2. OVERVIEW:
• WHAT ARE RECEPTORS
• TYPES OF RECEPTORS
• G PROTEIN COUPLED RECEPTORS
• STRUCTURE OF GPCR
• SINGNAL TRANSDUCER MECHANISM
• SECOND MESSENGERS
• RECENT ADVANCES
3. RECEPTOR:
• Any target molecule
with which a drug
molecule has to combine
in order to elicit its
specific effect
• A major group of drug
receptors consists of
proteins that normally
serve as receptors for
endogenous regulatory
ligands.
4.
5. Type 1: ligand-gated
ion channels
Type 2: G-protein-
coupled receptors
Type 3: receptor
kinases
Type 4: nuclear
receptors
Location Membrane Membrane Membrane Intracellular
Effector Ion channel Channel or enzyme Protein kinases Gene transcription
Time frame Milliseconds Seconds Hours Hours
Examples Nicotinic
acetylcholine
receptor, GABAA
receptor
Muscarinic
acetylcholine
receptor,
adrenoceptors
Insulin, growth
factors, cytokine
receptors
Steroid receptors
Structure Oligomeric assembly
of subunits
surrounding central
pore
Monomeric or
oligomeric assembly
of subunits
comprising seven
transmembrane
helices with
intracellular G-
protein-coupling
domain
Single
transmembrane
helix linking
extracellular
receptor domain to
intracellular kinase
domain
Monomeric
structure with
separate receptor-
and DNA-binding
domains
6. • Humans express over 800 GPCRs that make up the third largest
family of genes in humans.
• Majority of these are involved in sensory perception and the
remaining receptors regulate various physiological functions
including nerve activity, tension of smooth muscle, metabolism,
rate and force of cardiac contraction, and the glandular secretion.
• GPCRs are the targets for many drugs; perhaps half of all non-
antibiotic prescription drugs act at these receptors.
8. Structure:
GPCRs share a common
structural signature of
seven hydrophobic
transmembrane segments,
with an extracellular
amino terminus and an
intracellular carboxyl
terminus
Netter’s illustrated pharmacology
10. A:Rhodopsin family:
Short extracellular (N terminal) tail.
Ligand binds to transmembrane
helices (amines) or to extracellular
loops (peptides)
The largest group.
Receptors for most
• amine neurotransmitters,
• many neuropeptides,
• purines
• prostanoids
• cannabinoids
17. The adenylyl cyclase system
• cAMP is a nucleotide
• Synthesized within the cell from ATP by membrane-
bound, adenylyl cyclase
• Produced continuously
• Inactivated by hydrolysis to 5´-AMP, by the
Phosphodiesterase
• Common mechanism, namely the activation of
protein kinases
18. Effect of Glycogen on
the muscle cell
Rang et al: Rang & Dale’s Pharmacology 7e
22. Phospholipase-c signaling system
PIP2
IP3 DAG
Release of Ca+2
from ER
intracellular Ca+2
Along with Ca+2
Activate Protein
Kinase-C
Cellular functions- Proliferation, differentiation, apoptosis, cytoskeletal
Remodeling, vesicular trafficking, ion channels conductance,
neurotransmission
PLC
24. Targets that act through PLC and IP3
Acetylcholine M1 Glutamate Platelet derived growth
factor
Angiotensin II Vasopressin Serotonin 5 HT 2C
Oxytocin Histamine H1 GnRH
α1 Adrenergic agonist
Rang et al: Rang & Dale’s Pharmacology 7e
25. Effect of Toxins
Gαs Activated by cholera toxin
which blocks GTPase activity
Gαi Blocked by pertussis toxin and
prevents dissociation of αβϒ
complex
Gαo? Blocked by pertussis toxin
Rang et al: Rang & Dale’s Pharmacology 7e
26. G protein gated Ion Channels
• G-protein-coupled receptors
can control ion channel
function directly.
(A) Typically, the activated
effector protein begins a
signaling cascade which
leads to the eventual
opening of the ion channel.
(B) The GTP-bound α-subunit in
some cases can directly
activate the ion channel.
(C) In other cases, the activated
βγ-complex of the G protein
may interact with the ion
channel.
28. Receptor desensitization
Often, the effect of a drug gradually diminishes when
it is given continuously or repeatedly
• change in receptors
• translocation of receptors
• exhaustion of mediators
• increased metabolic degradation of the drug
• physiological adaptation
• active extrusion of drug from cells
31. Orphan GPCRs
• 200 or so known GPCRs whose endogenous ligands and
functions are not known
• Attempts have been made to deorphanise these
receptors
• Evidence that some recently deorphanised GPCRs, such
as orexin receptor, may dimerise or associate with more
classical GPCRs
33. GPCR mutations, disease and
novel drug discovery
• Loss of function mutations in GPCRs involved in the control of
endocrine systems
• Gain of function mutations in GPCRs also cause disease
• Mutations in GPCRs could be responsible for variations in drug
sensitivities among different populations
βγ-mediated effects occur at higher levels of receptor occupancy than α-mediated effects otherwise the action of it is same to alpha
These varied effects are, however, all brought about by a common mechanism, namely the activation of protein kinases by cAMP. Protein kinases regulate the function of many different cellular proteins by controlling protein phosphorylation
An intracellular enzyme play an imp. Role in signal transduction participate in phosphatidylinositol 4,5-bisphosphonate(PIP2) and lipid signaling in a calcium dependent manner.