By Dr Manjuprasad M.S

Moderator: Dr Vijayalaxmi MK

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Definition

Theories

Types

GPCRs

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The component of a cell or organism that

interacts with an agonist and initiates the

chain of events leading to agonist observed

effects.

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Occupation theory:

The interaction between the 2 molecules ie drug

and receptor to be governed by law of mass

action and the effect to be a direct function of

drug receptor complex

D+R DR E

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Intensity of response is proportional to the

fraction of receptors occupied by the drug and

maximal response occurs when all receptors are

occupied

Drugs exert All or none phenomenon

A drug and receptor have a complementary

structural features like lock and key

this theory just gave a fundamental concept

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Rate theory

Magnitude of response depends upon rate of

agonist/ receptor association and

dissociation.

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GPCR`s

Ligand gated ion channels/ionotropic

receptor

Kinase linked receptors

Nuclear receptors

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It was discovered by Alfred G.Gilman and

Martin Rodbel for which they won nobel prize

in physiology in 1994.

There are about more than 1000 known

GPCRs

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GPCRs are divided into three distinct families.

There is considerable sequence homology

between the members of one family, but none

between different families.

All have same seven-helix structure, but differ in

other respects, principally in the length of the

extracellular N terminus and the location of the

agonist binding domain.

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Group I,

the largest group, contains the receptors for

catecholamines, peptide hormones,

neuropeptides, and glycoproteins.

Group II, contains

the secretin/glucagon/vasoactive intestinal

peptide receptor family.

Group III

contains the metabotropic receptors (eg,

calcium-sensing and glutamate receptors)

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G-protein-coupled receptors consist of a single

polypeptide chain of up to 1100 residues .

comprises seven transmembrane α-helices, with

an extracellular N-terminal domain of varying

length, and an intracellular C-terminal domain.

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The helices are connected by 3 loops, both

intra and extracellularly.

3rd cytoplasmic loop couples to G-protein.

(heterotrimeric GTP binding proteins)

In synthesis of GPCR, during mRNA splicing,

additions/deletions/substitution of bases

lead to variation in specificity of receptor.

Leads to functional selectivity.

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2 Types

Heterotrimeric referred to as large G

proteins that are activated by GPCRs and are

made up of α,γ and β.

Small G proteins or monomeric belong to Ras

superfamily of small GTPases

involved in signal transduction.

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Associated with guanine nucleotides – GTP

and GDP.

α subunit interacts with GTP/GDP and also

has enzymatic action.

Remain as a complex due to addition of

hydrophobic groups

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Gαs , Gαolf : activates plasma membrane adenylyl

cyclases, increasing cAMP, which stimulates

phosphorylation of target proteins

Gαs and its downstream signaling can be covalently

activated by cholera toxin

.

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Gαi , Gαo : inhibit most adenylyl cyclases,

decreasing cellular cAMP.

Gαi and Gαo can be covalently inactivated and

their signaling turned off by Pertussis toxin.

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Gαq , Gα11 : activate phospholipase Cβ

Gα12 , Gα13 : enhance Rho kinase and change

expression of some genes

Gα transducin: activates cGMP phosphodiesterase

that cleaves and depletes cytoplasmic cGMP

(retina only)

Gα gustducin:activates cAMP phosphodiesterase

that cleaves and depletes cAMP (taste receptors)

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Adenylyl cyclase

Phospholipase C

Ion channels

Rho A/Rho Kinase

MAP Kinase

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Forskolin and fluoride ions can directly

activate cAMP

PDEs like theophylline, Rolipram, milrinone

can act indirectly by decreasing cAMP

degradation.

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Ex: vasopressin on liver cells.

Muscarinic and α adrenoceptor agonists

acting on smooth muscle and salivary glands.

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Can directly act on ion channels , without 2nd

messengers.

Especially influence K+ and Ca+ channels.ex:

m2 AChR in cardiac muscle – enhance K+

permeability.

Inhibitory drugs like opioids .

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Couples to G12-13 subtype

Free Gα interacts with guanosine nucleotide

exchange factor, facilitates GTP-GDP

exchange in Rho kinase.

Rho kinase involved in Pulmonary HTN.

Fasudil- under trials for use in Rx of

Pulmonary HTN.

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Involved in cell division,

apoptosis, and tissue regeneration.

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Phosphorylation

Receptor agonist complex internalization

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Four types of protease-activated receptors

(PARs), have been identified.

Eg.Thrombin activate PARs by snipping off

the end of the extracellular N-terminal tail

of the receptor to expose five or six N-

terminal residues that bind to receptor

domains in the extracellular loops

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It is thought to play a role in inflammatory

pain.

A PAR molecule can be activated only once,

because the cleavage cannot be reversed

Inactivation occurs by a further proteolytic

cleavage, or by desensitisation, involving

phosphorylation.

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Calcium sensing receptor: autosomal

dominant hypocalcemia

CXCR 4 : target of HIV

Endothelin receptor B(Etb) : hirschsprung’s

disease

Rhodopsin: in Retinitis pigmentosa.

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BIBLIOGRAPHY

Goodman and Gilman – 12th edition

Introduction to Physiology- Guyton – 11th edition

Essentials of medical pharmacology – K.D.Tripathi

Rang and Dales pharmacology 7th edition

Textbook of medical pharmacology – Padmaja

udaykumar

Basic clinical pharmacology Katzung 11th edition

Uptodate.com

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