Abstract
Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA2 and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G protein-coupled ADP receptors, namely the P2Y1 and P2Y12 receptor subtypes, while the P2X1 receptor ligand-gated cation channel is activated by ATP. The P2Y1 receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y12 receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs.
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References
Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451(7181):914–918
Jennings LK (2009) Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 102(2):248–257. doi:10.1160/TH09-03-0192
Jain S, Harris J, Ware J (2010) Platelets: linking hemostasis and cancer. Arterioscler Thromb Vasc Biol 30(12):2362–2367. doi:10.1161/ATVBAHA.110.207514
Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115(12):3378–3384
O'Sullivan BP, Linden MD, Frelinger AL 3rd, Barnard MR, Spencer-Manzon M, Morris JE, Salem RO, Laposata M, Michelson AD (2005) Platelet activation in cystic fibrosis. Blood 105(12):4635–4641. doi:10.1182/blood-2004-06-2098
Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O'Donnell E, Farndale RW, Ware J, Lee DM (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327(5965):580–583. doi:10.1126/science.1181928
Ross R, Glomset JA (1973) Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180(93):1332–1339
Burnstock G (2008) Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells. Pharmacol Rep 60(1):12–20
Born GV (1985) Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation 72(4):741–746
Mustard JF, Perry DW, Kinlough-Rathbone RL, Packham MA (1975) Factors responsible for ADP-induced release reaction of human platelets. Am J Physiol 228(6):1757–1765
Jones S, Evans RJ, Mahaut-Smith MP (2011) Extracellular Ca(2+) modulates ADP-evoked aggregation through altered agonist degradation: implications for conditions used to study P2Y receptor activation. Br J Haematol 153(1):83–91. doi:10.1111/j.1365-2141.2010.08499.x
Gachet C (2001) ADP receptors of platelets and their inhibition. Thromb Haemost 86(1):222–232
Rolf MG, Brearley CA, Mahaut-Smith MP (2001) Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha, beta-methylene ATP. Thromb Haemost 85(2):303–308
Mahaut-Smith MP, Tolhurst G, Evans RJ (2004) Emerging roles for P2X1 receptors in platelet activation. Platelets 15(3):131–144
Gordon JL (1986) Extracellular ATP: effects, sources and fate. Biochem J 233(2):309–319
Gachet C (2006) Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 46:277–300
Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58:281–341
Baurand A, Raboisson P, Freund M, Léon C, Cazenave JP, Bourguignon JJ, Gachet C (2001) Inhibition of platelet function by administration of MRS2179, a P2Y1 receptor antagonist. Eur J Pharmacol 412(3):213–221
Ohlmann P, de Castro S, Brown GG Jr, Gachet C, Jacobson KA, Harden TK (2010) Quantification of recombinant and platelet P2Y(1) receptors utilizing a [(125)I]-labeled high-affinity antagonist 2-iodo-N(6)-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate ([(125)I]MRS2500). Pharmacol Res 62(4):344–351. doi:10.1016/j.phrs.2010.05.007
Hechler B, Léon 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(1):152–159
Jin J, Daniel JL, Kunapuli SP (1998) Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem 273(4):2030–2034
Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, Herbert JM (1998) Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett 422(3):291–295
Léon 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(12):1731–1737
Mangin P, Ohlmann P, Eckly A, Cazenave JP, Lanza F, Gachet C (2004) The P2Y receptor plays an essential role in the platelet shape change induced by collagen when TxA2 formation is prevented. J Thromb Haemost 2(6):969–977
Jacobson KA, Boeynaems JM (2010) P2Y nucleotide receptors: promise of therapeutic applications. Drug Discov Today 15(13–14):570–578. doi:10.1016/j.drudis.2010.05.011
Boyer JL, Romero-Avila T, Schachter JB, Harden TK (1996) Identification of competitive antagonists of the P2Y1 receptor. Mol Pharmacol 50(5):1323–1329
Baurand A, Gachet C (2003) The P2Y(1) receptor as a target for new antithrombotic drugs: a review of the P2Y(1) antagonist MRS-2179. Cardiovasc Drug Rev 21(1):67–76
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):1–3
Kim HS, Ohno M, Xu B, Kim HO, Choi Y, Ji XD, Maddileti S, Marquez VE, Harden TK, Jacobson KA (2003) 2-Substitution of adenine nucleotide analogues containing a bicyclo[3.1.0]hexane ring system locked in a northern conformation: enhanced potency as P2Y1 receptor antagonists. J Med Chem 46(23):4974–4987
Waldo GL, Corbitt J, Boyer JL, Ravi G, Kim HS, Ji XD, Lacy J, Jacobson KA, Harden TK (2002) Quantitation of the P2Y(1) receptor with a high affinity radiolabeled antagonist. Mol Pharmacol 62(5):1249–1257
Boyer JL, Adams M, Ravi RG, Jacobson KA, Harden TK (2002) 2-Chloro N(6)-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate is a selective high affinity P2Y(1) receptor antagonist. Br J Pharmacol 135(8):2004–2010
Cattaneo M, Lecchi A, Ohno M, Joshi BV, Besada P, Tchilibon S, Lombardi R, Bischofberger N, Harden TK, Jacobson KA (2004) Antiaggregatory activity in human platelets of potent antagonists of the P2Y1 receptor. Biochem Pharmacol 68(10):1995–2002
Kaiser RA, Buxton IL (2002) Nucleotide-mediated relaxation in guinea-pig aorta: selective inhibition by MRS2179. Br J Pharmacol 135(2):537–545
Guns PJ, Korda A, Crauwels HM, Van Assche T, Robaye B, Boeynaems JM, Bult H (2005) Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta. Br J Pharmacol 146(2):288–295
Shen J, DiCorleto PE (2008) ADP stimulates human endothelial cell migration via P2Y1 nucleotide receptor-mediated mitogen-activated protein kinase pathways. Circ Res 102(4):448–456
Marques-da-Silva C, Burnstock G, Ojcius DM, Coutinho-Silva R (2011) Purinergic receptor agonists modulate phagocytosis and clearance of apoptotic cells in macrophages. Immunobiology 216(1–2):1–11. doi:10.1016/j.imbio.2010.03.010
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(6817):202–207
Zhang FL, Luo L, Gustafson E, Lachowicz J, Smith M, Qiao X, Liu YH, Chen G, Pramanik B, Laz TM, Palmer K, Bayne M, Monsma FJ Jr (2001) ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem 276(11):8608–8615
Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, Julius D (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 9(12):1512–1519. doi:10.1038/nn1805
Wihlborg AK, Wang L, Braun OO, Eyjolfsson A, Gustafsson R, Gudbjartsson T, Erlinge D (2004) ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol 24(10):1810–1815
Hogberg C, Svensson H, Gustafsson R, Eyjolfsson A, Erlinge D (2010) The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol 142(2):187–192. doi:10.1016/j.ijcard.2008.12.091
Cattaneo M (2011) The platelet P2Y receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 117(7):2102–2112. doi:10.1182/blood-2010-08-263111
Gachet C (2005) The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther 108(2):180–192
Kauffenstein G, Hechler B, Cazenave JP, Gachet C (2004) Adenine triphosphate nucleotides are antagonists at the P2Y12 receptor. J Thromb Haemost 2(11):1980–1988
Michelson AD (2009) New P2Y12 antagonists. Curr Opin Hematol 16(5):371–377. doi:10.1097/MOH.0b013e32832ea2f2
Hechler B, Eckly A, Ohlmann P, Cazenave JP, Gachet C (1998) The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol 103(3):858–866
Nieswandt B, Schulte V, Zywietz A, Gratacap MP, Offermanns S (2002) Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin alpha IIbbeta 3 activation in platelets. J Biol Chem 277(42):39493–39498
Dorsam RT, Kim S, Jin J, Kunapuli SP (2002) Coordinated signaling through both G12/13 and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets. J Biol Chem 277(49):47588–47595
Polgar J, Eichler P, Greinacher A, Clemetson KJ (1998) Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients. Blood 91(2):549–554
Gratacap MP, Herault JP, Viala C, Ragab A, Savi P, Herbert JM, Chap H, Plantavid M, Payrastre B (2000) FcgammaRIIA requires a Gi-dependent pathway for an efficient stimulation of phosphoinositide 3-kinase, calcium mobilization, and platelet aggregation. Blood 96(10):3439–3446
Nieswandt B, Bergmeier W, Eckly A, Schulte V, Ohlmann P, Cazenave JP, Zirngibl H, Offermanns S, Gachet C (2001) Evidence for cross-talk between glycoprotein VI and Gi-coupled receptors during collagen-induced platelet aggregation. Blood 97(12):3829–3835
Ohlmann P, Eckly A, Freund M, Cazenave JP, Offermanns S, Gachet C (2000) ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of Galphaq. Blood 96(6):2134–2139
Cattaneo M, Lombardi R, Zighetti ML, Gachet C, Ohlmann P, Cazenave JP, Mannucci PM (1997) Deficiency of (33P)2MeS-ADP binding sites on platelets with secretion defect, normal granule stores and normal thromboxane A2 production. Evidence that ADP potentiates platelet secretion independently of the formation of large platelet aggregates and thromboxane A2 production. Thromb Haemost 77(5):986–990
Cattaneo M, Lecchi A, Lombardi R, Gachet C, Zighetti ML (2000) Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet ‘primary secretion defect’ are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol 20(11):E101–E106
Cattaneo M, Canciani MT, Lecchi A, Kinlough-Rathbone RL, Packham MA, Mannucci PM, Mustard JF (1990) Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood 75(5):1081–1086
Trumel C, Payrastre B, Plantavid M, Hechler B, Viala C, Presek P, Martinson EA, Cazenave JP, Chap H, Gachet C (1999) A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood 94(12):4156–4165
Humbert M, Nurden P, Bihour C, Pasquet JM, Winckler J, Heilmann E, Savi P, Herbert JM, Kunicki TJ, Nurden AT (1996) Ultrastructural studies of platelet aggregates from human subjects receiving clopidogrel and from a patient with an inherited defect of an ADP-dependent pathway of platelet activation. Arterioscler Thromb Vasc Biol 16(12):1532–1543
Eckly A, Gendrault JL, Hechler B, Cazenave JP, Gachet C (2001) Differential involvement of the P2Y1 and P2YT receptors in the morphological changes of platelet aggregation. Thromb Haemost 85(4):694–701
Foster CJ, Prosser DM, Agans JM, Zhai Y, Smith MD, Lachowicz JE, Zhang FL, Gustafson E, Monsma FJ Jr, Wiekowski MT, Abbondanzo SJ, Cook DN, Bayne ML, Lira SA, Chintala MS (2001) Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 107(12):1591–1598
Ohlmann P, Laugwitz KL, Nurnberg B, Spicher K, Schultz G, Cazenave JP, Gachet C (1995) The human platelet ADP receptor activates Gi2 proteins. Biochem J 312(Pt 3):775–779
Jantzen HM, Milstone DS, Gousset L, Conley PB, Mortensen RM (2001) Impaired activation of murine platelets lacking G alpha(i2). J Clin Invest 108(3):477–483
Hardy AR, Jones ML, Mundell SJ, Poole AW (2004) Reciprocal cross-talk between P2Y1 and P2Y12 receptors at the level of calcium signaling in human platelets. Blood 104(6):1745–1752. doi:10.1182/blood-2004-02-05342004-02-0534
Haslam RJ (1973) Interactions of the pharmacological receptors of blood platelets with adenylate cyclase. Ser Haematol 6(3):333–350
Savi P, Pflieger AM, Herbert JM (1996) cAMP is not an important messenger for ADP-induced platelet aggregation. Blood Coagul Fibrinolysis 7(2):249–252
Daniel JL, Dangelmaier C, Jin J, Kim YB, Kunapuli SP (1999) Role of intracellular signaling events in ADP-induced platelet aggregation. Thromb Haemost 82(4):1322–1326
Yang J, Wu J, Jiang H, Mortensen R, Austin S, Manning DR, Woulfe D, Brass LF (2002) Signaling through Gi family members in platelets. Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem 277(48):46035–46042
Cosemans JM, Munnix IC, Wetzker R, Heller R, Jackson SP, Heemskerk JW (2006) Continuous signaling via PI3K isoforms beta and gamma is required for platelet ADP receptor function in dynamic thrombus stabilization. Blood 108(9):3045–3052. doi:10.1182/blood-2006-03-006338
Gratacap MP, Guillermet-Guibert J, Martin V, Chicanne G, Tronchere H, Gaits-Iacovoni F, Payrastre B (2011) Regulation and roles of PI3Kbeta, a major actor in platelet signaling and functions. Adv Enzyme Regul 51(1):106–116. doi:10.1016/j.advenzreg.2010.09.011
Jackson SP, Yap CL, Anderson KE (2004) Phosphoinositide 3-kinases and the regulation of platelet function. Biochem Soc Trans 32(Pt 2):387–392
Schoenwaelder SM, Ono A, Sturgeon S, Chan SM, Mangin P, Maxwell MJ, Turnbull S, Mulchandani M, Anderson K, Kauffenstein G, Rewcastle GW, Kendall J, Gachet C, Salem HH, Jackson SP (2007) Identification of a unique co-operative phosphoinositide 3-kinase signaling mechanism regulating integrin alpha IIb beta 3 adhesive function in platelets. J Biol Chem 282(39):28648–28658. doi:10.1074/jbc.M704358200
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 11(6):507–514
Lova P, Paganini S, Sinigaglia F, Balduini C, Torti M (2002) A Gi-dependent pathway is required for activation of the small GTPase Rap1B in human platelets. J Biol Chem 277(14):12009–12015
Lova P, Paganini S, Hirsch E, Barberis L, Wymann M, Sinigaglia F, Balduini C, Torti M (2003) A selective role for phosphatidylinositol 3,4,5-trisphosphate in the Gi-dependent activation of platelet Rap1B. J Biol Chem 278(1):131–138
Woulfe D, Jiang H, Mortensen R, Yang J, Brass LF (2002) Activation of Rap1B by G(i) family members in platelets. J Biol Chem 277(26):23382–23390
Larson MK, Chen H, Kahn ML, Taylor AM, Fabre JE, Mortensen RM, Conley PB, Parise LV (2003) Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI-mediated Rap1 activation in platelets. Blood 101(4):1409–1415
Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, Vanhaesebroeck B, Payrastre B, Gratacap MP (2010) Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo. Blood 115(10):2008–2013. doi:10.1182/blood-2009-04-217224
Li Z, Zhang G, Le Breton GC, Gao X, Malik AB, Du X (2003) Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases. J Biol Chem 278(33):30725–30731
Hirsch E, Bosco O, Tropel P, Laffargue M, Calvez R, Altruda F, Wymann M, Montrucchio G (2001) Resistance to thromboembolism in PI3Kgamma-deficient mice. FASEB J 15(11):2019–2021
Geiger J, Brich J, Honig-Liedl P, Eigenthaler M, Schanzenbacher P, Herbert JM, Walter U (1999) Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 19(8):2007–2011
Jin J, Kunapuli SP (1998) Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA 95(14):8070–8074
Léon C, Ravanat C, Freund M, Cazenave JP, Gachet C (2003) Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol 23(10):1941–1947
Léon C, Alex M, Klocke A, Morgenstern E, Moosbauer C, Eckly A, Spannagl M, Gachet C, Engelmann B (2004) Platelet ADP receptors contribute to the initiation of intravascular coagulation. Blood 103(2):594–600
Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S (2000) The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 110(4):925–934
Léon 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(5):718–723
Vial C, Hechler B, Léon C, Cazenave JP, Gachet C (1997) Presence of P2X1 purinoceptors in human platelets and megakaryoblastic cell lines. Thromb Haemost 78(6):1500–1504
Cattaneo M, Marchese P, Jacobson KA, Ruggeri Z (2002) New insights into the role of P2X1 in platelet function. Haematologica 87(10):13–14
Oury C, Sticker E, Cornelissen H, De Vos R, Vermylen J, Hoylaerts MF (2004) ATP augments von Willebrand factor-dependent shear-induced platelet aggregation through Ca2+-calmodulin and myosin light chain kinase activation. J Biol Chem 279(25):26266–26273
Hechler B, Lenain N, Marchese P, Vial C, Heim V, Freund M, Cazenave JP, Cattaneo M, Ruggeri ZM, Evans R, Gachet C (2003) A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo. J Exp Med 198(4):661–667. doi:10.1084/jem.20030144jem.20030144
Baurand A, Eckly A, Bari N, Leon C, Hechler B, Cazenave JP, Gachet C (2000) Desensitization of the platelet aggregation response to ADP: differential down-regulation of the P2Y1 and P2cyc receptors. Thromb Haemost 84(3):484–491
Hoffmann C, Ziegler N, Reiner S, Krasel C, Lohse MJ (2008) Agonist-selective, receptor-specific interaction of human P2Y receptors with beta-arrestin-1 and −2. J Biol Chem 283(45):30933–30941. doi:10.1074/jbc.M801472200
Baurand A, Eckly A, Hechler B, Kauffenstein G, Galzi JL, Cazenave JP, Leon C, Gachet C (2005) Differential regulation and relocalization of the platelet P2Y receptors after activation: a way to avoid loss of hemostatic properties? Mol Pharmacol 67(3):721–733. doi:10.1124/mol.104.004846
Reiner S, Ziegler N, Leon C, Lorenz K, von Hayn K, Gachet C, Lohse MJ, Hoffmann C (2009) beta-Arrestin-2 interaction and internalization of the human P2Y1 receptor are dependent on C-terminal phosphorylation sites. Mol Pharmacol 76(6):1162–1171. doi:10.1124/mol.109.060467
Mundell SJ, Jones ML, Hardy AR, Barton JF, Beaucourt SM, Conley PB, Poole AW (2006) Distinct roles for protein kinase C isoforms in regulating platelet purinergic receptor function. Mol Pharmacol 70(3):1132–1142. doi:10.1124/mol.106.023549
Hardy AR, Conley PB, Luo J, Benovic JL, Poole AW, Mundell SJ (2005) P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood 105(9):3552–3560. doi:10.1182/blood-2004-07-2893
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(6):2879–2881
Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A, Evans RJ (2006) Molecular properties of P2X receptors. Pflugers Archiv: Eur J Physiol 452(5):486–500. doi:10.1007/s00424-006-0073-6
Fontana P, Dupont A, Gandrille S, Bachelot-Loza C, Reny JL, Aiach M, Gaussem P (2003) Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 108(8):989–995
Staritz P, Kurz K, Stoll M, Giannitsis E, Katus HA, Ivandic BT (2009) Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene. Int J Cardiol 133(3):341–345. doi:10.1016/j.ijcard.2007.12.118
Fontana P, Gaussem P, Aiach M, Fiessinger JN, Emmerich J, Reny JL (2003) P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study. Circulation 108(24):2971–2973
Cavallari U, Trabetti E, Malerba G, Biscuola M, Girelli D, Olivieri O, Martinelli N, Angiolillo DJ, Corrocher R, Pignatti PF (2007) Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet 8:59. doi:10.1186/1471-2350-8-59
Bura A, Bachelot-Loza C, Ali FD, Aiach M, Gaussem P (2006) Role of the P2Y12 gene polymorphism in platelet responsiveness to clopidogrel in healthy subjects. J Thromb Haemost 4(9):2096–2097. doi:10.1111/j.1538-7836.2006.02113.x
Lev EI, Patel RT, Guthikonda S, Lopez D, Bray PF, Kleiman NS (2007) Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Thromb Res 119(3):355–360. doi:10.1016/j.thromres.2006.02.006
Zee RY, Michaud SE, Diehl KA, Chasman DI, Emmerich J, Gaussem P, Aiach M, Ridker PM (2008) Purinergic receptor P2Y, G-protein coupled, 12 gene variants and risk of incident ischemic stroke, myocardial infarction, and venous thromboembolism. Atherosclerosis 197(2):694–699. doi:10.1016/j.atherosclerosis.2007.07.001
Hetherington SL, Singh RK, Lodwick D, Thompson JR, Goodall AH, Samani NJ (2005) Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 25(1):252–257
Sibbing D, von Beckerath O, Schomig A, Kastrati A, von Beckerath N (2006) P2Y1 gene A1622G dimorphism is not associated with adenosine diphosphate-induced platelet activation and aggregation after administration of a single high dose of clopidogrel. J Thromb Haemost 4(4):912–914. doi:10.1111/j.1538-7836.2006.01869.x
Savi P, Herbert JM (2005) Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost 31(2):174–183
Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, Herbert JM (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 84(5):891–896
Savi P, Laplace MC, Herbert JM (1994) Evidence for the existence of two different ADP-binding sites on rat platelets. Thromb Res 76(2):157–169
Gachet C, Cattaneo M, Ohlmann P, Hechler B, Lecchi A, Chevalier J, Cassel D, Mannucci PM, Cazenave JP (1995) Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors. Br J Haematol 91(2):434–444
Mills DC, Puri R, Hu CJ, Minniti C, Grana G, Freedman MD, Colman RF, Colman RW (1992) Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arterioscler Thromb 12(4):430–436
Savi P, Zachayus JL, Delesque-Touchard N, Labouret C, Herve C, Uzabiaga MF, Pereillo JM, Culouscou JM, Bono F, Ferrara P, Herbert JM (2006) The active metabolite of clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts. Proc Natl Acad Sci USA 103(29):11069–11074
Meadows TA, Bhatt DL (2007) Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 100(9):1261–1275. doi:10.1161/01.RES.0000264509.36234.51
Tomasello SD, Tello-Montoliu A, Angiolillo DJ (2011) Prasugrel for the treatment of coronary thrombosis: a review of pharmacological properties, indications for use and future development. Expert Opin Investig Drugs 20(1):119–133. doi:10.1517/13543784.2010.538381
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357(20):2001–2015. doi:10.1056/NEJMoa0706482
Bhatt DL (2009) Prasugrel in clinical practice. N Engl J Med 361(10):940–942
Cattaneo M (2010) New P2Y(12) inhibitors. Circulation 121(1):171–179. doi:10.1161/CIRCULATIONAHA.109.853069
Storey RF (2011) Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors. Thromb Haemost 105(Suppl 1):S75–S81. doi:10.1160/THS10-12-0769
Ferreiro JL, Ueno M, Angiolillo DJ (2009) Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 7(10):1195–1201. doi:10.1586/erc.09.101
Nawarskas JJ, Clark SM (2011) Ticagrelor: a novel reversible oral antiplatelet agent. Cardiol Rev 19(2):95–100. doi:10.1097/CRD.0b013e3182099d8600045415-201103000-00011
Gurbel PA, Kereiakes DJ, Tantry US (2010) Ticagrelor for the treatment of arterial thrombosis. Expert Opin Pharmacother 11(13):2251–2259. doi:10.1517/14656566.2010.511175
Fabre JE, Nguyen M, Latour A, Keifer JA, Audoly LP, Coffman TM, Koller BH (1999) Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice. Nat Med 5(10):1199–1202
Lenain N, Freund M, Léon 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(6):1144–1149
Hechler B, Nonne C, Roh EJ, Cattaneo M, Cazenave JP, Lanza F, Jacobson KA, Gachet C (2006) MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice. J Pharmacol Exp Ther 316(2):556–563. doi:10.1124/jpet.105.094037
Morales-Ramos AI, Mecom JS, Kiesow TJ, Graybill TL, Brown GD, Aiyar NV, Davenport EA, Kallal LA, Knapp-Reed BA, Li P, Londregan AT, Morrow DM, Senadhi S, Thalji RK, Zhao S, Burns-Kurtis CL, Marino JP Jr (2008) Tetrahydro-4-quinolinamines identified as novel P2Y(1) receptor antagonists. Bioorg Med Chem Lett 18(23):6222–6226. doi:10.1016/j.bmcl.2008.09.102
Pfefferkorn JA, Choi C, Winters T, Kennedy R, Chi L, Perrin LA, Lu G, Ping YW, McClanahan T, Schroeder R, Leininger MT, Geyer A, Schefzick S, Atherton J (2008) P2Y1 receptor antagonists as novel antithrombotic agents. Bioorg Med Chem Lett 18(11):3338–3343
Thalji RK, Aiyar N, Davenport EA, Erhardt JA, Kallal LA, Morrow DM, Senadhi S, Burns-Kurtis CL, Marino JP Jr (2010) Benzofuran-substituted urea derivatives as novel P2Y(1) receptor antagonists. Bioorg Med Chem Lett 20(14):4104–4107. doi:10.1016/j.bmcl.2010.05.072
Zerr M, Hechler B, Freund M, Magnenat S, Lanois I, Cazenave JP, Léon C, Gachet C (2011) Major contribution of the P2Y1 receptor in purinergic regulation of TNFα-induced vascular inflammation. Circulation 123:2404–2413
Hechler B, Freund M, Ravanat C, Magnenat S, Cazenave JP, Gachet C (2008) Reduced atherosclerotic lesions in P2Y1/apolipoprotein E double-knockout mice: the contribution of non-hematopoietic-derived P2Y1 receptors. Circulation 118(7):754–763. doi:10.1161/CIRCULATIONAHA.108.788927
Oury C, Kuijpers MJ, Toth-Zsamboki E, Bonnefoy A, Danloy S, Vreys I, Feijge MA, De Vos R, Vermylen J, Heemskerk JW, Hoylaerts MF (2003) Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype. Blood 101(10):3969–3976
Kassack MU, Braun K, Ganso M, Ullmann H, Nickel P, Boing B, Muller G, Lambrecht G (2004) Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist. Eur J Med Chem 39(4):345–357
Hechler B, Magnenat S, Zighetti ML, Kassack MU, Ullmann H, Cazenave JP, Evans R, Cattaneo M, Gachet C (2005) Inhibition of platelet functions and thrombosis through selective or nonselective inhibition of the platelet P2 receptors with increasing doses of NF449 [4,4′,4″,4‴-(carbonylbis(imino-5,1,3-benzenetriylbis-(carbonylimino)))t etrakis-benzene-1,3-disulfonic acid octasodium salt]. J Pharmacol Exp Ther 314(1):232–243. doi:10.1124/jpet.105.084673
Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF (2007) Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 12(2):113–122
Li M, Zhang Y, Ren H, Zhu X (2007) Effect of clopidogrel on the inflammatory progression of early atherosclerosis in rabbits model. Atherosclerosis 194(2):348–356. doi:10.1016/j.atherosclerosis.2006.11.006
Afek A, Kogan E, Maysel-Auslender S, Mor A, Regev E, Rubinstein A, Keren G, George J (2009) Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res 77(3):364–369. doi:10.1016/j.mvr.2009.01.009
Schulz C, Konrad I, Sauer S, Orschiedt L, Koellnberger M, Lorenz R, Walter U, Massberg S (2008) Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo. Thromb Haemost 99(1):190–195
Evans DJ, Jackman LE, Chamberlain J, Crosdale DJ, Judge HM, Jetha K, Norman KE, Francis SE, Storey RF (2009) Platelet P2Y(12) receptor influences the vessel wall response to arterial injury and thrombosis. Circulation 119(1):116–122. doi:10.1161/CIRCULATIONAHA.107.762690
Patil SB, Jackman LE, Francis SE, Judge HM, Nylander S, Storey RF (2010) Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates a requirement for sustained P2Y12 inhibition to prevent subsequent neointima. Arterioscler Thromb Vasc Biol 30(12):2385–2391. doi:10.1161/ATVBAHA.110.210732
Di Virgilio F, Chiozzi P, Ferrari D, Falzoni S, Sanz JM, Morelli A, Torboli M, Bolognesi G, Baricordi OR (2001) Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97(3):587–600
Di Virgilio F, Solini A (2002) P2 receptors: new potential players in atherosclerosis. Br J Pharmacol 135(4):831–842
Gresele P, Grasselli S, Todisco T, Nenci GG (1985) Platelets and asthma. Lancet 1(8424):347
Pitchford SC, Momi S, Giannini S, Casali L, Spina D, Page CP, Gresele P (2005) Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood 105(5):2074–2081. doi:10.1182/blood-2004-06-2282
Paruchuri S, Tashimo H, Feng C, Maekawa A, Xing W, Jiang Y, Kanaoka Y, Conley P, Boyce JA (2009) Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med 206(11):2543–2555. doi:10.1084/jem.20091240
Maitre B, Freund M, Hechler B, Léon C, Heim V, Cazenave JP, Hanau D, Gachet C (2008) Involvement of the P2Y1 receptor in asthmatic airway inflammation (abstract). In: Purinergic signalling. Purines 2008 Meeting, 29 June–2 July 2008, Coppenhagen, Denmark, pp. S1–S210
Bambace NM, Holmes CE (2011) The platelet contribution to cancer progression. J Thromb Haemost 9(2):237–249. doi:10.1111/j.1538-7836.2010.04131.x
Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11(2):123–134. doi:10.1038/nrc3004
Yeaman MR (2010) Platelets in defense against bacterial pathogens. Cell Mol Life Sci 67(4):525–544. doi:10.1007/s00018-009-0210-4
Semple JW, Italiano JE, Freedman J (2011) Platelets and the immune continuum. Nature reviews 11(4):264–274. doi:10.1038/nri2956
McMorran BJ, Marshall VM, de Graaf C, Drysdale KE, Shabbar M, Smyth GK, Corbin JE, Alexander WS, Foote SJ (2009) Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 323(5915):797–800. doi:10.1126/science.1166296
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Hechler, B., Gachet, C. P2 receptors and platelet function. Purinergic Signalling 7, 293–303 (2011). https://doi.org/10.1007/s11302-011-9247-6
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DOI: https://doi.org/10.1007/s11302-011-9247-6