SIGNALING TRANSDUCES ONE EVENT

INTO ANOTHER
In its broadest context, cell signaling involves the
transduction of some event into another event.
In sensory transduction, a sensory cell is exposed to
some external signal that is transduced to produce a
nervous signal, the action potential. As we will see
later in Chapter 3.2, this action potential can move
along cell membranes to rapidly convey the signal,
the action potential, to remote parts of the sensory
neuron. The action potential is then transduced to
release neurotransmitter at the synapse—the gap
between one neuron and another. The neurotransmit-
ter is then transduced to form the response of the
postsynaptic cell, the one on the other side of the
synapse. In the case of cutaneous (skin) senses, the
original sensory signal is mechanical—a push or a
pull on the nerves in the skin. The mechanical signal
is transduced to an electrical signal, and the electrical
signal is then transduced to a chemical signal.
This simple series of events illustrates the use of
mechanical, electrical, and chemical signals in the
body (see Figure 2.8.1).

The sensory cell transduces At a terminal, the action

a mechanical stimulus to an potential is transduced to
electrical signal, the action a chemical signal,
potential a neurotransmitter
Sensory neuron cell body
Interneuron

Action potential
Mechanical stimulus
The final response can be
a mechanical, chemical, or
electrical response

The action potential moves The postsynaptic cell

along neuron cell processes transduces the chemical
to convey the signal to distant signal to another electrical
parts of the cell signal

FIGURE 2.8.1 Transduction of signals. Some kinds of sensory cells can transduce mechanical stimuli to electrical signals which can be conveyed along
their surface for rapid spatial relay of the signal. At the end of the cell, the electrical signal is transduced to a chemical signal to convey the signal
across the gap between the cells. The postsynaptic cell transduces this chemical signal back to an electrical signal.
SIGNALS ELICIT A VARIETY OF
CLASSES OF CELLULAR RESPONSES
Intra- and intercellular signals begin a cascade of events
that eventually changes cell behavior. The response of
cells to signaling events includes altered:
G ion transport;
G metabolism;
G gene expression or differentiation;
G shape, movement, or force production;
G cell growth or cell division;
G apoptosis or programmed cell death.

ELECTRICAL SIGNALS AND

NEUROTRANSMITTERS ARE FASTEST;
ENDOCRINE SIGNALS ARE SLOWEST
The speed of response to an initial stimulus depends on
the mode of delivery of the signal and the mechanism
of the response in the target cells. Electrical signals
are the fastest way to transmit a signal from one place
in the body to another, in milliseconds, but the overall
response depends on what happens in the target cell.
If the response involves changes in activity of proteins
already present in the target cell, the response can be
rapid. If the response involves altered gene expression
that requires synthesis of new protein, response can
take hours. If it involves altered cell growth, it can take
days to complete. Neurotransmitter signaling is the
fastest response, followed by changes in cell shape or
the development of force. Endocrine signals are slowest
but last longer.
 ■ Types of Intercellular Signaling Molecules

Endocrine factor: A chemical messenger that is released into the

TABLE 12–1 Some Signals to Which Cells Respond
circulation to produce effects distant from the point of release. Also Antigens Light
referred to as a hormone. Originally, hormones were considered
Cell surface Mechanical touch
a product of a ductless gland; however, many organs are now
considered “endocrine.”
glycoproteins/
oligosaccharides Microbial, insect
Paracrine factor: A chemical messenger that is released from one pathogens
cell to produce effects on a neighboring cell. Neurotransmitters, Developmental signals
cytokines, morphogens, and many growth factors exert paracrine Extracellular matrix Neurotransmitters
effects.
components Nutrients
Autocrine factor: A chemical messenger that exerts actions on the
same cell from which it is released. Many endocrine and paracrine Growth factors Odorants
factors also play roles in autocrine signaling, exerting negative or Hormones Pheromones
positive feedback on their own release, roles that are especially
important in neuronal and cytokine signaling. Hypoxia Tastants
Juxtacrine factor: A chemical messenger that remains affixed to
the cell in which it is produced and exerts actions on a physically
juxtaposed cell. The mechanism by which a T cell and an antigen-
presenting cell establish an immunological “synapse” is an example
of juxtacrine signaling.

TABLE 16–2 SOME FOREIGN SUBSTANCES THAT ACT ON CELL–SURFACE RECEPTORS

Substance Normal Signal Receptor Action Effect

Barbiturates and γ-aminobutyric acid stimulate GABA-activated ion-channel- relief of anxiety; sedation
benzodiazepines (GABA) coupled receptors
(Valium and Ambien)

Nicotine acetylcholine stimulates acetylcholine-activated ion- constriction of blood vessels; elevation

channel-coupled receptors of blood pressure

Morphine and heroin endorphins and stimulate G-protein-coupled opiate analgesia (relief of pain); euphoria
enkephalins receptors

Curare acetylcholine blocks acetylcholine-activated ion- blockage of neuromuscular transmission,

channel-coupled receptors resulting in paralysis

Strychnine glycine blocks glycine-activated ion-channel- blockage of inhibitory synapses in spinal

coupled receptors cord and brain, resulting in seizures and
muscle spasm

Capsaicin heat stimulates temperature-sensitive ion- induces painful, burning sensation;

channel-coupled receptors prolonged exposure paradoxically leads
to pain relief

Menthol cold stimulates temperature-sensitive ion- in moderate amounts, induces a cool

channel-coupled receptors sensation; in higher doses, can cause
burning pain
VOLTAGE-GATED Ca21 CHANNELS
TRANSDUCE AN ELECTRICAL SIGNAL
TO AN INTRACELLULAR Ca21 SIGNAL
Cells maintain a very low intracellular [Ca21] (,100 nM) 4. Direct activation of enzymes: Ca21 can directly
to avoid Ca21 precipitation with phosphate and organic bind to some enzymes, such as PKC, and activate
phosphates (ATP, etc.) present in high concentrations them. Figure 2.8.3 illustrates these aspects of
in the cytoplasm. The low cytoplasmic [Ca21] allows Ca21 signaling in cells.
increases in cytoplasmic [Ca21] to be used as a signal.
Multiple types of voltage-gated Ca21 channels (voltage-
dependent calcium channel, VDCCs) reside on the surface
membrane of many cells. Depolarization of the cell
membrane opens these channels, causing Ca21 to move
from the ECF, with 1.2 mM [Ca21], to the intracellular
compartment. The cytoplasm contains a number of
proteins that bind Ca21 with high affinity and that change
shape or activity upon Ca21 binding. The effects of
increasing cytoplasmic [Ca21] include the following:
1. Stimulus
secretion coupling: The increased
[Ca21] binds to Ca21 sensors on vesicles, causing
the fusion of the secretory vesicles with the plasma
membrane and release of secreted products into
the ECF.
2. Excitation
contraction coupling: The increased
[Ca21] binds to Ca-sensitive elements on contrac-
tile filaments or cytoskeletal elements, causing
either force development or shortening by muscle
cells.
3. Calmodulin-dependent activation of enzymes:
Calmodulin is a small cytosolic protein that
binds four Ca21 molecules and then activates
many enzymes such as myosin light chain kinase Calcium regulation
in smooth muscle. Intracellular Ca2+ concentration, [Ca2+]i, is critically
important as a regulator of cell function.
• Intracellular Ca2+ is determined by (a) Ca2+ entry; (b)
Ca2+ extrusion; and (c) Ca2+ exchange between the
cytosol, endoplasmic or sarcoplasmic reticulum (ER,
SR), lysosomes and mitochondria.
• Calcium entry occurs by various routes, including
voltage- and ligand-gated calcium channels and
Na+–Ca2+ exchange.
• Calcium extrusion depends mainly on an ATP-driven
Ca2+ pump.
• Calcium ions are actively taken up and stored by the
ER/SR, from which they are released in response to
various stimuli.
• Calcium ions are released from ER/SR stores by (a)
the second messenger inositol trisphosphate (IP3)
acting on IP3 receptors; or (b) increased [Ca2+]i itself
acting on ryanodine receptors, a mechanism known as
Ca2+-induced Ca2+ release.
• Other second messengers, cyclic ADP-ribose and
nicotinic acid dinucleotide phosphate, also promote
the release of Ca2+ from Ca2+ stores.
• Depletion of ER/SR Ca2+ stores promotes Ca2+ entry
through the plasma membrane, via store-operated
channels.
• Calcium ions affect many aspects of cell function by
binding to proteins such as calmodulin, which in turn
bind other proteins and regulate their function.
 2 1 An action potential or depolarization of the
Ca rushes in from the high ECF surface membrane opens voltage-
[Ca2+] to the low cytoplasmic [Ca2+] dependent Ca channels on the surface

3
Increased cytoplasmic [Ca2+] binds to
Ca sites on target proteins
Ca2+

VDCC

Synaptotagmin 4D
... directly activating some enzymes
Ca2+

4A RyR1 PKC
... causing stimulus-secretion Ca2+
coupling in neurons or most CSQ
Calmodulin Ca2+
endocrine cells Ca2+

Ca2+
TnC Ca2+
MLCK

Ca2+
4B Ca2+
... activating contraction in muscle
cells Ca2+
Ca 2+
Inactive Active
4C... binding to calmodulin, activating
a variety of enzymes

FIGURE 2.8.3 Electrically coupled calcium signaling. Depolarization of the cell membrane opens a calcium channel that lets Ca21 into the cell. At rest,
the cytoplasmic [Ca21] is very low. Upon stimulation, influx of Ca21 raises the [Ca21] enough for Ca21 to bind to Ca21-binding sites on specific
proteins. Ca21 binding to synaptotagmin causes fusion of secretory vesicles with the plasma membrane. Binding to troponin C (TnC) activates force in
skeletal or cardiac muscle. Ca21 binding to calmodulin activates a number of enzymes such as MLCK (myosin light chain kinase) involved in smooth
muscle contraction. In other cases, Ca21 directly activates some enzymes; PKC is shown. RyR1 is the ryanodine receptor on the endoplasmic reticulum
membrane; CSQ is calsequestrin, a calcium-binding protein in the lumen of some ER membranes.
 Agonists
(e.g. glutamate, ATP)

Depolarisation
Ca2+

SOC LGC VGCC

ATP PMCA

Sto
NCX
er
IP3
ep Ca2+
d
le Na+
ti
Agonists NAADP
on
sig
nal
GPCRs

ATP
TPC1/2
IP3R Ca RyR SERCA
sensor Ca2+
Ca2+ H+

Endoplasmic reticulum Lysosome

Plasma membrane
Fig. 4.1 Regulation of intracellular calcium. The main routes of transfer of Ca2+ into, and out of, the cytosol, endoplasmic reticulum
(ER) and lysosomal structures are shown for a typical cell (see text for details). Black arrows: routes into the cytosol. Blue arrows: routes
out of the cytosol. Red arrows: regulatory mechanisms. The state of the ER store of Ca2+ is monitored by the sensor protein Stim1, which
interacts directly with the store-operated calcium channel (SOC) to promote Ca2+ entry when the ER store is depleted. Normally, [Ca2+]i is
regulated to about 10−7 mol/L in a ‘resting’ cell. Mitochondria (not shown) also function as Ca2+ storage organelles but release Ca2+ only
under pathological conditions, such as ischaemia (see pp. 55–56). There is recent evidence for a lysosomal store of Ca2+, activated by the
second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) through a two-pore domain calcium channel (TPC). GPCR, G
protein–coupled receptor; IP3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; LGC, ligand-gated cation channel; NCX,
Na+–Ca2+ exchange transporter; PMCA, plasma membrane Ca2+-ATPase; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic
reticulum ATPase; VGCC, voltage-gated calcium channel.
1. Receptors largely determine the quantitative relations
between dose or concentration of drug and pharmacologic
effects. The receptor’s affinity for binding a drug determines the
concentration of drug required to form a significant number of
drug-receptor complexes, and the total number of receptors
may limit the maximal effect a drug may produce.
2. Receptors are responsible for selectivity of drug action.
The molecular size, shape, and electrical charge of a drug
determine whether—and with what affinity—it will bind to
a particular receptor among the vast array of chemically dif-
ferent binding sites available in a cell, tissue, or patient.
Accordingly, changes in the chemical structure of a drug can
dramatically increase or decrease a new drug’s affinities for
different classes of receptors, with resulting alterations in
therapeutic and toxic effects.
3. Receptors bring about the actions of pharmacologic
agonists and antagonists.
 % Maximal Response
A B
100 100

50 50
EC50 EC50
0 0
[A] Log [A]
Figure 3–2 Graded responses (y axis as a percentage of maximal response) expressed as a function of the concentra-tion of drug A present at the
receptor. The hyperbolic shape of the curve in panel A becomes sigmoid when plotted semi-logarithmically, as in panel B. The concentration of
drug that produces 50% of the maximal response quantifi es drug activity and is referred to as the EC50 (effective concentration for 50%
response). The range of concentrations needed to fully depict the dose-response relationship (∼3 log 10 [10] units) is too wide to be useful in
the linear for-mat of Figure 3–2 A; thus, most dose-response curves use log [Drug] on the x axis, as in Figure 3–2 B. Dose-response curves
presented in this way are sigmoidal in shape and have 3 properties: threshold, slope, and maximal asymptote. These 3 parameters quantitate
the activity of the drug.

Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the
dose or concentration (abscissa), transforming the hyperbolic curve of Figure 2–1 into a sigmoid curve with a
linear midportion (eg, Figure 2–2). This transformation is convenient because it expands the scale of the
concentration axis at low concentrations (where the effect is changing rapidly) and compresses it at high
concentrations (where the effect is changing slowly), but otherwise has no biologic or pharmacologic
significance.
• A drug is called an agonist when binding to the receptor results in a
response.
• A drug is called an antagonist when binding to the receptor is not
associated with a response; the drug has an effect only by preventing
an agonist from binding to the receptor.
• Occupancy: The proportion of receptors to which a drug is
bound.

• Affinity is the ability of a drug to bind to receptor, shown by the Affinity is how well a drug and
proximity of the curve to the y axis (if the curves are parallel); the a receptor recognize each other.
nearer the y axis, the greater the affinity.
• Inversely related to Kd of the drug
• Selectivity: Relative affinity or activity of a drug between differ-
ent receptor types. Largely replaced the concept of specificity,
since it is improbable that any drug is specific for a particular
receptor.

• Efficacy: The ability of an agonist to elicit a response following Efficacy is the maximal effect an
binding. agonist can achieve at the highest
practical concentration.
• Potency: A measure of the concentration of a drug (agonist or
antagonist) at which it is effective. Potency is the quantity of drug
required to achieve a desired effect.

• In D-R measurements, the chosen

effect is usually 50% of maximal
effect but clinically any size
response can be sought.
100 A
B
80
% Maximal effect

60
C
40
20
0
0.1 1.0 10.0
Drug concentration
Concentration-response curves for drugs A, B, and C are presented. Drugs A and B have equal effi
cacy, but drug A is more potent than drug B. Drug C is less effi cacious and less potent than either
drug A or drug B.

Efficacy: Efficacy is the magnitude of response a drug causes

when it interacts with a receptor. Efficacy is dependent on the num-
ber of drug–receptor complexes formed and the intrinsic activity of
the drug (its ability to activate the receptor and cause a cellular
response). Maximal efficacy of a drug (Emax) assumes that the drug
occupies all receptors, and no increase in response is observed in
response to higher concentrations of drug. The maximal response
differs between full and partial agonists, even when the drug occu-
pies 100% of the receptors. Similarly, even though an antagonist
occupies 100% of the receptor sites, no receptor activation results
and Emax is zero. Efficacy is a more clinically useful characteristic
than potency, since a drug with greater efficacy is more therapeuti-
cally beneficial than one that is more potent.
Parallel and Nonparallel D-R Curves

A B X
% Response 100 100

% Response
Y
50 50

Log dose of drug Log dose of drug

Figure I-2-1. D-R Curves for 2 Drugs Acting on Same (left)

and Different (right) Receptors

It may be seen from the log dose-response curves above that:

• When 2 drugs interact with the same receptor (same pharmacologic
mechanism), the D-R curves will have parallel slopes. Drugs A and B
have the same mechanism; drugs X and Y do not.
• Affinity can be compared only when 2 drugs bind to the same receptor.
Drug A has a greater affinity than drug B.
• In terms of potency, drug A has greater potency than drug B, and X is
more potent than Y.
• In terms of efficacy, drugs A and B are equivalent. Drug X has greater
efficacy than drug Y.
 Figure 1–3 describes a useful model of drug-receptor interaction.
As indicated, the receptor is postulated to exist in the inactive, Effect

nonfunctional form (Ri) and in the activated form (Ra). Ther- Ri Ra

modynamic considerations indicate that even in the absence of
any agonist, some of the receptor pool must exist in the Ra form D D
some of the time and may produce the same physiologic effect
as agonist-induced activity. This effect, occurring in the absence
Ri – D Ra – D
of agonist, is termed constitutive activity. Agonists have a much
Effect
higher affinity for the Ra configuration and stabilize it, so that a
large percentage of the total pool resides in the Ra–D fraction and
a large effect is produced. The recognition of constitutive activity
may depend on the receptor density, the concentration of cou- Ra + Da
pling molecules (if a coupled system), and the number of effectors Full agonist
in the system.

Response
Ra + Dpa
Partial agonist
Ra + Ri
Ra + Dant + Ri + Dant
Constitutive Antagonist
activity Ri + Di
Inverse agonist
Log Dose

The hypothetical receptor is able to assume two conformations. In the Ri conformation, it is inactive and
produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate
downstream mechanisms that produce a small observ-able effect, even in the absence of drug (constitutive
activity). In the absence of drugs, the two isoforms are in equilibrium, and the Ri form is favored. Conventional full
agonist drugs have a much higher affinity for the Ra conformation, and mass action thus favors the formation of
the Ra–D complex with a much larger observed effect. Partial agonists have an intermediate affinity for both Ri
and Ra forms. Conventional antagonists, according to this hypothesis, have equal affinity for both receptor forms
and maintain the same level of constitutive activity. Inverse agonists, on the other hand, have a much higher
affinity for the Ri form, reduce constitutive activity, and may produce a contrasting physiologic result.
In the figure below, drug B is a full agonist while drugs A and C are partial agonists.

B
100
% Response

A C
50

Log dose of drug

Figure I-2-2. Efficacy and Potency of Full and Partial Agonists

• Drug A is more potent than drug C, and drug B is more potent than
drug C.
• However, no general comparisons about potency can be made between
drugs A and B because the former is a partial agonist and the latter
is a full agonist.
• At low responses, A is more potent than B, but at high responses, the
reverse is true.
Duality of Partial Agonists
In the figure below, the lower curve represents effects of a partial agonist when
used alone; its ceiling effect is 50% of maximal in this example.

A dose of full agonist

100

% Response + Partial agonist

50

Partial agonist alone

Log dose of partial agonist

Figure I-2-3. Duality of Partial Agonists

• The upper curve shows the effect of increasing doses of the partial
agonist on the maximal response (100%) achieved in the presence of
or by pretreatment with a full agonist.
• As the partial agonist displaces the full agonist from the receptor, the
response is reduced—the partial agonist is acting as an antagonist.
 COMPETITIVE ANTAGONISM
In the presence of a competitive antagonist, the agonist
occupancy (i.e. proportion of receptors to which the agonist
is bound) at a given agonist concentration is reduced,
because the receptor can accommodate only one molecule
at a time. However, because the two are in competition,
raising the agonist concentration can restore the agonist
occupancy (and hence the tissue response). The antago-
nism is therefore said to be surmountable, in contrast to
other types of antagonism (see later) where increasing the
agonist concentration fails to overcome the blocking effect.
The salient features of competitive antagonism are:

• shift of the agonist log concentration–effect curve to

the right, without change of slope or maximum (i.e.
antagonism can be overcome by increasing the
concentration of the agonist)
• linear relationship between agonist dose ratio and
antagonist concentration
Competitive antagonism is the most direct mechanism by
which one drug can reduce the effect of another (or of an
endogenous mediator).

IRREVERSIBLE COMPETITIVE OR NON COMPETITiVE ANTAGONISM

▼ Irreversible competitive antagonism occurs when the antagonist
binds to the same site on the receptor as the agonist but dissociates
very slowly, or not at all, from the receptors, with the result that no
change in the antagonist occupancy takes place when the agonist is
applied.
Irreversible competitive antagonism occurs with drugs that possess
reactive groups that form covalent bonds with the receptor.
Antagonism and Potentiation
Graded dose-response curves also provide information about antagonists
(drugs that interact with receptors to interfere with their activation by agonists).

Control Competitive
100
Potentiation Antagonism
% Response

Noncompetitive

Log dose of drug

Figure I-2-4. D-R Curves of Antagonists and Potentiators

• Pharmacologic antagonism (same receptor)

– Competitive antagonists (cause parallel shift to the right in D-R
curve for agonists)
º Can be reversed by increasing dose of agonist drug
º Appear to decrease potency of agonist
– Noncompetitive antagonists (cause nonparallel shift to the right)
º Can be only partially reversed by increasing dose of agonist
º Appear to decrease efficacy of the agonist
• Physiologic antagonism (different receptor)
– Two agonists with opposing action antagonize each other
– Example: a vasoconstrictor with a vasodilator
• Chemical antagonism:
– Formation of a complex between effector drug and another compound
– Example: protamine binds to heparin to reverse its actions
• Potentiation
Potentiation: when one drug does not elicit a response
on its own but enhances the response to another drug.
– Causes a parallel shift to the left to the D-R curve
– Appears to increase potency of agonist
 Drug Receptor Effects

Agonist +

A+C A alone

Response
–
A+B
B

A+D

Log Dose
Competitive
inhibitor

Allosteric
activator

Allosteric inhibitor

FIGURE 1–2 Drugs may interact with receptors in several ways. The effects resulting from these interactions are
diagrammed in the dose-response curves at the right. Drugs that alter the agonist (A) response may activate the
agonist binding site, compete with the agonist (competitive inhibitors, B), or act at separate (allosteric) sites, increasing
(C) or decreasing (D) the response to the agonist. Allosteric activators (C) may increase the efficacy of the agonist or its
binding affinity. The curve shown reflects an increase in efficacy; an increase in affinity would result in a leftward shift of
the curve.
 FIGURE 2–2 Logarithmic transformation of the dose axis and
experimental demonstration of spare receptors, using different
concentrations of an irreversible antagonist. Curve A shows ago-
nist response in the absence of antagonist. After treatment with a
A B C
low concentration of antagonist (curve B), the curve is shifted to
the right. Maximal responsiveness is preserved, however, because
Agonist effect

D the remaining available receptors are still in excess of the number

0.5 required. In curve C, produced after treatment with a larger concen-
tration of antagonist, the available receptors are no longer “spare”;
instead, they are just sufficient to mediate an undiminished maximal
response. Still higher concentrations of antagonist (curves D and E)
E reduce the number of available receptors to the point that maximal
response is diminished. The apparent EC50 of the agonist in curves D
and E may approximate the Kd that characterizes the binding affinity
of the agonist for the receptor.

EC50 (A) EC50 (B) EC50 (C) EC50 (D,E) Kd

Agonist concentration (C) (log scale)

the total number of downstream signaling mediators present in
the cell, so that a maximal response occurs without occupancy of
Receptor-Effector Coupling & Spare all receptors. In other cases, “spareness” of receptors appears to be
Receptors temporal. For example, β-adrenoceptor activation by an agonist
When an agonist occupies a receptor, conformational changes promotes binding of guanosine triphosphate (GTP) to a trimeric
occur in the receptor protein that represent the fundamental basis G protein, producing an activated signaling intermediate whose
of receptor activation and the first of often many steps required lifetime may greatly outlast the agonist-receptor interaction (see
to produce a pharmacologic response. The overall transduction also the following section on G Proteins & Second Messengers).
process that links drug occupancy of receptors and pharmacologic Here, maximal response is elicited by activation of relatively few
response is called coupling. The relative efficiency of occupancy- receptors because the response initiated by an individual ligand-
response coupling is determined, in part, at the receptor itself; full receptor-binding event persists longer than the binding event
agonists tend to shift the conformational equilibrium of receptors itself. Irrespective of the biochemical basis of receptor reserve,
more strongly than partial agonists (described in the text that fol- the sensitivity of a cell or tissue to a particular concentration of
lows). Coupling is also determined by “downstream” biochemical agonist depends not only on the affinity of the receptor for bind-
events that transduce receptor occupancy into cellular response. ing the agonist (characterized by the Kd) but also on the degree of
For some receptors, such as ligand-gated ion channels, the rela- spareness—the total number of receptors present compared with
tionship between drug occupancy and response can be simple the number actually needed to elicit a maximal biologic response.
because the ion current produced by a drug is often directly pro- The concept of spare receptors is very useful clinically because
portional to the number of receptors (ion channels) bound. For it allows one to think precisely about the effects of drug dosage
other receptors, such as those linked to enzymatic signal transduc- without having to consider (or even fully understand) biochemical
tion cascades, the occupancy-response relationship is often more details of the signaling response. The Kd of the agonist-receptor
complex because the biologic response reaches a maximum before interaction determines what fraction (B/Bmax) of total receptors
full receptor occupancy is achieved. will be occupied at a given free concentration (C) of agonist
Many factors can contribute to nonlinear occupancy-response regardless of the receptor concentration:
coupling, and often these factors are only partially understood. A
useful concept for thinking about this is that of receptor reserve
or spare receptors. Receptors are said to be “spare” for a given
pharmacologic response if it is possible to elicit a maximal bio- Imagine a responding cell with four receptors and four effectors.
logic response at a concentration of agonist that does not result Here the number of effectors does not limit the maximal response,
in occupancy of all of the available receptors. (Figure 2–2). and the receptors are not spare in number. Consequently, an
What accounts for the phenomenon of spare receptors? In agonist present at a concentration equal to the Kd will occupy 50%
some cases, receptors may be simply spare in number relative to of the receptors, and half of the effectors will be activated, produc-
ing a half-maximal response (ie, two receptors stimulate two effec-
tors). Now imagine that the number of receptors increases tenfold
to 40 receptors but that the total number of effectors remains con-
stant. Most of the receptors are now spare in number. As a result,
a much lower concentration of agonist suffices to occupy 2 of the
40 receptors (5% of the receptors), and this same low concentra-
tion of agonist is able to elicit a half-maximal response (two of four
effectors activated). Thus, it is possible to change the sensitivity of
tissues with spare receptors by changing receptor number.
SPARE RECEPTORS
▼ Stephenson (1956), studying the actions of acetylcholine analogues
in isolated tissues, found that many full agonists were capable of
eliciting maximal responses at very low occupancies, often less than
1%. This means that the mechanism linking the response to receptor
occupancy has a substantial reserve capacity. Such systems may be
said to possess spare receptors, or a receptor reserve. The existence of
spare receptors does not imply any functional subdivision of the
receptor pool, but merely that the pool is larger than the number
needed to evoke a full response. This surplus of receptors over the
number actually needed might seem a wasteful biological arrangement.
But in fact it is highly efficient in that a given number of agonist–
receptor complexes, corresponding to a given level of biological
response, can be reached with a lower concentration of hormone or
neurotransmitter than would be the case if fewer receptors were
provided. Economy of hormone or transmitter secretion is thus
achieved at the expense of providing more receptors.