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2005 | 52 | 2 | 411-415
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Adenosine diphosphate receptors on blood platelets - potential new targets for antiplatelet therapy

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Platelets play a key role not only in physiological haemostasis, but also under pathological conditions such as thrombosis. Platelet activation may be initiated by a variety of agonists including thrombin, collagen, thromboxane or adenosine diphosphate (ADP). Although ADP is regarded as a weak agonist of blood platelets, it remains an important mediator of platelet activation evoked by other agonists, which induce massive ADP release from dense granules, where it occurs in molar concentrations. Thus, ADP action underlies a positive feedback that facilitates further platelet aggregation and leads to platelet plug formation. Additionally, ADP acts synergistically to other, even weak, agonists such as serotonin, adrenaline or chemokines. Blood platelets express two types of P2Y ADP receptors: P2Y_1 and P2Y_12. ADP-dependent platelet aggregation is initiated by the P2Y1 receptor, whereas P2Y_12 receptor augments the activating signal and promotes platelet release reaction. Stimulation of P2Y_12 is also essential for ADP-mediated complete activation of GPIIb-IIIa and GPIa-IIa, and further stabilization of platelet aggregates. The crucial role in blood platelet biology makes P2_Y12 an ideal candidate for pharmacological approaches for anti-platelet therapy.

Physical description
  • Department of Haemostasis and Haemostatic Disorders, Medical University Hospital Nr. 2, Medical University of Łódź, Łódź, Poland
  • Department of Haemostasis and Haemostatic Disorders, Medical University Hospital Nr. 2, Medical University of Łódź, Łódź, Poland
  • Department of Haemostasis and Haemostatic Disorders, Medical University Hospital Nr. 2, Medical University of Łódź, Łódź, Poland
  • Ahmad SS, London FS, Walsh PN (2003) The assembly of the factor X-activating complex on activated human platelets. J Thromb Haemost 1: 48-59.
  • Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, Koller B, Phillips DR, Conley PB (2003) P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest 112: 398-406.
  • Arjomand H, Roukoz B, Surabhi SK, Cohen M (2003) Platelets and antiplatelet therapy in patients with diabetes mellitus. J Invasive Cardiol 15: 264-269.
  • Awtry EH, Loscalzo J (2000) Aspirin. Circulation 101: 1206-1218.
  • Bennett CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ, Tsai HM (2000) Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342: 1773-1777.
  • Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ (2002) Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 90: 625-628.
  • Boyer JL, Romero-Avila T, Schachter JB, Harden TK (1996) Identification of competitive antagonists of the P2Y1 receptor. Mol Pharmacol 50: 1323-1329.
  • Boyer JL, Mohanram A, Camaioni E, Jacobson KA, Harden TK (1998) Competitive and selective antagonism of P2Y1 receptors by N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate. Br J Pharmacol 124: 1-3.
  • Cattaneo M (2003) The platelet P2Y receptors as targets for new antithrombotic drugs. J Thromb Haemost 1: 1133-1135.
  • Chan SW, Gallo SJ, Kim BK, Guo MJ, Blackburn GM, Zamecnik PC (1997) P1,P4-Dithio-P2,P3-monochloromethylene diadenosine 5',5'''-P1,P4-tetraphosphate: A novel antiplatelet agent. Proc Natl Acad Sci USA 94: 4034-4039.
  • Conley PB, Delaney SM (2003) Scientific and therapeutic insights into the role of the platelet P2Y12 receptor in thrombosis. Curr Opin Hematol 10: 333-338.
  • Curtin R, Cox D, Fitzgerald D (2002) Clopidogrel and ticlopidyne. In Platelets. Michelson AD, ed, pp 787-801. Elsevier Science, USA.
  • Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP (2003) Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101: 3908-3914.
  • Dorsam RT, Kunapuli SP (2004) Central role of the P2Y12 receptor in platelet activation. J Clin Invest 113: 340-345.
  • Feng D, Lindpaintner K, Larson MG, Rao VS, O’Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Silbershatz H, D’Agostino RB, Muller JE, Myers RH, Levy D, Tofler GH (1999) Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 19: 1142-1147.
  • Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, Gaussem P (2003a) Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 108: 989-995.
  • Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL (2003b) P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation 108: 2971-2973.
  • Fox SC, Behan MW, Heptinstall S (2004) Inhibition of ADP-induced intracellular Ca2+ responses and platelet aggregation by the P2Y12 receptor antagonists AR-C69931MX and clopidogrel is enhanced by prostaglandin E1. Cell Calcium 35: 39-46.
  • Gachet C (2001a) ADP receptors of platelets and their inhibition. Thromb Haemost 86: 222-232.
  • Gachet C (2001b) Identification, characterization, and inhibition of the platelet ADP receptors. Int J Hematol 74: 375-381.
  • Gachet C, Cazenave JP (2002) Platelet receptors: ADP. In Platelets in Thrombotic and Non-thrombotic Disorders. Gresele P, Page CP, Fuster VVJ eds, pp 127-139. Cambridge University Press, Cambridge.
  • Gibbins JM (2004) Platelet adhesion signalling and the regulation of thrombus formation. J Cell Sci 117: 3415-3425.
  • Greco NJ, Tonon G, Chen W, Luo X, Dalal R, Jamieson GA (2001) Novel structurally altered P(2X1) receptor is preferentially activated by adenosine diphosphate in platelets and megakaryocytic cells. Blood 98: 100-107.
  • Hartwig JH (2002) Platelet structure. In Platelets. Michelson AD, ed, pp 37-52. Elsevier Science, USA.
  • Haseruck N, Erl W, Pandey D, Tigyi G, Ohlmann P, Ravanat C, Gachet C, Siess W (2004) The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors. Blood 103: 2585-2592.
  • Hechler B, Leon C, Vial C, Vigne P, Frelin C, Cazenave JP, Gachet C (1998) The P2Y1 receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation. Blood 92: 152-159.
  • Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409: 202-207.
  • Hourani SMO (2000) Pharmacology of the platelet ADP receptors: agonists and antagonists. Haematologica 85: 309-319.
  • Jin J, Quinton TM, Zhang J, Rittenhouse SE, Kunapuli SP (2002) Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors. Blood 99: 193-198.
  • Kunapuli SP, Dorsam RT, Kim S, Quinton TM (2003) Platelet purinergic receptors. Curr Opin Pharmacol 3: 175-180.
  • Lasne D, Krenn M, Pingault V, Arnaud E, Fiessinger JN, Aiach M, Rendu F (1997) Interdonor variability of platelet response to thrombin receptor activation: influence of PlA2 polymorphism. Br J Haematol 99: 801-807.
  • Lenain N, Freund M, Leon C, Cazenave JP, Gachet C (2003) Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist. J Thromb Haemost 1: 1144-1149.
  • Leon C, Hechler B, Freund M, Eckly A, Vial C, Ohlmann P, Dierich A, LeMeur M, Cazenave JP, Gachet C (1999) Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice. J Clin Invest 104: 1731-1737.
  • Leon C, Freund M, Ravanat C, Baurand A, Cazenave JP, Gachet C (2001) Key role of the P2Y(1) receptor in tissue factor-induced thrombin-dependent acute thromboembolism: studies in P2Y(1)-knockout mice and mice treated with a P2Y(1) antagonist. Circulation 103: 718-723.
  • Luzak B, Golanski J, Rozalski M, Watala C (2003) Effect of the 807 c/t polymorphism in glycoprotein ia on blood platelet reactivity. J Biomed Sci 10: 731-737.
  • MacKenzie AB, Mahaut-Smith MP, Sage SO (1996) Activation of receptor-operated cation channels via P2X1 not P2T purinoceptors in human platelets. J Biol Chem 271: 2879-2881.
  • Mahaut-Smith MP, Ennion SJ, Rolf MG, Evans RJ (2000) ADP is not an agonist at P2X(1) receptors: evidence for separate receptors stimulated by ATP and ADP on human platelets. Br J Pharmacol 131: 108-114.
  • Michelson AD, Furman MI, Goldschmidt-Clermont P, Mascelli MA, Hendrix C, Coleman L, Hamlington J, Barnard MR, Kickler T, Christie DJ, Kundu S, Bray PF (2000) Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation 101: 1013-1018.
  • Mills DC (1996) ADP receptors on platelets. Thromb Haemost 76: 835-856.
  • Nandanan E, Jang SY, Moro S, Kim HO, Siddiqui MA, Russ P, Marquez VE, Busson R, Herdewijn P, Harden TK, Boyer JL, Jacobson KA (2000) Synthesis, biological activity, and molecular modeling of ribose-modified deoxyadenosine bisphosphate analogues as P2Y(1) receptor ligands. J Med Chem 43: 829-842.
  • Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts MF (2002) Does the P(2X1del) variant lacking 17 amino acids in its extracellular domain represent a relevant functional ion channel in platelets? Blood 99: 2275-2277.
  • Patrono C (2003) Aspirin resistance: definition, mechanisms and clinical read-outs. J Thromb Haemost 1: 1710-1713.
  • Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50: 413-492.
  • Rozalski M, Watala C (2002) Antagonists of platelet fibrinogen receptor are less effective in carriers of Pl(A2) polymorphism of beta(3) integrin. Eur J Pharmacol 454: 1-8.
  • Schror K (1997) Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 23: 349-356.
  • Storey F (2001) The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets 12: 197-209.
  • Szczeklik A, Undas A, Sanak M, Frolow M, Wegrzyn W (2000) Relationship between bleeding time, aspirin and the PlA1/A2 polymorphism of platelet glycoprotein IIIa. Br J Haematol 110: 965-967.
  • Vial C, Rolf MG, Mahaut-Smith MP, Evans RJ (2002) A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors. Br J Pharmacol 135: 363-372.
  • Walkowiak B, Baraniak J, Cierniewski CS, Stec W (2002) Inhibition of ADP-triggered blood platelet aggregation by diadenosine polyphosphate analogues. Bioorg Med Chem Lett 12: 1959-1962.
  • Watala C, Golanski J, Rozalski M, Boncler MA, Luzak B, Baraniak J, Korczynski D, Drygas W (2003) Is platelet aggregation a more important contributor than platelet adhesion to the overall platelet-related primary haemostasis measured by PFA-100? Thromb Res 109: 299-306.
  • Wong S, Appleberg M, Ward CM, Lewis DR (2004) Aspirin resistance in cardiovascular disease: a review. Eur J Vasc Endovasc Surg 27: 456-465.
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