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GENETIC VARIATION IN GPCR
This document presents a seminar by R. Rekha on genetic variations in G-protein coupled receptors (GPCRs) and their implications in pharmacology and disease. It discusses the structure, function, and polymorphisms of GPCRs, emphasizing their role in signaling pathways and disease associations. Specific examples of genetic mutations affecting receptor functionality and related medical conditions are also provided.
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GENETIC VARIATION IN GPCR
- 1. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 1 A Seminar as a part of curricular requirement For 1 year M. Pharm 1 semester Presented by R. REKHA (Reg. No. 20L81S0111) Under the guidance/Mentorship of Dr. K. SOMASEKHAR REDDY, M.Pharm., Ph.D, Associate professor And Head of Department of pharmacology GENETIC VARIATION IN GPCR
- 2. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 2 • Introduction • G-Protein couple Receptor • Genetic variation in GPCRs • V2 Vasopressin Receptor • Thrombroxane Receptor • P2Y 12ADP Receptor • Chemokine Receptor • Biogenic amine receptors • References Contents
- 3. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 3 • G-Protein also known as guanine nucleotide-binding proteins. • family of protein that act as a molecular switches inside the cell. • Activity regulated by factors that controls their ability to bind to and hydrolyze GTP into GDP. • When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPase. • There are two classes of G proteins a. monomeric small GTPase b. heterotrimeric G protein complexes (alpha (α), beta (β) and gamma (γ) subunit) Introduction
- 4. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 4 Structure of GPCR
- 5. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 5 1.Sequence variations of the human genome: • Introduces variability in genetic make-up • Suspected to play a main role in diseases & variable response in drug therapy • Polymorphism- refers to sequence variation leading to occurrence of two or more clearly different forms. • Single nucleotide polymorphism accounts for approx. 80% of all sequence variations. Genetic variations may be due to
- 6. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 6 • Comprises a large class of membrane proteins – encoded by approx. 600 human genes. • Molecular architecture might permit the prediction of functionally relevant domains where sequence variations are more likely to alter receptor function. • Normally, TM domains are highly conserved, the loops are variable in sequence & length, &the C- and N-terminals tails represents the most diverse elements. Structure & function of GPCRs
- 7. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 7 • GPCR limited by the primary sequence and teritary structure • GPCR thought to be couple to heterotrimeric G proteins composed of α, β and γ subunits. It display considerable heterogenecity, with a predicted number of 27 different α, 5 β and 13 γ subunits. • Main sites of contact between receptor and G proteins include the third intracellular loop, but i1, i2 and the C- terminus have also been reported to contribute G protein coupling • Proteins like protein kinases, arrestin & phosphatases modulates receptor functions at distinct domains that are possible targets for polymorphic effects. GPCR coupling to G proteins and other signaling pathways
- 8. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 8 • Ca++, acetyl choline, glutamate, bradykinin, prostaglandins, & the large polypeptide FSH bind to the same site. • Distinct binding sites appear to exist, either embedded within the pocket formed by the 7- TMD bundle within the membrane, at pockets formed by the extracellular loops, or in the N- terminus. • The thrombin receptor family represents a special case whereas the protease activity of the ligand thrombin cleaves a portion of the N- terminus. The newly generated N-terminus then serves as a tethered ligand. GPCR binding pockets
- 9. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 9 • GPCRs appear to be activated by ligand binding to many different sites of the protein . • At the opioid receptors, peptide endorphins bind primarily to the extracellular loops, whereas opioid alkaloids dock deep into the 7- TMD core. • Sequence variation in the receptor protein can affect ligand binding or the structural integrity of the receptor , indirectly changing ligand binding Human µ opioid Receptor: • Sequence variation in the receptor protein can affect ligand binding or the structural integrity of the receptor , indirectly changing ligand binding
- 10. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 10 • Exchange of single amino acid residues can lead to constitutive receptor activation. • Considerable number of human polymorphisms enhance signalling (gain of function) or even activate the receptor constitutively, causing serious genetic disorders. Spontaneous GPCR signalling:
- 11. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 11 • GPCRs are flexible structures and may accommodate ligands in various ways. • It exists in multiple conformations. • Discrete signalling pathways are triggered by discrete conformational states of GPCR Multiple receptor conformations with distinct functions
- 12. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 12 Sequence variations of GPCRs and associated diseases .
- 13. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 13 Several inactivating sequence variants of peptide receptors have been associated with congenital disorders For example, 1. A point mutation causing trunsduction of thyrotropin stimulating hormone receptor leads to leydig’s cell hyperplasia.(activating mutation) Truncated TM5, D578G, T398M 2. Inactivating mutations of the ACTH receptor are associated with familial glucocorticoid deficiency . 3.The mutation occurs in the large N-terminus , the binding site for glycoprotein hormone receptor, leading to toxic multinodular goiter. S120R, R201Stop, S74I, V254C Impaired or enhanced agonist signalling efficacy:
- 14. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 14 V2 vasopressin receptors • A number of mutations in the gene encoding the V2 vasopressin receptor leads to functionally inactive receptor protein and are causative for nephrogenic diabetes insipidus.(missense mutations) • This a clear indication that receptor activity depends on intact signalling pathways.(multiple SNPs; decreased ligand binding.
- 15. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 15 • This receptor performs an essential role in haemostasis by inducing platelet aggregation. • An R60L amino acid substitution in the first cytoplasmic loop of TBXA2 receptor causes a dominantly inherited bleeding disorder characterised by defective platelet response to TBXA2. • This leads to decreased agonist-induced second messenger formation. Thromboxane A2 Receptor
- 16. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 16 • This receptor sub-type is shown to be the target for anti-thrombotic drugs such as ticlodipine & clopidogrel. • 2-nucleotide deletion in a region mapping to the end of TMD6, associated with a rare bleeding disorder. P2Y 12ADP Receptor
- 17. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 17 Fusin and CKR5 have been identified as a co- receptors for the cellular entry of HIV. Similarly , certain chemokines were found to block HIV entry into cells. • Natural resistance can be either by high endogenous levels of chemokines or by mutations of the receptors. • A 32 bp deletion in CKR5 leading to a frame shift and a non functional protein appeared to protect homozygous carriers against HIV infection & blocking its entry. • Val 64 substitution with Ile was shown to result in heterodimerisation of CCR2 with CCRorCXCR4,thereby promoting resistancetoAIDS Chemokine receptors
- 18. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 18 • The R16G substitution in the β2 adrenoreceptors has been associated with nocturnal asthma whereas W64R in the β3 receptor expressed in adipocytes are involved in energy metabolism – is linked with obesity. Biogenic amine receptors
- 19. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 19 I. Sela, G. Golan, M. Strajbl, meenakshi gupta, G-protein couple receptor 2017;10;5 II. D. Rivenzon-segal, S.Bar-Haim, I. Bloch, B. Inbal, A. Sahitrit, E. Ben- Zeev,, M. Fithman, Y. Markus, H. Senderowitz, O. Kales. Genetic variations of g-protein couple receptor. Current Topics in Medicinal Chemistry, 2010;10;6 References
- 20. RIPER AUTONOMOUS NAAC & NBA (UG) SIRO-DSIR Raghavendra Institute of Pharmaceutical Education and Research - Autonomous K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 20