Receptor- ligand gated,enzyme linked, nuclear.

PHARMACOLOGY DRUG RECEPTOR
LIGAND GATED RECEPTOR
ENZYME LINKED RECEPTOR
NUCLEAR RECEPTOR

1. Ligand gated receptor Enzyme linked receptor Nuclear receptor DR MANISH MOHAN

2. LIGAND-GATED ION CHANNELS Ionotropic receptors. Nervous system -excitatory ( Ach , glutamate) - inhibitory( glycine or GABA) Fast synaptic transmission E.g. - Nicotinic Acetylcholine receptor at NM junction. - GABA A receptor

3. Molecular structure Commonest- heteromeric assemblies of 4 or 5 subunits  e.g. -Pentameric – nAchr -Tetrameric –NMDA Transmembrane helices arranged around a central aqueous channel.

4. NICOTINIC ACETYLCHOLINE RECEPTOR Molecular structure Nicotinic acetylcholine receptor- pentameric ( α, β, γ and δ) 2 acetylcholine binding sites. Each subunit contains 4 membrane-spanning α-helices.

5. Gating mechanism Ligand binding Conformational change Channel opening Ion flow Depolarization/hyperpolarization

6. NICOTINIC ACETYLCHOLINE RECEPTOR

7. ENZYME LINKED RECEPTOR

8. Enzyme linked receptor…. Activation - growth factor, cytokines, hormones Effects – gene transcription Basic structure- Events –cell growth and differentiation   Single membrane spanning helical region

9. Enzyme linked receptor types- 1 . Receptor tyrosine kinases (RTKs) - insulin, EGF Cytokine receptors ( JAK-STAT ) - γ- interferon , prolactin 3. Receptor serine/threonine kinases - TGF 4 . Others ( Toll-like Receptors, TNF- α)

10. Receptor tyrosine kinases (RTKs)- Large, cysteine-rich extracellular domains. Short transmembrane domains. The intracellular region containing tyrosine kinase domains. E.g.- growth factor and ephrin

11. GATING MACHANISM Agonist binding    Dimerization autophosphorylation Binding and phosphorylation of SH2 bound protein RAS/RAF activation Gene transcription

12. CLINICAL SIGNIFICANCE- Imatinib - Chronic myeloid leukemia - GIST Sunitinib-   renal cell carcinoma  (RCC) -  imatinib -resistant GIST

13. Cytokine receptors ( JAK-STAT Receptor) • These receptors have no intrinsic enzymatic activity. • Intracellular domain - intracellular tyrosine kinase (JAK). • JAKs phosphorylate other proteins termed STATs.. • E.g.- γ- interferon, prolactin .

14. GATING MECHANISM Cytokine binding Dimerization of receptor Activation of Jak Binding and phosphorylation of STATs Dimerization of STAT Gene transcription

15. Clinical significance – under trial Baricitinib   - Rheumatoid arthritis ( Jak 1 and Jak2) 2. Filgotinib – Crohn's disease (jak1 )

16. Receptor serine/threonine kinases- Analogous to the receptor tyrosine kinases Phosphorylation of serine and/or threonine The activated receptor , phosphorylates SMAD e.g. TGF-β

17. MECHANISM OF ACTION Agonist binding Dimerization of receptor Phosphorylation of kinase Phosphorylation of SMAD Gene transcription

18. CLINICAL SIGNIFICANCE Under trial (phase 3) SELUMETINIB -differentiated thyroid cancer -K-Ras protein mutated non-small cell lung cancer.

19. Toll-Like Receptors- Signaling related to the innate immune system. • Highly expressed in hematopoietic cells. Ligands - pathogen products (lipids, peptidoglycans, lipopeptides) and viruses. Activation of these receptors produces an inflammatory responses

20. MECHANISM OF ACTION Ligand-induced dimerization MAL/MyD88 recruitment ( IRAKs autophosphorylation) TRAF6 activation Interaction with TAB1 and TAK1 Phosphorylation of the NF- κ B Transcription

21. Clinical significance Imiquimod (TLR 7 AGONIST) -basal cell carcinoma -actinic keratosis -genital warts

22. Receptor Guanylyl Cyclase Smallest family of transmembrane receptors Ligand binding stimulates intrinsic receptor guanylyl cyclase activity GTP is converted to cGMP E.g. B –type natriuretic peptide

23. NUCLEAR RECEPTORS

24. Nuclear receptors- NRs can directly interact with DNA - “ ligand activated transcription factors”. These transduce signals by modifying gene transcription. E.g. glucocorticoids, mineralocorticoids, Vit D and A

25. STRUCTURE

26. TYPES OF NUCLEAR RECEPTOR CLASS 1 CLASS 2 Location Cytosolic Nuclear Ligand binding Homodimers Heterodimers often with RXR Mechanism of action Translocation to nucleus. Binding to HREs Complexed with co-repressors, which are displaced following ligand binding, allowing the binding of trans activators E.G. Estrogen ( Er α ) Glucocorticoid( GR α ) Retinoid X (RXR α,β,γ ) Thyroid hormone (TR α,β )

27. MECHANISM –CLASS 1 RECEPTOR

28. MECHANISM OF ACTION –CLASS 1 Hormone binding Homodimerization(cytoplasm) Translocation to nucleus Binding to HRE Gene transcription

29. MECHANISM –CLASS 2 RECEPTOR

30. LIGANDS AND TARGET GENES RECEPTOR TYPE LIGAND DISEASE TARGET PPAR- α Fibrates ( clofibrate , fenofibrate) Hyperlipidemia PPAR- β Thiazolidinediones Type 2 DM GR Dexamethasone prednisolone Inflammatory syndromes

31. SUMMARY Ligand gated receptor Enzyme linked receptor - Tyrosine kinase receptor -JAK /stat receptor -Toll like receptor -Guanylyl cyclase receptor Nuclear receptor

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