly
addition, Kv channel targeting could facilitate specific rectifying, K⫹ channels (Table 1). These (K⫹) channels
interactions between Kv channels and modulatory/regu- are the primary determinants of myocardial action poten-
latory proteins, including protein kinases and phospha- tial repolarization, and regional differences in K⫹ channel
tases, as has been clearly demonstrated in the protein densities and properties underlie observed variations in
kinase A-mediated regulation of cardiac IKs channels, that action potential waveforms and contribute to the genera-
appears to be mediated by an A-kinase anchoring protein tion of normal cardiac rhythms. Voltage-gated inward
or AKAP (330, 331). Ca2⫹ channel currents and the Na⫹ channel “window”
Interestingly, it has also been demonstrated that Kv1 current, however, also contribute to myocardial action
␣-subunits contain PDZ-binding domains (145) and that potential repolarization. The pivotal role played by the
Kv1.5 binds directly to the actin-binding protein ␣-acti- Nav channel “window” current, for example, has been
nin-2 (329). Further studies revealed that members of elegantly demonstrated in electrophysiological studies
three subfamilies of Kv ␣-subunits, Kv1.5, Kv2.1, and characterizing mutations in SCN5A that underlie long
Kv4.2, bind to ␣-actinin-2, interactions that affect the QT3, as well as in computer-based simulations (Fig. 4) of
properties and the functional expression of the resulting cellular electrical activity (73, 90, 141, 188).
Kv ␣-subunit-encoded K⫹ currents (329). These observa- Molecular cloning has revealed an unexpected diver-
tions suggest that several Kv ␣-encoded Kv channels sity of ion channel pore-forming ␣-subunits (Tables 2, 4,
likely also interact directly with the actin cytoskeleton via and 6) and accessory subunits (Tables 3 and 5) that
␣-actinin-2 (Fig. 6). It has also been reported that Kv4 contribute to the formation of the various inward and
␣-subunits interact directly with filamin (401) and that outward current-carrying channels (Table 1) identified
this interaction regulates the functional cell surface ex- electrophysiologically in myocardial cells. Similar to the
pression and the localization of Kv4-encoded channels electrophysiological diversity of myocardial K⫹ channels
(401). Subsequent studies revealed that actin depolymer- (Table 1), the molecular analysis has revealed that multi-
ization modulates the cell surface expression of heterolo- ple voltage-gated (Kv) (Table 4) and inwardly rectifying
gously expressed Kv4-encoded channels (529). Similar to (Kir) (Table 6) K⫹ channel pore-forming ␣-subunits, as
Nav channels, these observations suggest the interesting well as a number of accessory subunits of these (Kir and
and potentially important hypothesis that myocardial Kv Kv) channels (Table 5), are expressed in the myocardium.
channels also function as components of macromolecular A variety of in vitro and in vivo experimental approaches
complexes containing the channel components and a va- have been exploited to probe the relationship(s) between
riety of scaffolding and regulatory proteins linked to the these subunits and functional myocardial K⫹ channels,
actin cytoskeleton (Fig. 6). and important insights have been provided through mo-
Recently, it was also suggested that Kir3-encoded lecular genetics and the application of techniques that
channels interact with integrin (344), suggesting that myo- allow functional channel expression to be manipulated
cardial K⫹ channel expression and functioning may also directly. In contrast to the progress made in defining the
be linked to the extracellular matrix. Although clearly in roles of the various Kv and the Kir ␣-subunits in the
the very early stages, it seems reasonable to suggest that generation of functional myocardial Kv and Kir channels,
the link between the cytoskeleton (as well, perhaps, as there is very little known about the functional roles of the
the extracellular matrix) in the regulation of myocardial K2P ␣-subunits (Table 6). In addition, the specific and/or
K⫹ channel expression, localization, and functioning has multiple functional roles of most of the known K⫹ chan-
been made. Further studies, aimed at exploring the roles nel accessory subunits (Table 5) remain to be clarified.
of the cytoskeleton and the extracellular matrix in regu- Defining the molecular correlates/compositions of the
lating myocardial K⫹ channel expression, distribution, various myocardial K⫹ channels will facilitate future ef-

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 MOLECULAR PHYSIOLOGY OF CARDIAC REPOLARIZATION 1239

forts focused on delineating the molecular mechanisms and figures presented in this review and to Dr. Kevin Sampson
controlling the properties and the functional expression for conducting the simulations illustrated in Figures 4 and 7.
of these channels. Address for reprint requests and other correspondence:
In addition to the diversity of pore-forming and ac- J. M. Nerbonne, Dept. of Molecular Biology and Pharmacology,
Washington University Medical School, 660 South Euclid Ave.,
cessory channel subunits (Tables 2– 6), several recent
St. Louis, MO 63110 (E-mail: [email protected]).
studies, exploiting a combination of molecular, biochem-
ical, and electrophysiological approaches, have revealed a GRANTS
rather staggering array of proteins that seem likely to
We gratefully acknowledge the long-standing and contin-
contribute to regulating the properties, the cell surface ued financial support for our research endeavors provided by
expression, and/or the subcellular localization of func- the National Heart, Lung, and Blood Institute of the National
tional myocardial membrane ion channels (Fig. 6). Taken Institutes of Health.
together, the results of these studies suggest that myocar-

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