Receptors

Receptors

1. Receptors By Dr Manjuprasad M.S Moderator: Dr Vijayalaxmi MK 1

2. overview Definition Theories Types GPCRs 2

3. definition The component of a cell or organism that interacts with an agonist and initiates the chain of events leading to agonist observed effects. 3

4. Occupation theory: The interaction between the 2 molecules ie drug and receptor to be governed by law of mass action and the effect to be a direct function of drug receptor complex D+R DR E 4

5. Intensity of response is proportional to the fraction of receptors occupied by the drug and maximal response occurs when all receptors are occupied Drugs exert All or none phenomenon A drug and receptor have a complementary structural features like lock and key this theory just gave a fundamental concept 5

6. Rate theory Magnitude of response depends upon rate of agonist/ receptor association and dissociation. 6

7. types GPCR`s Ligand gated ion channels/ ionotropic receptor Kinase linked receptors Nuclear receptors 7

8. GPCR It was discovered by Alfred G.Gilman and Martin Rodbel for which they won nobel prize in physiology in 1994. There are about more than 1000 known GPCRs 8

9. GPCRs are divided into three distinct families. There is considerable sequence homology between the members of one family, but none between different families. All have same seven-helix structure, but differ in other respects, principally in the length of the extracellular N terminus and the location of the agonist binding domain. 9

10. Group I, the largest group, contains the receptors for catecholamines , peptide hormones, neuropeptides , and glycoproteins . Group II, contains the  secretin /glucagon/ vasoactive  intestinal peptide receptor family. Group III contains the metabotropic receptors ( eg , calcium-sensing and glutamate receptors) 10

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12. G-protein-coupled receptors consist of a single polypeptide chain of up to 1100 residues . comprises seven transmembrane α-helices, with an extracellular N-terminal domain of varying length, and an intracellular C-terminal domain. 12

13. The helices are connected by 3 loops, both intra and extracellularly . 3 rd cytoplasmic loop couples to G-protein. ( heterotrimeric GTP binding proteins) In synthesis of GPCR, during mRNA splicing, additions/deletions/substitution of bases lead to variation in specificity of receptor. Leads to functional selectivity. 13

14. G proteins 2 Types Heterotrimeric referred to as large G proteins that are activated by GPCRs and are made up of α , γ and β . Small G proteins or monomeric belong to Ras superfamily of small GTPases involved in signal transduction. 14

15. Associated with guanine nucleotides – GTP and GDP. α subunit interacts with GTP/GDP and also has enzymatic action. Remain as a complex due to addition of hydrophobic groups 15

16. G protein α lpha G α s  , G α olf   : activates plasma membrane adenylyl cyclases , increasing cAMP , which stimulates phosphorylation of target proteins Gα s   and its downstream signaling can be covalently activated by cholera toxin . 16

17. Gα i   , Gα o   : inhibit most adenylyl cyclases , decreasing cellular cAMP .   Gα i   and Gα o   can be covalently inactivated and their signaling turned off by Pertussis toxin.  17

18. G α q  , G α 11  : activate phospholipase C β Gα 12  , Gα 13  : enhance Rho kinase and change expression of some genes  G α transducin : activates cGMP phosphodiesterase that cleaves and depletes cytoplasmic cGMP (retina only) G α gustducin:activates cAMP phosphodiesterase that cleaves and depletes cAMP (taste receptors) 18

19. Mechanism of action 19

20. Targets for G- proteins Adenylyl cyclase Phospholipase C Ion channels Rho A/Rho Kinase MAP Kinase 20

21. Adenylyl cyclase 21

22. Forskolin and fluoride ions can directly activate cAMP PDEs like theophylline , Rolipram , milrinone can act indirectly by decreasing cAMP degradation. 22

23. Phospholipase c 23

24. Ex: vasopressin on liver cells. Muscarinic and α adrenoceptor agonists acting on smooth muscle and salivary glands. 24

25. Ion channels Can directly act on ion channels , without 2 nd messengers. Especially influence K + and Ca + channels.ex : m2 AChR in cardiac muscle – enhance K + permeability. Inhibitory drugs like opioids . 25

26. Rho/ Rho kinase system Couples to G 12-13 subtype Free G α interacts with guanosine nucleotide exchange factor, facilitates GTP-GDP exchange in Rho kinase . Rho kinase involved in Pulmonary HTN. Fasudil - under trials for use in Rx of Pulmonary HTN. 26

27. MAP kinase Involved in cell division, apoptosis , and tissue regeneration . 27

28. Receptor desensitisation Phosphorylation Receptor agonist complex internalization 28

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30. Protease activated receptors Four types of protease-activated receptors (PARs), have been identified. Eg.Thrombin activate PARs by snipping off the end of the extracellular N-terminal tail of the receptor to expose five or six N-terminal residues that bind to receptor domains in the extracellular loops 30

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32. It is thought to play a role in inflammatory pain. A PAR molecule can be activated only once, because the cleavage cannot be reversed Inactivation occurs by a further proteolytic cleavage, or by desensitisation , involving phosphorylation . 32

33. GPCR mutations in diseases Calcium sensing receptor: autosomal dominant hypocalcemia CXCR 4 : target of HIV Endothelin receptor B( Etb ) : hirschsprung’s disease Rhodopsin : in Retinitis pigmentosa . 33

34. BIBLIOGRAPHY Goodman and Gilman – 12 th edition Introduction to Physiology- Guyton – 11 th edition Essentials of medical pharmacology – K.D.Tripathi Rang and Dales pharmacology 7 th edition Textbook of medical pharmacology – Padmaja udaykumar Basic clinical pharmacology Katzung 11 th edition Uptodate.com 34