P2 receptors and platelet function

Purinergic Signalling

Volumn 7, Issue 3, 2011, Pages 293-303

  Hechler, Béatrice ^a   Gachet, Christian ^a  

^a UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

ADP; Antiplatelet drugs; AZD6140; Cangrelor; Clopidogrel; Haemostasis; P2X1; P2Y12; P2Y1; Prasugrel; Thienopyridine; Thrombosis; Ticagrelor

Indexed keywords

EID: 80052377991     PISSN: 15739538     EISSN: 15739546     Source Type: Journal    
DOI: 10.1007/s11302-011-9247-6     Document Type: Article

References (148)

1. Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451(7181): 914-918.
2. 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.
3. 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.
4. Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115(12): 3378-3384.
5. 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.
6. 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.
7. 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.
8. Burnstock G (2008) Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells. Pharmacol Rep 60(1): 12-20.
9. Born GV (1985) Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation 72(4): 741-746.
10. 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.
11. 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.
12. Gachet C (2001) ADP receptors of platelets and their inhibition. Thromb Haemost 86(1): 222-232.
13. 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.
14. Mahaut-Smith MP, Tolhurst G, Evans RJ (2004) Emerging roles for P2X1 receptors in platelet activation. Platelets 15(3): 131-144.
15. Gordon JL (1986) Extracellular ATP: effects, sources and fate. Biochem J 233(2): 309-319.
16. Gachet C (2006) Regulation of platelet functions by P2 receptors. Annu Rev Pharmacol Toxicol 46: 277-300.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. Boyer JL, Romero-Avila T, Schachter JB, Harden TK (1996) Identification of competitive antagonists of the P2Y1 receptor. Mol Pharmacol 50(5): 1323-1329.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. Kaiser RA, Buxton IL (2002) Nucleotide-mediated relaxation in guinea-pig aorta: selective inhibition by MRS2179. Br J Pharmacol 135(2): 537-545.
34. 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.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. 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.
43. Gachet C (2005) The platelet P2 receptors as molecular targets for old and new antiplatelet drugs. Pharmacol Ther 108(2): 180-192.
44. 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.
45. Michelson AD (2009) New P2Y12 antagonists. Curr Opin Hematol 16(5): 371-377. doi: 10. 1097/MOH. 0b013e32832ea2f2.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
52. 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.
53. 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.
54. 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.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. Haslam RJ (1973) Interactions of the pharmacological receptors of blood platelets with adenylate cyclase. Ser Haematol 6(3): 333-350.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. Jackson SP, Yap CL, Anderson KE (2004) Phosphoinositide 3-kinases and the regulation of platelet function. Biochem Soc Trans 32(Pt 2): 387-392.
70. 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.
71. 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.
72. 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.
73. 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.
74. 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.
75. 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.
76. 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.
77. 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.
78. 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.
79. 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.
80. 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.
81. 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.
82. 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.
83. 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.
84. 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.
85. 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.
86. Cattaneo M, Marchese P, Jacobson KA, Ruggeri Z (2002) New insights into the role of P2X1 in platelet function. Haematologica 87(10): 13-14.
87. 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.
88. 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.
89. 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.
90. 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.
91. 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.
92. 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.
93. 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.
94. 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.
95. 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.
96. 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.
97. 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.
98. 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.
99. 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.
100. 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.
101. 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.
102. 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.
103. 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.
104. 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.
105. 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.
106. 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.
107. 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.
108. 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.
109. 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.
110. 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.
111. 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.
112. 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.
113. 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.
114. 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.
115. Bhatt DL (2009) Prasugrel in clinical practice. N Engl J Med 361(10): 940-942.
116. Cattaneo M (2010) New P2Y(12) inhibitors. Circulation 121(1): 171-179. doi: 10. 1161/CIRCULATIONAHA. 109. 853069.
117. 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.
118. 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.
119. 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.
120. 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.
121. 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.
122. 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.
123. 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.
124. 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.
125. 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.
126. 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.
127. 1 receptor in purinergic regulation of TNFα-induced vascular inflammation. Circulation 123: 2404-2413.
128. 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.
129. 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.
130. 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.
131. 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.
132. 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.
133. 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.
134. 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.
135. 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.
136. 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.
137. 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.
138. 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.
139. Di Virgilio F, Solini A (2002) P2 receptors: new potential players in atherosclerosis. Br J Pharmacol 135(4): 831-842.
140. Gresele P, Grasselli S, Todisco T, Nenci GG (1985) Platelets and asthma. Lancet 1(8424): 347.
141. 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.
142. 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.
143. 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.
144. 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.
145. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11(2): 123-134. doi: 10. 1038/nrc3004.
146. Yeaman MR (2010) Platelets in defense against bacterial pathogens. Cell Mol Life Sci 67(4): 525-544. doi: 10. 1007/s00018-009-0210-4.
147. Semple JW, Italiano JE, Freedman J (2011) Platelets and the immune continuum. Nature reviews 11(4): 264-274. doi: 10. 1038/nri2956.
148. 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.