Receptors

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 CONTENTS
• Introduction - receptor

• Drug – receptor interactions

• Cell surface receptors

• Intracellular receptors

• Comparison of receptor types

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 RECEPTOR?


Specialized areas of cell to which drugs get
bound.

 They are regulatory protein macro molecules

 Drug should have –selectivity to a receptor ;

receptor should have - ligand specificity to
elicit action.
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D r u g R e c e p t o r I n t e ra c ti o n s

 Effect of drug is attributed to two factors

 Affinity : tendency of the drug to bind to receptor

and form D-R complex .

 Efficacy or intrinsic activity : ability of the drug to

trigger pharmacological responses after forming D-R

complex .
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CONTD…

Based on affinity and intrinsic activity :

 Full agonist : high affinity

high intrinsic activity

Eg. Methacholine on acetylcholine receptors

 Antagonist : only affinity

 no intrinsic activity Eg. Atropine on
muscarinic receptors
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CONTD..

 Partialagonist: full affinity

intrinsic activity low
Eg. Naloxene on opioid receptors
saralasin on angiotensin receptors

 Inverse
agonist: full affinity
intrinsic activity
Eg. Beta carbolines on
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BZP receptor.
CLASSIFICATION -

Cell surface Intracellular

1. Inotropic 1. Nuclear receptors

3. Metabotropic

5. Ligand regulated
trans membrane
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 A. Cell surface receptor
1. G- Protein Coupled Receptor (GPCR )
• metabotropic or 7-transmembrane
spanning (heptahelical) receptors.
• coupled to intracellular effector systems
via a G-protein, GPCR.
 mAChRs, adrenoceptors, DA, 5-HT,
opiate, peptide, purinoceptors,
orphans etc 11
STRUCTURE

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 -ROLE
• Membrane resident proteins – recognize activated
GPCRs- pass message to effector system.
• Occurs in interaction with guanine nucleotides ;
freely moving in cytoplasm.
• α, β and γ subunits – trimer in resting state.
• The 3 subunits are attached to GPCR through fatty
acid chain – reaction called prenylation.

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SUBTYPES
G-PROTEIN RECEPTOR FOR SIGNALLING
PATHWAY
GS Beta adrenergic Adenylyl cyclase
amines, glucagon
histamine, serotonin CAMP
•Excitatory effects
Gi1, Gi2, Gi3 Alpha2 adrenergic adenylyl cyclase
amines, mAchR, CAMP
opioid, Cardiac K+
serotonin channel open-
hear
Golf Olfactory epithelium t ratecyclase
Adenylyl
–CAMP
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G- RECEPTOR SIGNALLING
PROTEIN FOR PATHWAY
GO NT ,Opioid Not
cannabinoid clear
Gq mAchR, PLC
serotonin IP3 , DAG
5HT1C Cytoplasmic Ca
Gt1 , Gt2 Rhodopsin
and cGMP
colour phosphodiesteras
opsins in
retinal rod and cGMP
cone cells
e- 18
Systems involved in s i g n a l t r a n sd uc t i o n

 The adenyly cyclase / cAMP system

 The Phospholipase C / inositol phosphate system
 The Ion channels
 The Rho A /Rho kinase system

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Adenylyl Cyclase/ cAMP System
 c AMP –nucleotide synthesized from ATP - by adenylyl cyclase,
metabolized by PDE.
 Regulate enzymes of metabolism, growth, contractile
proteins of muscle.
 NT - acts on GPCR –Gs/Gi activated –produce effects– by inc
or dec. activity of adenylyl cylase-and cAMP.
 c AMP- activate - Protein kinases-activate/inactivate enzymes
by phosphorylation – cellular events.

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 P ho s ph o l i p a s e C - Inositol System

• Phospholipase C : Cleaves membrane

phospholipids - phosphoinositides.
• PLC beta – cleaves phosphatidylinositol (4,5)
bis Phosphate PIP2 into DAG and IP3.

• DAG and IP3- Secondary messengers – elicit

cellular responses.

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 ION CHANNELS
 GPCR- directly control ion channel-without secondary
messenger. Eg. mAchR in heart – activate K+ channel.

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SYSTEM

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 2. ENZYME LINKED RECEPTORS
 Involved in growth, proliferation, differentiation or
survival-called growth factors.
 Mediate actions of protein mediators- GF,
cytokines , harmones- insulin and leptin.
 Slow – require the expression of new genes.
 Single membrane spanning helix - extracellular
ligand binding domain - intracellular domain.
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Structure of Kinases linked
receptors
Extracellular domain
Binds to the ligand (growth factor)

Trans membrane domain

Y
Y
Intracellular domain
Y
Endogenous kinases bind
and get phosphorlated
Y

Y
Y 28
 TYPES
 Receptor Tyrosine Kinases (RTK)

Eg. EGF , NGF , insulin receptor

 Serine/ threonine kinases Eg. TGF
 Cytokine receptors Eg.
Cytokines , CSF
 Guanylyl cyclase receptors Eg. ANP

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 Gene Kinase cascade
transcription

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 Important pathways activated :
1.The Ras/Raf/mitogen- activated protein (MAP)
kinase pathway
 activated by tyrosine kinases.
 important in cell division, growth,
differentiation.
2. The JAK/STAT pathway
- activated by cytokines.

- controls synthesis and release of

inflammatory mediators. 31
 3. Ion Channel Linked Receptors

• Also called ionotropic receptors.

• involved mainly in fast synaptic transmission.
Eg: nAchR, GABAA, and glutamate receptors of
the NMDA, AMPA and kainate types.

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 Characteristi cs of ion channels
• Protein molecules form water filled pores
that span the membrane.

• Switch between open and closed states.

• Rate and Direction of movement depends on

electrochemical gradient of the ions

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 Structure
• Ligand binding site in extracellular domain.
 4 subunits α, β, γ and δ.
 α2, β, γ - pentameric str - 2 ligand binding
sites
• Each subunit spans the membrane 4 times; all
subunits form a central pore.

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Ligand binding
site

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GATING MECHANISM IN GABA A
RECEPTOR

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 Due to the concentration changes of different ions the
following effects are seen.
 Increase in Na and Ca levels- excitatory
 Decrease in Na and Ca levels- inhibitory
 Increase in K levels – inhibitory
 Decrease in K levels – excitatory
 Increase in Cl levels – inhibitory
 Decrease in Cl levels- excitatory

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IMPORTANCE
 Generation , propagation of nerve impulse.
 Synaptic transmission of neurons.
 Muscle contraction.
 Salt balance.
 Hormone release.
 Muscle relaxants , anti-arrhythmatics, anesthetics –
act by blocking ion channels.

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 B. Intracellular Receptors
 Ligand activated transcription factors.
 Present in soluble form – either in cytoplasm or
nucleus – freely diffusible.
 Transduce signals by- modifying gene transcription.
 Eg: steroid hormones, thyroid hormones, vit D and A,
orphan receptors
 Play vital role in endocrine signaling and metabolic
regulation.
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 Summary
 Extensive research done on Receptor pharmacology
 lead to discovery of new drug targets for
treatment of several diseases.
 Still requires discovery of new receptor types and the
mechanisms of many orphan receptors that can result
in effective treatment of many diseases.
 Requires development of receptor crystallization
etc.
 Much to be discovered about the nuclear receptors. 44