Class receptors 1&2


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Class receptors 1&2

  2. 2.  Receptor is defined as a macro molecule or an assembly of macro molecules 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.
  3. 3. TRANSMEMBRANE RECEPTORS METABOTROPIC RECEPTORS  G protein-coupled receptors  Muscarinic acetylcholine receptor (Acetylcholine and M uscarine)  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)
  4. 4. 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 receptor Intra cellular ligands  cyclic nucleotide-gated ion channels  IP3 receptor  IntracellularATP receptors  Ryanodine receptor
  5. 5. Receptor tyrosine kinases These 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
  6. 6.  Affinity  Efficacy  Agonists  Partial agonists  Antagonists  Inverse agonists  Antagonists
  7. 7.  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.
  8. 8. When the hormone binds to the receptor conformat Ional 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.
  9. 9. ligand binding changes the confirmation of the receptor so 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
  10. 10.  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)
  11. 11. Lipid soluble ligands that Penetrate cell mmb Receptors 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
  12. 12.  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
  13. 13.  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
  14. 14.  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
  15. 15.  Potential molecular target for medicines  May bind to allosteric site  ACE inhibitors  AChE inhibitors
  16. 16.  Open, Closed  Refractory  Local anaesthetics,  antianginal drugs,  Antiarrhythmic drugs
  17. 17.  time dependent response  Desensitization is generally reversible  Slow confirmational change  Inability to activate adenylate cyclase
  18. 18.  Down regulation-Prolonged exposure to high concentration of agonist reduction in number of receptors available for activationinternalisation  Up regulation-Prolonged occupation of receptor by antagonist leads to an increase in number of receptorsexternalisation
  19. 19. DISEASE DOWNREGULATION UPREGULATION ASTHMA-salbutamol ß adrenoceptor Depression-TCAs ß adrenoceptor α adrenoceptor Endogenous depression α adrenoceptor ß adrenoceptor Thyrotoxicosis –T3,T4 ß adrenoceptor
  20. 20.  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%
  21. 21.  Fast up regulation  Pharmacological basis of tardive dyskinesia  Long term dopamine receptor blockade  Supersensitive new dopamine receptors
  22. 22.  Myasthenia gravis  Insulin resistant diabetes  Testicular feminization
  23. 23. CHEMICAL ACTION  Neutralisation  Chelation  Ion exchangers PHYSICAL ACTION  Osmosis  Adsorption  Protectives  Demulcents  Astringents  Saturation in biophase
  24. 24.  By counterfeit or false incorporation mechanisms  By virtue of being protoplasmic poisons  Through formation of antibodies  Through placebo action  By targeting specific genetic changes