HOW G-PROTEIN COUPLED RECEPTORS(GPCR) WORKS
Receptor is a macromolecule or a blind site located on the surface or inside the effector cell, that serve to recognize the signal molecule /drug and initiate the response to it. Receptors are structured protein molecules when ligand / chemical attaches it produces response.
The following criteria have been utilized in classifying receptors.
- Pharmacological action :-
Classification is based on the relative potentials of selective agonists and antagonists , this is used in delineating M and N cholinergic alpha and beta adrenergic H1 and H2 histaminergic receptors etc.,
- Tissue distribution:-
The relative organ / tissue distribution is the basis for designating the sub type
Example:- The cardiac Beta adrenergic receptors as Beta 1 while the bronchial as Beta 2.
- Ligand binding :-
Measurement of specific binding of high affinity radio labelled ligand to cellular fragments in-vitro multiple 5HT receptors were distinguished and auto radiography helped in mapping the distribution of receptors in brain and other organs.
- Transducer pathway :-
Receptors subtypes may be distinguished by the mechanism through which their activation linked to the response.
Example:- Muscarinic cholinergic receptors acts through G-protein , Nicotinic cholinergic receptor gates influx of Na+ ions etc.,
- Molecular cloning :-
The receptor protein is cloned and its detailed amino acid sequence as well as three dimensional structure is worked out
Silent receptors :-
These are sites which bind specific drugs but no pharmacological response is elicited , they are called inert binding sites or sites of loss.
Example:- plasma proteins which have binding sites for many drugs.
- Based on the molecular structure and the nature of the linkage i,e on the transduction , receptors are distinguished in to 5 major categories. They are as follows :-
- G-protein coupled receptors.
- Ion channel receptors .
- Transmembrane enzyme linked receptors
- Transmembrane JAK-STAT binding receptors
- Nuclear receptors.
G-protein coupled receptors :-
These receptors are present on the membrane , the attainment of the substrate or the drug particle occurs with the attachment to G-protein , these receptors are linked to the effector through one or more GTP activated proteins., the structure of the receptors molecule consists of the 1 alpha helical membrane spanning hydrophobic amino acid segments which run in to 3 extracellular and 3 intracellular loops . The G proteins float in the membrane with their exposed domain lying in the cytosol , the activated alpha sub unit carrying GTP dissociates from the other two subunits and either activates or inhibits the effector, the Beta gamma Daimer has also been shown to activate receptor operated K+ channels to inhibit voltage gated ca2+ channels and to promote GPCR desensitization at higher rates of activation., A number of G-proteins distinguished by their alpha subunits have been described below.
Mostly amine and other receptors are associated with G-alpha s receptors , it stimulates adenylyl cyclase, causing increased cAMP formation .
This receptor is activated by cholera toxin which blocks GTPase activity thus preventing inactivation .
Ex:- catecholamines, histamine,serotonin
Opioid and cannabinoid receptors and amine receptors are associated with G-alpha I receptors inhibit adenylyl cyclase, decreasing cAMP formation , this is blocked by pertussis toxin which prevents dissociation of alpha beta gamma complex.
Opioid, cannabinoid receptors are associated with this receptors , this is blocked by pertussis toxin. This occurs mainly in Nervous system
G- alpha q:-
Amine, peptide and prostanoid receptors are associated with the receptors , this receptors activate phospolipase c, increasing production of second messengers inositol tri phosphate and diacylglycerol.
G-beta gamma units
All G-protein coupled receptors are associated with this receptors , these receptors perform the following functions :-
- Activates potassium channels
- Inhibits voltage gates calcium channels
- Activates GPCR kinases
- Activates mitogen activated protein kinase cascade
- It also performs the functions which are performed by Galpha subunit receptors.
Mechanism of action of GPCR receptors :-
- The alpha subunit has the GTPase activity the bound GTP is slowly hydrolyzed to GDP , the alpha subunit then dissociates from the effector to rejoin its other subunits .
- It is done only after the effector has been activated or inhibited for several seconds and the signals has been greatly amplified , the rate of GTP hydrolysis by the alpha subunit and thus period for which it remains activated is regulated by another protein called regulator of G-protein signaling (RGS)
- The onset time of response through GPCR’s is in seconds., GPCR constitutes of largest family and include receptors for many hormones and slow transmitters for example the muscarinic acetyl choline receptors adrenergic receptors and chemokine receptors
- There are three major effector pathways through which GPCR’s function they are as follows:-
- Adenylyl cyclase : cAMP pathway
- Phospholipase C : Ip3 DAG pathway
- Channel regulation
- Tripathi, Essentials of Medical Pharmacology, Jaypee Brother‟s
- H.P Rang, M. M. dale & J.M. Ritter, Pharmacology,