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P2Y receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [2-3,41]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y6 is mainly activated by UDP; P2Y14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [70]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca2+ from intracellular stores. P2Y11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y12, P2Y13, and P2Y14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [70]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [53], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [14,65].
Receptors
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P2Y1 receptor
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P2Y2 receptor
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P2Y4 receptor
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P2Y6 receptor
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P2Y11 receptor
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P2Y12 receptor
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P2Y13 receptor
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P2Y14 receptor
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Further reading
* Key recommended reading is highlighted with an asterisk
* Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA et al.. (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev, 58 (3): 281-341. [PMID:16968944]
Burnstock G. (2007) Purine and pyrimidine receptors. Cell Mol Life Sci, 64 (12): 1471-83. [PMID:17375261]
Burnstock G, Verkhratsky A. (2012) Purinergic signalling and the nervous system. In (Springer) 1-715.
Erlinge D. (2011) P2Y receptors in health and disease. Adv Pharmacol, 61: 417-39. [PMID:21586366]
Jacobson KA. (2013) Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates. J Med Chem, 56 (10): 3749-67. [PMID:23597047]
* Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, Miras-Portugal MT, Novak I, Schöneberg T, Perez-Sen R et al.. (2020) Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol, 177 (11): 2413-2433. [PMID:32037507]
Jacobson KA, Ivanov AA, de Castro S, Harden TK, Ko H. (2009) Development of selective agonists and antagonists of P2Y receptors. Purinergic Signal, 5 (1): 75-89. [PMID:18600475]
* Jacobson KA, Paoletta S, Katritch V, Wu B, Gao ZG, Zhao Q, Stevens RC, Kiselev E. (2015) Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. Mol Pharmacol, 88 (2): 220-30. [PMID:25837834]
von Kügelgen I, Harden TK. (2011) Molecular pharmacology, physiology, and structure of the P2Y receptors. Adv Pharmacol, 61: 373-415. [PMID:21586365]
* von Kügelgen I, Hoffmann K. (2016) Pharmacology and structure of P2Y receptors. Neuropharmacology, 104: 50-61. [PMID:26519900]
Weisman GA, Woods LT, Erb L, Seye CI. (2012) P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS Neurol Disord Drug Targets, 11 (6): 722-38. [PMID:22963441]
References
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73. Yerxa BR, Sabater JR, Davis CW, Stutts MJ, Lang-Furr M, Picher M, Jones AC, Cowlen M, Dougherty R, Boyer J et al.. (2002) Pharmacology of INS37217 [P(1)-(uridine 5')-P(4)- (2'-deoxycytidine 5')tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis. J Pharmacol Exp Ther, 302 (3): 871-80. [PMID:12183642]
74. Zech G, Hessler G, Evers A, Weiss T, Florian P, Just M, Czech J, Czechtizky W, Görlitzer J, Ruf S et al.. (2012) Identification of high-affinity P2Y₁₂ antagonists based on a phenylpyrazole glutamic acid piperazine backbone. J Med Chem, 55 (20): 8615-29. [PMID:22984835]
75. Zhang D, Gao ZG, Zhang K, Kiselev E, Crane S, Wang J, Paoletta S, Yi C, Ma L, Zhang W et al.. (2015) Two disparate ligand-binding sites in the human P2Y1 receptor. Nature, 520 (7547): 317-21. [PMID:25822790]
76. Zhang K, Zhang J, Gao ZG, Zhang D, Zhu L, Han GW, Moss SM, Paoletta S, Kiselev E, Lu W et al.. (2014) Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature, 509 (7498): 115-8. [PMID:24670650]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Maria-Pia Abbracchio (Chairperson)
Kenneth A. Jacobson (Co-chairperson)
Geoffrey Burnstock (Past chairperson)
Jean-Marie Boeynaems
Stefania Ceruti
Marta Fumagalli
Christian Gachet
Brian F. King
Davide Lecca
Christa E. Müller
Gary A. Weisman |
Other contributors:
José L. Boyer
Rebecca Hills
Robert G. Humphries
Kazu Inoue
Maria Teresa Miras-Portugal
Vera Ralevic |
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Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
A series of 4-alkyloxyimino derivatives of uridine-5'-triphosphate which could be useful for derivatization as fluorescent P2Y2/4/6 receptor probes has been synthesized [45].
Single nucleotide polymorphisms of the P2YR1 gene have been associated to different platelet reactivity to ADP [32]. Three frequent nonsynonymous P2Y2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca2+ influx in transfected cells, and might therefore play a role in disease development [13]. ATP acts as partial agonist/antagonist at the human P2Y4 receptor [70]. Although UTP was also shown to be a biased agonist at P2Y11, this is still under debate [61,72]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype that is approved in Japan and South Korea for the management of dry eye disease [53], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [14, 65]. A group of single nucleotide polymorphisms in the P2Y12 gene, forming the so called P2Y12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [18]. The platelet-type bleeding disorder due to P2Y12 receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [17]. The P2Y13 receptor Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y12 locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [4]. The P2Y14 receptor, previously considered to exclusively bind sugar nucleotides such as UDP-glucose, UDP-galactose, UDP-glucuronic acid and UDP-N-acethyl-glucosamine [19], has been demonstrated to bind also UDP [15]. UDP was also shown to competitively antagonise the UDP-glucose response at the human recombinant P2Y14 receptor [28].