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RECEPTORS-1

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Receptor

Receptor is defined as a macromolecule or an assembly of macromolecules or binding site with functional

correlates located on surface or inside the effector cell that serves to recognize the signal molecule or drug and initiate the response to it by altering the enzyme activity, permeability to ions, conformational features or genetic material in the nucleus.

Classification of receptors TRANSMEMBRANE RECEPTORSMETABOTROPIC RECEPTORS

G protein-coupled receptors Muscarinic acetylcholine

receptor (Acetylcholine and Muscarine)

Adenosine receptors Adrenoceptors GABA receptors, Type-B (γ-

Aminobutyric acid or GABA) Angiotensin receptors Cannabinoid receptors

Cholecystokinin receptors Dopamine receptors Glucagon receptors Metabotropic glutamate

receptors Histamine receptors Olfactory receptors Opioid receptors ( Protease-activated receptors Rhodopsin (a photoreceptor

protein) Secretin receptors Serotonin

receptors, except Type-3 (Serotonin, 5-Hydroxy tryptamine or 5-HT)

Classification of receptors

Ionotropic receptors are heteromeric or homomeric oligomers. They are receptors that

respond to extracellular ligands and receptors that respond to intracellular ligands.

Extra cellular ligands Nicotinic acetylcholine receptor Glycine receptor (GlyR) GABA receptors: GABA-A, GABA-C Glutamate receptors: NMDA receptor, AMPA receptor, and Kainate recptr 5-HT3 receptorIntra cellular ligands cyclic nucleotide-gated ion channels IP3 receptor Intracellular ATP receptors Ryanodine receptor

Classification of receptors

Receptor tyrosine kinasesThese receptors detect ligands and propagate signals via the tyrosine kinase of their intracellular domains. This family of receptors includes; Erythropoietin receptor (Erythropoietin) Insulin receptor (Insulin) Eph receptors Insulin-like growth factor 1 receptor various other growth factor and cytokine receptors

Mechanism of action of drugs

Affinity Efficacy Agonists Partial agonists Antagonists Inverse agonists Antagonists

GPCR

Transmembrane proteins include G protein-linked receptors and they are seven-pass trans membrane proteins.

When a chemical - a hormone or a pharmaceutical agent - binds to the receptor on the outside of the cell, this triggers a series of chemical reactions

including the movement and binding of the G-protein.

transformation of GDP into GTP and activation of second messengers.

G-PROTEINS –RECEPTORS AND EFFECTORS

GPCR

When the hormone binds to the receptor conformatIonal change occurs in the G complex and it binds GTP instead of GDP.This binding occurs to the α-subunit and it dissociates from β

and γ subunit.The αs protein has intrinsic GTPase activity and it catalyses the

conversion of GTP- GDP,The three subunits again recombine, and is again ready for

another cycle of activation.

GPCR

Ion channel receptors

ligand binding changes the confirmation of the receptorso that specific ions flow through it -the resultant ion movement alters the electric

potential across the plasma membrane found in high numbers on neuronal plasma membranes e.g. ligand-gated channels for sodium and potassium plasma membrane of muscle cells binding of acetylcholine results in ion movement and

eventual contraction of muscle

Receptor tyrosine kinases

lack intrinsic catalytic activity binding of the ligand results in the formation of a

receptor dimer (2 receptors) This dimer than activates a class of protein called

tyrosine kinases This activation results in the phosphorylation of

downstream targets by these tyrosine kinases (stick phosphate groups onto tyrosines within the target protein)

Nuclear receptors

Lipid soluble ligands that Penetrate cell mmbReceptors contain DNA-binding domains and act as ligand-regulated transcriptional activators or suppressors

Ligand binding of the receptors triggers the formation of a dimeric complex that can interact with specific DNA sequences (=“Response Elements”) to induce transcription. Effects of nuclear receptor agonists can persist for hours or days after plasma concentration has fallen

Second messengers-C AMP Hormone stimulation of Gs protein-coupled receptors leads to activation

of adenylyl cyclase and synthesis of the second messenger cAMP most commonly studied second messenger (cAMP-dependent protein kinases or PKAs) cAMP has a wide variety of effects depending on the cell type and the

downstream PKAs and other kinases In adipocytes, increased cAMP activates a PKA that stimulates

production of fatty acids In ovarian cells another PKA will respond to cAMP by increase estrogen

synthesis second messenger systems allow for amplification of an extracellular

signal one epinephine molecule can bind one GPCR – this can result in the

synthesis of multiple cAMP molecules which can go on to activate and amplified number of PKAs

Second messengers - IP3 and DAG

IP3 and DAG – breakdown products of phosphotidylinositol (PI) produced upon activation of multiple hormone receptor types

(GPCRs and RTKs) Calcium – IP3 production results in the opening of calcium-

channels on the plasma membrane of the ER – release of calcium

a rise in calcium in pancreatic beta cells triggers the exocytosis of insulin

a rise in intracellular calcium also triggers contraction of muscle cells

much study has been done on the binding of calcium to a protein called calmodulin and the effect of this complex on gene expression

Common signal pathway

The effects of activation of GPCRs and RTKs is more complicated than a simple step-by-step cascade

Stimulation of either GPCRs or RTKs often leads to production of multiple second messengers, and both types of receptors promote or inhibit production of many of the same second messengers

in addition, RTKs can promote a signal transduction cascade that eventually acts on the same target as the GPCR

therefore the same cellular response may be induced by multiple signaling pathways by distinct mechanisms

Interaction of different signaling pathways permits fine-tuning of cellular activities

Common signal pathway

Enzymes as receptors

Potential molecular target for medicines

May bind to allosteric site ACE inhibitors AChE inhibitors

Voltage operated channels Open, Closed Refractory Local anaesthetics, antianginal drugs, Antiarrhythmic drugs

RECEPTOR DESENSITIZATION time dependent response Desensitization is generally reversible Slow confirmational change Inability to activate adenylate cyclase

Up and down regulation of receptors Down regulation-Prolonged exposure to high

concentration of agonist reduction in number of receptors available for activationinternalisation

Up regulation-Prolonged occupation of receptor by antagonist leads to an increase in number of receptorsexternalisation

RECEPTOR REGULATION

DISEASE DOWNREGULATION UPREGULATION

ASTHMA-salbutamol ß adrenoceptor

Depression-TCAs ß adrenoceptor α adrenoceptor

Endogenous depression

α adrenoceptor ß adrenoceptor

Thyrotoxicosis –T3,T4 ß adrenoceptor

Spare receptors

The drug can produce maximal response even when less than 100% of the receptors are occupied

The remaining unoccupied receptors are just serving as receptor reserve

Insulin receptors-90% β receptors on heart 5-10%

Denervation supersensitivity

Fast up regulation Pharmacological basis of tardive dyskinesia Long term dopamine receptor blockade Supersensitive new dopamine receptors

Receptor related diseases

Myasthenia gravis Insulin resistant diabetes Testicular feminization

Non-receptor mediated mechanisms

CHEMICAL ACTION

Neutralisation Chelation Ion exchangers

PHYSICAL ACTION

Osmosis Adsorption Protectives Demulcents Astringents Saturation in biophase

Non-receptor mediated mechanisms

By counterfeit or false incorporation mechanisms By virtue of being protoplasmic poisons Through formation of antibodies Through placebo action By targeting specific genetic changes

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