G protein coupled receptors new

g protein coupled receptors

1. G-Protein C oupled R eceptors BY- DR. RENU YADAV RESIDENT PHARMACOLOGY

2. Contents Receptor and its types Physiology of GPCR GPCR as target for drug designing GPCR associated diseases Future prospects and conclusions

3. Definition A receptor is defined as a macromolecule or binding site located on th e surface or inside of the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function.

4. Types of receptors G- protein receptors : largest Ion channel receptors/ ligand gated receptors : fastest Transmembrane enzyme-linked receptors : eg tyrosine kinase Jak-stat receptors : JAK- J anus kinase, STAT – signal transducer and activator of transcription. Eg. Cytokines, GH, prolactin, interferons Nuclear receptors : steroids, thyroxine, vit D, vit A.

5. GPCR

6. Gs Gq Gi G-Protein is made up of 20 alpha 6 beta subunit 12 gamma subunits GDP Beta-gamma complex

7. Actions of G-alpha Gs Adenylyl cyclase activation Ca channel opening Gi Adenynyl cyclase inhibition K+ channel opening Go Ca channel inhibition Gq Phospholipase C activation

8. 3 Major Pathways of GPCR CAMP Dependant Pathway Phospholipase C : IP3- DAG pathway Channel regulation

9. cAMP dependant effects Via protein kinase A Increased contractility of heart Relaxation of smooth muscles Glycogenolysis, lipolysis Water conservation by kidneys Steroid hormone synthesis 2 . cAMP response element binding protein(CREB) 3. EPACs (CAMP regulated guanine nucleotide exchange factors)

10. Phospholipase C pathway

11. G-PROTEIN RECEPTORS Gs Beta adrenergic Glucagon Histamine Serotonin 5HT 4-7 Gi Alpha2 Opioid Serotonin Cannabinoids Gq Apha1 H1 Vasopressin (type1)

12. Desensitization Mechanism Down-regulation or reduction of receptor number Sequestration or apparent shielding of receptors 3. Uncoupling from G-Proteins

13. GPCR as drug targets Receptor Drug and some key indication Alpha-1 receptor Antagonist eg Tamsulosin to treat enlarged prostate Beta-1 Antagonists eg propranolol, atenolol for hypertension Beta-2 Agonists in bronchial asthma D-2 Antagonists eg haloperidol , clozapine in schizophrenia Agonists eg levodopa in parkinsons

14. Diseases associated with G-proteins 1. Gene mutations: loss of function eg color blindness gain of function 2. Bacterial toxins: Eg cholera 3. Altered GPCR folding

15. Orphan GPCR Receptors which lack their pharmacological identity Focus of intense research First orphan GPCR was G 21 later found to be 5HT 1A

16. Recent developments Ligand- induced selective signalling (LISS) : It states that different ligand selectively recruits different intracellular signalling protein to produce different phenotypic effects. There are many ways GPCR can signal independently of G-proteins. A case has been made to abandon the term as couple receptor and call them transmembrane receptors. GPCR are new therapeutic targets for type 2 diabetes.