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Gene Review

P2RY12  -  purinergic receptor P2Y, G-protein coupled...

Homo sapiens

Synonyms: ADP-glucose receptor, ADPG-R, BDPLT8, HORK3, P2T(AC), ...
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Disease relevance of P2RY12

  • Here we show that at the relatively high concentration of agonist most likely found at the site of a local thrombus, dual inhibition of the P2Y12 receptor and calcium mobilization result in a complete inhibition of PAR4-induced aggregation, while having no effect on either thrombin or PAR1-mediated platelet aggregation [1].
  • HORK3, when transfected in the rat glioma cell subline (C6-15), responded to 2-methylthio-ADP (2MeSADP) (EC(50) = 0.08 nM) and ADP (EC(50) = 42 nM) with inhibition of forskolin-stimulated cAMP accumulation [2].
  • In conclusion, microaggregates of platelets via P2Y12 receptors could play a key role in the hypersensitivity of platelets in diabetic patients, and the measurement of microaggregation could be a useful marker to estimate of thrombogenesis [3].
  • The P2Y12-mediated stimulation of proliferation required the pertussis toxin-sensitive activation of PI3-kinase/Akt upstream of MAP-kinases [4].
  • Both analogues were inactive (IC50>10 microM) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells [5].

High impact information on P2RY12

  • The molecular identity of the Gi-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder has a defect in this gene [6].
  • Central role of the P2Y12 receptor in platelet activation [7].
  • This study was designed to determine the role of P2Y12 in platelet thrombosis and how its complete absence affects the thrombotic process [8].
  • Using an in vivo mesenteric artery injury model and real-time continuous analysis of the thrombotic process, we observed that the time for appearance of first thrombus was delayed and that only small, unstable thrombi formed in P2Y12-/- mice without reaching occlusive size, in the absence of aspirin [8].
  • The raft-associated P2Y12 oligomers represented the functional form of the receptor, as demonstrated by binding and signal transduction studies [9].

Chemical compound and disease context of P2RY12

  • Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well-established target of antithrombotic drugs like ticlopidine or clopidogrel, which have proved efficacy in many clinical trials and experimental models of thrombosis [10].
  • Further analysis of the rat brain pIC50 data against those available for three of the AR-C compounds in reversing P2Y12-mediated adenylyl cyclase inhibition in rat platelets (r2=0.96) and rat C6 glioma cells (r2=1.00) demonstrated that the three P2Y receptors are pharmacologically indistinguishable [11].

Biological context of P2RY12


Anatomical context of P2RY12


Associations of P2RY12 with chemical compounds

  • Other nucleotides were able to activate SP1999 with a rank order of potency 2-MeS-ATP = 2-MeS-ADP > ADP = adenosine 5'-O-2-(thio)diphosphate > 2-Cl-ATP > adenosine 5'-O-(thiotriphosphate) [15].
  • Besides the ADP analogue 2-MeS-ADP, other platelet agonists such as collagen and the TXA(2)-mimetic U46619 also induce p27 and p31 tyrosine phosphorylation in a P2Y12 receptor-dependent manner [13].
  • Blockade of ADP receptors, P2Y12 with AR-C69931MX and P2Y1 with A3P5P, respectively, further suppressed collagen-induced PMP formation [16].
  • P2Y12 is known to couple to activation of PI3 kinase and inhibition of adenylate cyclase, but we showed that neither of these signalling events couples to regulation of shape change by this receptor [19].
  • Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270 [20].
  • Stimulation of P2Y12 receptor or direct inhibition of diacylglycerol kinase potentiated the effect of membrane-permeable sn-1,2-dioctanoylglycerol on platelet aggregation and pleckstrin phosphorylation, in association with inhibition of its phosphorylation to phosphatidic acid [21].

Physical interactions of P2RY12

  • Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12 receptor [22].

Regulatory relationships of P2RY12

  • These results further demonstrate the P2Y1 receptor selectivity of MRS2365 and illustrate the occurrence of agonist-induced desensitization of the P2Y1 receptor of human platelets studied in the absence of P2Y12 receptor activation [22].
  • We conclude that P2Y12 plays a potentiatory role in ADP-induced shape change through regulation of the Rho kinase pathway, potentiating both myosin phosphorylation and actin polymerisation, and this forms part of an important signalling pathway additional to its well-established Gi-coupled pathways [19].
  • To address the mechanism that regulates alphavbeta3 activity in platelets, we measured the effect of the P2Y1 antagonist adenosine 3'-phosphate-5'-phosphate (A3P5P) and the P2Y12 antagonist AR-C66096 on ADP-stimulated platelet adhesion to osteopontin and vitronectin [23].
  • BACKGROUND: Insulin inhibits platelet aggregation by suppressing the P2Y12 pathway [24].

Other interactions of P2RY12

  • The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation [25].
  • ADP activates human platelets through two G-protein coupled receptors, P2Y1 and P2Y12, to induce a range of functional responses [19].
  • Activation of Rap1B induced by thrombin was not affected by preincubation of platelets with the anti-GPIbalpha monoclonal antibody AK2 in the absence of ADP scavengers or a P2Y12 antagonist but was totally abolished when secreted ADP was neutralized or after blockade of the P2Y12 receptor [26].
  • MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4nM at the P2Y1 receptor, with >10000-fold selectivity in comparison to P2Y12 and P2Y13 receptors [27].
  • Conversely, the P2Y12-mediated reorganization of the actin cytoskeleton was Gi-independent, requiring activation of RhoA and Rho-kinase [4].

Analytical, diagnostic and therapeutic context of P2RY12


  1. PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. Holinstat, M., Voss, B., Bilodeau, M.L., McLaughlin, J.N., Cleator, J., Hamm, H.E. J. Biol. Chem. (2006) [Pubmed]
  2. Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor. Takasaki, J., Kamohara, M., Saito, T., Matsumoto, M., Matsumoto, S., Ohishi, T., Soga, T., Matsushime, H., Furuichi, K. Mol. Pharmacol. (2001) [Pubmed]
  3. P2Y12 receptors play a significant role in the development of platelet microaggregation in patients with diabetes. Matsuno, H., Tokuda, H., Ishisaki, A., Zhou, Y., Kitajima, Y., Kozawa, O. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  4. Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor. Soulet, C., Sauzeau, V., Plantavid, M., Herbert, J.M., Pacaud, P., Payrastre, B., Savi, P. J. Thromb. Haemost. (2004) [Pubmed]
  5. Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor. Kim, Y.C., Lee, J.S., Sak, K., Marteau, F., Mamedova, L., Boeynaems, J.M., Jacobson, K.A. Biochem. Pharmacol. (2005) [Pubmed]
  6. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Hollopeter, G., Jantzen, H.M., Vincent, D., Li, G., England, L., Ramakrishnan, V., Yang, R.B., Nurden, P., Nurden, A., Julius, D., Conley, P.B. Nature (2001) [Pubmed]
  7. Central role of the P2Y12 receptor in platelet activation. Dorsam, R.T., Kunapuli, S.P. J. Clin. Invest. (2004) [Pubmed]
  8. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. Andre, P., Delaney, S.M., LaRocca, T., Vincent, D., DeGuzman, F., Jurek, M., Koller, B., Phillips, D.R., Conley, P.B. J. Clin. Invest. (2003) [Pubmed]
  9. The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Savi, P., Zachayus, J.L., Delesque-Touchard, N., Labouret, C., Hervé, C., Uzabiaga, M.F., Pereillo, J.M., Culouscou, J.M., Bono, F., Ferrara, P., Herbert, J.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Gachet, C. Pharmacol. Ther. (2005) [Pubmed]
  11. 2-Alkylthio-substituted platelet P2Y12 receptor antagonists reveal pharmacological identity between the rat brain Gi-linked ADP receptors and P2Y12. Vasiljev, K.S., Uri, A., Laitinen, J.T. Neuropharmacology (2003) [Pubmed]
  12. Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets. Hardy, A.R., Jones, M.L., Mundell, S.J., Poole, A.W. Blood (2004) [Pubmed]
  13. P2Y12 ADP receptor-dependent tyrosine phosphorylation of proteins of 27 and 31 kDa in thrombin-stimulated human platelets. Fälker, K., Lange, D., Presek, P. Thromb. Haemost. (2005) [Pubmed]
  14. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Cattaneo, M., Zighetti, M.L., Lombardi, R., Martinez, C., Lecchi, A., Conley, P.B., Ware, J., Ruggeri, Z.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. Zhang, F.L., Luo, L., Gustafson, E., Lachowicz, J., Smith, M., Qiao, X., Liu, Y.H., Chen, G., Pramanik, B., Laz, T.M., Palmer, K., Bayne, M., Monsma, F.J. J. Biol. Chem. (2001) [Pubmed]
  16. Collagen-induced generation of platelet-derived microparticles in whole blood is dependent on ADP released from red blood cells and calcium ions. Takano, K., Asazuma, N., Satoh, K., Yatomi, Y., Ozaki, Y. Platelets (2004) [Pubmed]
  17. Differential regulation and relocalization of the platelet P2Y receptors after activation: a way to avoid loss of hemostatic properties? Baurand, A., Eckly, A., Hechler, B., Kauffenstein, G., Galzi, J.L., Cazenave, J.P., Léon, C., Gachet, C. Mol. Pharmacol. (2005) [Pubmed]
  18. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Angiolillo, D.J., Fernandez-Ortiz, A., Bernardo, E., Ramírez, C., Cavallari, U., Trabetti, E., Sabaté, M., Jimenez-Quevedo, P., Hernández, R., Moreno, R., Escaned, J., Alfonso, F., Bañuelos, C., Costa, M.A., Bass, T.A., Pignatti, P.F., Macaya, C. Thromb. Res. (2005) [Pubmed]
  19. Evidence that the purinergic receptor P2Y12 potentiates platelet shape change by a Rho kinase-dependent mechanism. Hardy, A.R., Hill, D.J., Poole, A.W. Platelets (2005) [Pubmed]
  20. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Ding, Z., Kim, S., Dorsam, R.T., Jin, J., Kunapuli, S.P. Blood (2003) [Pubmed]
  21. The Gi-coupled P2Y12 receptor regulates diacylglycerol-mediated signaling in human platelets. Guidetti, G.F., Lova, P., Bernardi, B., Campus, F., Baldanzi, G., Graziani, A., Balduini, C., Torti, M. J. Biol. Chem. (2008) [Pubmed]
  22. (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human platelets. Bourdon, D.M., Mahanty, S.K., Jacobson, K.A., Boyer, J.L., Harden, T.K. J. Thromb. Haemost. (2006) [Pubmed]
  23. Concurrent signaling from Galphaq- and Galphai-coupled pathways is essential for agonist-induced alphavbeta3 activation on human platelets. Paul, B.Z., Vilaire, G., Kunapuli, S.P., Bennett, J.S. J. Thromb. Haemost. (2003) [Pubmed]
  24. Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. Angiolillo, D.J., Bernardo, E., Ramírez, C., Costa, M.A., Sabaté, M., Jimenez-Quevedo, P., Hernández, R., Moreno, R., Escaned, J., Alfonso, F., Bañuelos, C., Bass, T.A., Macaya, C., Fernandez-Ortiz, A. J. Am. Coll. Cardiol. (2006) [Pubmed]
  25. The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation. Nylander, S., Mattsson, C., Ramström, S., Lindahl, T.L. Thromb. Res. (2003) [Pubmed]
  26. Contribution of protease-activated receptors 1 and 4 and glycoprotein Ib-IX-V in the G(i)-independent activation of platelet Rap1B by thrombin. Lova, P., Campus, F., Lombardi, R., Cattaneo, M., Sinigaglia, F., Balduini, C., Torti, M. J. Biol. Chem. (2004) [Pubmed]
  27. Agonists and antagonists for P2 receptors. Jacobson, K.A., Costanzi, S., Joshi, B.V., Besada, P., Shin, D.H., Ko, H., Ivanov, A.A., Mamedova, L. Novartis Found. Symp. (2006) [Pubmed]
  28. P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Fontana, P., Gaussem, P., Aiach, M., Fiessinger, J.N., Emmerich, J., Reny, J.L. Circulation (2003) [Pubmed]
  29. Thrombopoietin complements G(i)- but not G(q)-dependent pathways for integrin {alpha}(IIb){beta}(3) activation and platelet aggregation. Campus, F., Lova, P., Bertoni, A., Sinigaglia, F., Balduini, C., Torti, M. J. Biol. Chem. (2005) [Pubmed]
  30. Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. von Kügelgen, I. Pharmacol. Ther. (2006) [Pubmed]
  31. Activation of P2Y1 receptor triggers two calcium signaling pathways in bone marrow erythroblasts. Paredes-Gamero, E.J., Craveiro, R.B., Pesquero, J.B., França, J.P., Oshiro, M.E., Ferreira, A.T. Eur. J. Pharmacol. (2006) [Pubmed]
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