Receptors and Drug

Action

Dr. Subasini
Pharmacology Department
Ishik University, Erbil
 Receptors and Drug Action
 Receptor
 Receptor is defined as a macromolecule or
binding site located on the surface or inside the
effector cell that serves to recognize the signal
molecule / drug and initiate the single response to
it, but itself has no other function.
 Functions of receptors are
 • Recognition and binding of the ligand.
 • Propagation of the message.
 • To amplify the signal.
Receptors
 Type of Receptor
 1. Ion-channel-linked receptors (Ionotropic
receptors)
 2. G-protein-linked receptors
(Metabotropic receptors)
 3. Enzyme-linked receptors (Kinase linked
receptor)
 4. Nuclear receptor (Cytosolic receptor)
 Molecular mechanism of receptor /Signal
transduction pathway
The three stages of cell signaling are,
o Reception
o Transduction
o Response
The series of steps involved is
1. Reception of the signal depends on the
receptor protein.
2. The binding signaling molecule activates
the receptor, which in turn activates the
one or more intracellular signaling
pathways.
3. The target is effector proteins, which are
activated when signaling path way is
activated and implement the appropriate
changes in cell behavior.
 1. Ion channel receptor
1. Ion channel linked receptors are cell membrane bound
receptors are also called ligand-gated ion channels.
2. A ligand-gated ion channel receptor acts as a gate
when the receptor changes shape.
3. When a drug (agonist) molecule binds to an ion
channel and the channel opens, allowing the ions to
move in or out of the cell following their electrical
gradients.
4. The subsequent flow of ions through these channels
can elicit cellular response in the form of
depolarization or hyperpolarization of the cell
membrane.
 Ion channel receptor – cont….
 Ex: Nicotinic-cholinergic receptor, GABAA/B
, Glutamate & Glycine receptors.
 Nicotinic cholinergic receptor channel permits
passage of Na+ ions results in depolarisation.
 Benzodiazepines bind the GABA receptor
chloride channel complex and facilitate the
opening of the channel
 Ion channel receptor- cont.…..
Receptors:
•Specific areas of cell membranes (proteins, glycoproteins)*
•When bound to ligand, positive or negative biological responce

Ligand

cellmembrane with receptor

Biological responce
Signal transduction mechanism
Signal transduction mechanism
Ligand binds to ion channel

Opening of ion channels

Increase diffusion across membrane

Change in electrical charge

Cell response (i.e. Contraction/ conduction

 2. G-protein-coupled receptors
(Metabotropic receptors)
 G protein-coupled receptors (GPCRs) are the largest family of cell-
surface receptors, also known as seven-trans membrane domain
receptors, because they pass through the cell membrane seven
times.
 A GPCR is a plasma membrane receptors which are coupled to the
effector system (enzymes/channels) through GTP binding protein
called as G-protein.
 G-proteins are heterotrimeric, with 3 subunits α, β, γ.
 There are three main varieties of G-protein (Gs, Gi and Gq), among
these Gs and Gi produce stimulation or inhibition of adenyl cyclase
, respectively, while Gq controls phospholipase – C activity.
 Ex: Muscarinic-cholinergic receptor, adrenoceptors,
dopaminergic receptor & 5-HT receptor.
G-Protein coupled receptor
structure
 G protein coupled receptor signal
transduction pathway
 In resting state, GDP is bind to α subunit of α-β-γ trimer.
 When the receptor is activated by the binding of an agonist a
conformational changes occurs results in a high affinity for the α-β
& γ trimer of G-Protein.
 During this process GDP dissociates from α-β-γ subunit while
GTP associates in its place.
 Binding of GTP activates the α-subunit and ultimately dissociates
the remaining β & γ subunits
 The free α-GTP subunit then activates the effector/target cells.
 This is called activation state or switch on state.
G protein coupled receptor signal
transduction pathway- cont…
 G protein coupled receptor signal
transduction pathway
 The GTPase of the α-subunit quickly hydrolyses GTP to
GDP and the resultant α-GDP unit then dissociate from
effector and reunite with β-γ unit, complete the cycle.
 Resetting to switch back to the off state.
 Primarily there are three G-protein coupled effector
system through which the G-Protein coupled receptor
works
 a) The Adenylyl cyclase: cAMP system
 b) The Phospholipase-C: Inositol phosphate system
 c) Ion channels
 a) The Adenylyl cyclase: cAMP
effector signal transduction
 All receptors that act via cyclic AMP are coupled to a stimulatory G protein
(Gs), which activates adenylyl cyclase and thereby increases cyclic AMP
concentration.
 Another G protein, called inhibitory G protein (Gi), inhibits adenylyl cyclase,
but it mainly acts by directly regulating ion channels rather than by decreasing
cyclic AMP content.
 b) The Phospholipase-C: Inositol
phosphate signal transduction system
 In this signaling pathway signaling molecule
(ligand) bind to the receptor linked to G-proteins
(Gq) and activate the membrane enzyme
phospholipase-C (PLC).
 Stimulation of PLC leads to the hydrolysis of
Phosphotidyl inositol 4,5 diphosphate (PIP2)
[phospholipid component of plasma membrane]
 On hydrolysis PIP2 splits into two second
messengers: diacylglycerol (DAG) and inositol-1,
4, 5-tri-phosphate (IP3).
 The Phospholipase-C: Inositol phosphate signal
transduction system cont…….
 IP3 being water soluble diffuse through cytoplasm where it trigger the release of
Ca2+ from storage vesicles. The raised concentration of Ca2+ promotes the
binding of Ca2+ to calmodulin which regulate the activity of various enzymes.
 DAG activates a phospholipid and the calcium sensitive protein kinase - C
(PKC) which then phosphorylates specific protein leads to the response.
 c) Ion channel regulation
 G-couple receptors can control the functioning
of ion channel (e.g. K+ and Ca2+ channels) by
the mechanisms that do not involve any role of
secondary messengers.
E.g.:
 In cardiac muscle, muscarinic Ach receptor.
 Opioid analgesics reduce neuronal excitability
by opening K+ channel by this mechanism.
 3. Enzyme-linked receptors
(Kinase linked receptor)
 Enzyme-linked receptor, also known as a catalytic receptor, is a
trans membrane receptor, where the binding of an extracellular
ligand causes enzymatic activity on the intracellular side.
 The agonist binding site and inner face catalytic site are
interconnected through a single trans membrane stretch of peptide
chain. They are protein kinases and hence are also known as
kinase linked receptors.
 There are two major subgroups of such receptors.
 a. Those that have intrinsic enzymatic activity.
 b. Those that lack intrinsic enzymatic activity, but bind a JAK-
STAT kinase on activation.
 a) Intrinsic enzyme receptor
 The intracellular domain is either a protein kinase or guanylyl
cyclase.
 In most cases they are protein kinase and hence are also known
as kinase linked receptor.
 Agonist binding induces dimerization of receptor molecules and
activates the kinase to autophosphorylate tyrosine residues on
each other, increasing their affinity for binding substrate proteins
and carrying forward the cascade of tyrosine phosphorylations.
 Intracellular events are triggered by phosphorylation of relevant
proteins, many of which carry a SH2 domain.
Intrinsic enzyme receptor – cont..
 b) JAK-STAT kinase binding
receptor
 It is sub type of enzyme linked receptor. These consist of 2 identical single-pass
trans membrane proteins embedded in the plasma membrane. Each of their
cytoplasmic ends binds a molecule of a Janus kinase ("JAK").
 The JAK-STAT system consists of three main components: (1) a receptor (2)
Janus kinase (JAK) and (3) Signal Transducer and Activator of Transcription
(STAT).
Enzyme-linked receptors signal
transduction path way
 4. Nuclear receptors (Cytosolic
receptor)
 They are intercellular proteins which are in an inactive
state.
 Binding of agonist activates the receptor.

 The agonist- receptor complex move to the nucleus

where it interacts with DNA, regulate gene
transcription and thereby directs the synthesis of
specific protein to regulate the activity of target cells.

 E.g: Steroidal hormones, thyroid hormones, Vit-D and

retinoids.
Nuclear receptors (Cytosolic
receptor

Drug
Drugs that do not act on receptors: Drugs that do act on receptors:
Acetylcholin
(Neurotransmittor)
Antacida: CaCO3 + HCl ca. 5Å
Acetylcholin Agonists

Diuretica (osmotic) O
Pilocarpine
O
N Carbacholin
Me
O N
Akylating agents (cancer) O
H
H2N N O
O O N
Cl
H
Cl

Cl
N
Cl
N Nu Acetylcholin Antagonists
N
Nu
Atropin Cyclopentolat
N
N
Psoralenes
OH
OH O
O
O O O
N N
O O N N O
HN R NH2 HN R
O O NH2
N h N Agonist:
O O O O O O
R' R'
Binds to (have affinity for) receptor
Binding leads to biolog. responce
(Agonists have intrinsic activity / efficacy)

Antagonist:
Affinity for receptor
No intrinsic activity
 Types of receptors
Super- Endogenous General structures
family ligands

1 Fast neurotransmittors Ligand gated ion chanels

ex. Acetylcholine

2 Slow neurotransm.
ex. Noradrenalin G-Protein coupled receptors
Hormones

3 Insuline Enzyme coupled receptors

Growth factors Catalytic receptors

4 Steroid hormones Cytoplasmic receptors

Thyroid hormones
Vitamin A, D
Types, distribution and function
Stimulatory Receptors Inhibitory Receptors

a1 a2

b1 b2

All the tissues to be All the tissues to be inhibited

stimulated have a 1 AR should have b 2
except Heart, JGA and except pre-synaptic nerve ending,
Adipose tissue (β1) platelets, beta cells (α2)
 Heart
 Adrenaline (Epinephrine)
 Cardiac stimulant
 Increase in heart rate (+ Chronotropic effect)
 Increase in myocardial contractility ( + Inotropic
effect)
 Increase in conduction velocity ( + Dromotropic
effect)
 Increase in cardiac output
 Increase in automaticity
Suggested Reading
 Katzung BG. Basic & clinical pharmacology.
8th ed., 2001.
 Katzung BG, Trevor AJ. Examination &board
review pharmacology. 5th ed. 1998.
 Goodman&Gilman. Basic pharmacology. 9th
ed., 1996.
 Pharmacology, Lippincott’s Illustrated
Reviews 1992.
Thank you for your attention