Molecular Mechanisms of Drug Action and Cell Signaling
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This document discusses cellular signalling and molecular mechanisms of drug action. It describes the different types of cell signalling including extracellular signals like hormones and intracellular signals like calcium and cyclic nucleotides. It also explains different receptor types like G-protein coupled receptors and ligand-gated ion channels. Additionally, it covers molecular mechanisms of drug action like receptor occupancy models and transducer mechanisms. Finally, it discusses ion channels involved in cellular signalling like sodium, calcium and potassium channels as well as their pharmacological modulation.
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Molecular Mechanisms of Drug Action and Cell Signaling
- 1. MOLECULAR MECHANISM OF DRUG ACTION
- 2. CELLULAR SIGNALLING What is cell signalling Cell signalling within, between & among the cell & their classification A. EXTRACELLULAR- protein, peptides, AA, hormones, PG, Steroids, etc 1) Intracrine – signal produced & stayed in target cell itself 2) Autocrine – target cell, are secreted and effects on target cell via receptor 3) Paracrine - target cell in viscinity,,,eg Neurotransmitter Local chemical mediators- GF, PG 4) Endocrine- duct, hormone,distant cell-- insulin, thyroxine, adrenaline 5) Juxtracrine- signal targets adjascent cell 6) Gaseous- NO, CO 7) Neuronal- synapses
- 4. B. INTRACELLULAR • Ca2+ : ions • DG, ceramide : lipid derivatives • IP3 : carbohydrate derivatives • cAMP cGMP : nucleotides • Ras, JAK, Raf : proteins SECOND MESSENGER Ca2+,DAG, Ceramide, IP3, cAMP, cGMP THIRD MESSENGER- transmit signal from outside to inside or inside to outside of nucleus/ DNA binding protein
- 5. MOLECULAR MECHANISM OF DRUG ACTION RECEPTOR OCCUPANCY :- The receptor concept Nature of drug receptor interaction 1.Receptor occupancy model- Law of mass action More receptor occupied more effect at equilibrium
- 6. 2.two state receptor model- inactive and active 3.ternary complex model- ligand,receptors and G-protein 4. competitive inhibitory model.
- 7. TRANSDUCER MECHANISM What are receptors ? Able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules. Glycoprotein / lippoprotein 1. G-Protein coupled receptors 2. ligand gated Ion channel receptors 3. Enzyme linked receptor 4. Nuclear/Steroidal receptor
- 8. LIGAND GATED ION CHANNEL RECEPTORS
- 9. LIGAND GATED ION CHANNEL RECEPTORS Nicotinic acetylcholine receptor NMDA- type glutamate receptor Glycine receptor GABAA receptor Serotonin receptor (5-HT3)
- 10. NMDA- type glutamate receptors
- 11. ENZYME LINKED RECEPTORS 1. Intrinsic tyrosine kinase receptors 2. JAK-STAT kinase binding receptors
- 13. CYCLIC NUCLEOTIDES cAMP - 3’5’-cyclic adenosine monophosphate, cGMP- 3’5’-cyclic guanosine monophosphate, cCMP- cytidine 3',5'-monophosphate, and cUMP- uridine 2',3'-cyclic phosphate. cyclic nucleotide Known binding proteins Pathway/Biological association cAMP 1.protein kinase A 2.cyclic nucleotide-gated ion channels 3.Epac 4.Catabolite Activator Protein (CAP) 1.smooth muscle relaxation[14] 2.photo/olfactory receptors[3] 3.glucagon production in pancreatic beta cells[15] 4.lac operon regulation in E. coli[16][17] cGMP 1.cGMP-dependent protein kinase (PKG) 2.cyclic nucleotide-gated ion channels 1.smooth muscle relaxation[14] 2.photo/olfactory receptors[3] cCMP 1.cGMP kinase I 1.smooth muscle [12][18]
- 15. CALCIUM Calcium- major intracellular cation Calcium – heart (ion channel) As second messenger Role of Calcium at – Skeletal Muscle neurone
- 17. IP3 AND DAG
- 18. IP3-DAG PATHWAY
- 19. ION CHANNELS AND THEIR MODULATORS Sodium Calcium Potassium Types – voltage gated or ligand gated Modulators- 1. SODIUM ION- a) Voltage Gated b) Ligand gated - Role in Action potential
- 21. DIVERSITY- Subunits- a) alpha subunit b) Beta subunit Sr.n o Protein name gene Expression profile associated 1 Nav 1.1 SCN 1A Central & peripheral neuron, myocytes Febrile epilepsy 2 Nav 1.1 SCN 2A -’’- Inherited seizures 3 Nav 1.3 SCN 3A -”- ------ 4 Nav 1.4 SCN 4A -”- Paralysis,myotoni a 5 Nav 1.5 SCN 5A Cardiac myocytes, central neuron Long QT syndromes
- 22. Sr.no Protein name gene Expression profile Associated 6 Nav 1.6 SCN 8A Skeletal muscle Epilepsy 7 Nav 1.7 SCN 9A DRG Fibromyalgia 8 Nav 1.8 SCN 10A DRG ------------ 9 Nav 1.9 SCN 11A DRG ------------- 10 Nax SCN 7A Heart,uterus,SM -------------- -- β-subunit Nav β1-- Nav β4
- 23. PHARMACOLOGICAL MODULATION Activators- Aconitine Batracotoxin Brevetoxin Ciguatoxin Veratridine Gating modifiers- Peptide based toxin- µ-conotoxin Δ-atracotoxin Scorpian venum Blocker- Class-1 A- Quinidine, procainamide B- Lidocaine C- propafenone
- 25. VOLTAGE GATED CALCIUM CHANNEL type voltage Αlpha 1- subunit Genes occurance L-type High volt. Activated(HVA ) α2, δ,β,γ Cav 1.1-1.4 SM, dendrites & spines P-type Or Q-type HVA α2, δ,β Cav2.1 Purkinje neurones,cerebellar granules N-type HVA α2, δ/β, β3,β4 Cav2.2 Trough out brain R-type Intermidiate voltage α2, δ,β Cav2.3 Cerebellar granule cells T-type Low voltage ----------- Cav3.1-3.3 Bones, neuronal cell having pacemaker activity
- 26. Sr no. type Gated by gene location Function 1 IP3 IP3 ITPR1-3 ER/SR Release ca+ 2 Rynodine receptor DHPR,in T- tubule RyR1-3 ER/SR Release in myocytes 3 Two pore channel ------- ---------------- ----- ------------- ------- 4 Store operated Indirectly by ER/SR depletion of ca+ ORAI1-3 Plasma membrane -------- LIGAND GATED CALCIUM CHANNEL
- 27. PHARMACOLOGY OF CALCIUM CHANNEL Calcium channel blockers- 1. L-type- DHPD, phenylalkylamines, benzothiazepines. 2. P/Q – type- ω-Agatotoxin 3. N- type- ω-conotoxin 4. R-type-SNX 482 5. t-type- ethosuccimide Activators– GPCR , Calcium etc.(may be)
- 28. POTASSIUM CHANNEL Structure and types:- a.2T1P, b.6T1P, c.8T2P, d.4T2P
- 29. K CHANNEL
- 30. K CHANNEL class subclass function blocker Activators Ca+ Activated 6T&1P BK Sk Decrease then increase intracellular calcium Cellular calcium Charybdotoxin apamin 1-EBIO NS309 CYPPA Inwardly rectifying 2T&1P ROMK GPCR regulated Kir ATP sensing Recification& secretion of K Mediate or inhibit effects of GPCR Close when high ATP -- Ifenprodil Tolbutamide etc ---- GPCR agonist pinacidil Tandem pre domain 4T&2P TWICK TREK TASK TALK 1&2 THICK & TESK Resting mem. Pot. bupivacaine Halothane Voltage gated hERG(Kv11.1) Repolarisation Tetraethyl ammonium Ritagabine
- 31. THANK YOU