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G protein coupled receptor
G-protein coupled receptors (GPCRs) are the largest family of membrane receptors and the target of many drugs. They have seven transmembrane domains and signal through G proteins and second messengers like cAMP or IP3. Upon ligand binding, the GPCR activates a G protein that then activates or inhibits downstream effectors to produce a cellular response. GPCRs regulate many physiological functions and half of all drugs target these receptors. Recent research focuses on deorphaning orphan GPCRs and understanding how GPCR mutations can cause disease.
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G protein coupled receptor
- 1. G-PROTEIN COUPLED RECEPTOR Moderator Dr. DilshadAli Rizvi Fardan Qadeer JR II
- 2. OVERVIEW: • WHAT ARERECEPTORS • TYPES OF RECEPTORS • G PROTEIN COUPLED RECEPTORS • STRUCTURE OF GPCR • SINGNAL TRANSDUCER MECHANISM • SECOND MESSENGERS • RECENT ADVANCES
- 3. RECEPTOR: • Any targetmolecule with which a drug molecule has to combine in order to elicit its specific effect • A major group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands.
- 5. Type 1: ligand-gated ionchannels Type 2: G-protein- coupled receptors Type 3: receptor kinases Type 4: nuclear receptors Location Membrane Membrane Membrane Intracellular Effector Ion channel Channel or enzyme Protein kinases Gene transcription Time frame Milliseconds Seconds Hours Hours Examples Nicotinic acetylcholine receptor, GABAA receptor Muscarinic acetylcholine receptor, adrenoceptors Insulin, growth factors, cytokine receptors Steroid receptors Structure Oligomeric assembly of subunits surrounding central pore Monomeric or oligomeric assembly of subunits comprising seven transmembrane helices with intracellular G- protein-coupling domain Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain Monomeric structure with separate receptor- and DNA-binding domains
- 6. • Humans expressover 800 GPCRs that make up the third largest family of genes in humans. • Majority of these are involved in sensory perception and the remaining receptors regulate various physiological functions including nerve activity, tension of smooth muscle, metabolism, rate and force of cardiac contraction, and the glandular secretion. • GPCRs are the targets for many drugs; perhaps half of all non- antibiotic prescription drugs act at these receptors.
- 7. Netter’s illustrated pharmacology SelectedG Protein Coupled Receptor/Ligands Hormones Thyroid hormone Parathyroid hormone FSH Vasopressin LH ACTH Glucagon Autocoids: Histamine 5-HT Leukotrienes Bradykinin Autonomic Nervous Control: Muscarinic Cholinergic Receptors Epinephrine Others: Angiotensin Melatonin Adenosine Dopamine Glutamate Neuropeptide Y GABA Somatostatins Opioids
- 8. Structure: GPCRs share acommon structural signature of seven hydrophobic transmembrane segments, with an extracellular amino terminus and an intracellular carboxyl terminus Netter’s illustrated pharmacology
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- 10. A:Rhodopsin family: Short extracellular(N terminal) tail. Ligand binds to transmembrane helices (amines) or to extracellular loops (peptides) The largest group. Receptors for most • amine neurotransmitters, • many neuropeptides, • purines • prostanoids • cannabinoids
- 11. B:Secretin/glucagon receptor family: Receptors forpeptide hormones • secretin • glucagon • calcitonin Intermediate extracellular tail incorporating ligand-binding domain
- 12. C:Metabotropic glutamate receptor/ calciumsensor family Smallest group • Metabotropic glutamate receptors • GABAB receptors • Ca2+-sensing receptors Long extracellular tail incorporating ligand-binding domain
- 13. The transducer mechanism Ligandreceptor interaction Second Messenger pathway Protein activation
- 14. Rang et al:Rang & Dale’s Pharmacology 7e
- 15. G-protein subunits withsecond messenger β γα Gs Gi Gq cAMP stimulation β receptor Histamine Serotonin Dopamine cAMP inhibition α2 receptor M2 receptor Opioid receptor D2 receptor 5HT1 receptor PLC (IP3 & DAG) α1 M1 AT1 5HT2 Vasopressin •Activate potassium channels • Inhibit voltage- gated calcium channels • Activate mitogen- activated protein kinase cascade.
- 17. The adenylyl cyclasesystem • cAMP is a nucleotide • Synthesized within the cell from ATP by membrane- bound, adenylyl cyclase • Produced continuously • Inactivated by hydrolysis to 5´-AMP, by the Phosphodiesterase • Common mechanism, namely the activation of protein kinases
- 18. Effect of Glycogenon the muscle cell Rang et al: Rang & Dale’s Pharmacology 7e
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- 20.
- 22. Phospholipase-c signaling system PIP2 IP3DAG Release of Ca+2 from ER intracellular Ca+2 Along with Ca+2 Activate Protein Kinase-C Cellular functions- Proliferation, differentiation, apoptosis, cytoskeletal Remodeling, vesicular trafficking, ion channels conductance, neurotransmission PLC
- 23.
- 24. Targets that actthrough PLC and IP3 Acetylcholine M1 Glutamate Platelet derived growth factor Angiotensin II Vasopressin Serotonin 5 HT 2C Oxytocin Histamine H1 GnRH α1 Adrenergic agonist Rang et al: Rang & Dale’s Pharmacology 7e
- 25. Effect of Toxins GαsActivated by cholera toxin which blocks GTPase activity Gαi Blocked by pertussis toxin and prevents dissociation of αβϒ complex Gαo? Blocked by pertussis toxin Rang et al: Rang & Dale’s Pharmacology 7e
- 26. G protein gatedIon Channels • G-protein-coupled receptors can control ion channel function directly. (A) Typically, the activated effector protein begins a signaling cascade which leads to the eventual opening of the ion channel. (B) The GTP-bound α-subunit in some cases can directly activate the ion channel. (C) In other cases, the activated βγ-complex of the G protein may interact with the ion channel.
- 27. Increase Ca++ DecreaseCa++ Increase K+ Adrenergic β1 (Heart) Dopamine D2 Adrenergic α2 Adenosine A1 Muscarinic M2 GABA-B Dopamine D2 Somatostatin 5-HT 1A Opioid K GABA B
- 28. Receptor desensitization Often, theeffect of a drug gradually diminishes when it is given continuously or repeatedly • change in receptors • translocation of receptors • exhaustion of mediators • increased metabolic degradation of the drug • physiological adaptation • active extrusion of drug from cells
- 29. Rang et al:Rang & Dale’s Pharmacology 7e
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- 31. Orphan GPCRs • 200or so known GPCRs whose endogenous ligands and functions are not known • Attempts have been made to deorphanise these receptors • Evidence that some recently deorphanised GPCRs, such as orexin receptor, may dimerise or associate with more classical GPCRs
- 32. British Journal ofPharmacology (2008) 153 S339–S346
- 33. GPCR mutations, diseaseand novel drug discovery • Loss of function mutations in GPCRs involved in the control of endocrine systems • Gain of function mutations in GPCRs also cause disease • Mutations in GPCRs could be responsible for variations in drug sensitivities among different populations
- 34. mAbs 2:6, 594-606;November/December 2010; © 2010 Landes Bioscience
Editor's Notes
- #16 βγ-mediated effects occur at higher levels of receptor occupancy than α-mediated effects otherwise the action of it is same to alpha
- #19 These varied effects are, however, all brought about by a common mechanism, namely the activation of protein kinases by cAMP. Protein kinases regulate the function of many different cellular proteins by controlling protein phosphorylation
- #23 An intracellular enzyme play an imp. Role in signal transduction participate in phosphatidylinositol 4,5-bisphosphonate(PIP2) and lipid signaling in a calcium dependent manner.