Identification of the platelet ADP receptor targeted by antithrombotic drugs

Nature - Tập 409 Số 6817 - Trang 202-207 - 2001
Hollopeter, Gunther1, Jantzen, Hans-Michael2, Vincent, Diana2, Li, Georgia2,3, England, Laura1,4, Ramakrishnan, Vanitha2, Yang, Ruey-Bing2, Nurden, Paquita5, Nurden, Alan5, Julius, David1, Conley, Pamela B.2
1Department of Cellular and Molecular Pharmacology and Program in Neuroscience, University of California, San Francisco, San Francisco, USA
2Cor Therapeutics Inc., South San Francisco, USA
3Advanced Medicine , South San Francisco, USA
4Fibrogen, South San Francisco, USA
5UMR 5533 CNRS, Hôpital Cardiologique, Pessac, France

Tóm tắt

Platelets have a crucial role in the maintenance of normal haemostasis, and perturbations of this system can lead to pathological thrombus formation and vascular occlusion, resulting in stroke, myocardial infarction and unstable angina. ADP released from damaged vessels and red blood cells induces platelet aggregation through activation of the integrin GPIIb–IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that potentiates the actions of many platelet activators1. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes2,3. The P2Y1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation4,5. The second ADP receptor required for aggregation (variously called P2YADP, P2YAC, P2Ycyc or P2TAC) is coupled to the inhibition of adenylyl cyclase through Gi. 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 clopidogrel6,7,8 and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder10 has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.

Từ khóa


Tài liệu tham khảo

citation_journal_title=Thromb. Haemost.; citation_title=ADP receptors on platelets.; citation_author=DC Mills; citation_volume=76; citation_publication_date=1996; citation_pages= 835-856; citation_doi=10.1055/s-0038-1650674; citation_id=CR1

citation_journal_title=Thromb. Haemost.; citation_title=Evidence for two distinct G-protein-coupled ADP receptors mediating platelet activation.; citation_author=HM Jantzen; citation_volume=81; citation_publication_date=1999; citation_pages= 111-117; citation_doi=10.1055/s-0037-1614427; citation_id=CR2

citation_journal_title=J. Biol. Chem. ; citation_title=Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets.; citation_author=JL Daniel; citation_volume=273; citation_publication_date=1998; citation_pages=2024-2029; citation_doi=10.1074/jbc.273.4.2024; citation_id=CR3

citation_journal_title=J. Clin. Invest. ; citation_title=Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y1 receptor-null mice.; citation_author=C Leon; citation_volume=104; citation_publication_date=1999; citation_pages=1731-1737; citation_doi=10.1172/JCI8399; citation_id=CR4

citation_journal_title= Nature Med.; citation_title=Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice.; citation_author=JE Fabre; citation_volume=5; citation_publication_date=1999; citation_pages=1199-1202; citation_doi=10.1038/13522; citation_id=CR5

citation_journal_title= Biochem. Pharmacol.; citation_title=The thienopyridine ticlopidine selectively prevents the inhibitory effects of ADP but not of adrenaline on cAMP levels raised by stimulation of the adenylate cyclase of human platelets by PGE1.; citation_author=C Gachet; citation_volume=40; citation_publication_date=1990; citation_pages=2683-2687; citation_doi=10.1016/0006-2952(90)90587-B; citation_id=CR6

citation_journal_title=Thromb. Haemost.; citation_title=ADP receptor induced activation of guanine nucleotide binding proteins in rat platelet membranes—an effect selectively blocked by the thienopyridine clopidogrel.; citation_author=C Gachet; citation_volume=68 ; citation_publication_date=1992; citation_pages=79-83; citation_doi=10.1055/s-0038-1656322; citation_id=CR7

citation_journal_title=Arterioscler. Thromb.; citation_title=Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase; citation_author=DCB Mills; citation_volume=12; citation_publication_date=1992; citation_pages=430-436; citation_doi=10.1161/01.ATV.12.4.430; citation_id=CR8

citation_journal_title=Br. J. Pharmacol.; citation_title=A novel, highly potent and selective antagonist at human platelet P2T-purinoreceptors.; citation_author=RG Humphries, W Tomlinson, A H Ingall, PA Cage, P Leff; citation_volume=113; citation_publication_date=1994; citation_pages=1057-1063; citation_doi=10.1111/j.1476-5381.1994.tb17100.x; citation_id=CR9

citation_journal_title=J. Clin. Invest.; citation_title=An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets.; citation_author=P Nurden; citation_volume= 95; citation_publication_date=1995; citation_pages=1612-1622; citation_doi=10.1172/JCI117835; citation_id=CR10

citation_journal_title=J. Biol. Chem.; citation_title=Gβγ binds directly to the G protein-gated K+ channel, IKACh.; citation_author=G Krapivinsky, L Krapivinsky, K Wickman, D Clapham; citation_volume=270; citation_publication_date=1995; citation_pages=29059- 29062; citation_doi=10.1074/jbc.270.49.29059; citation_id=CR11

citation_journal_title=Biochem. J.; citation_title=The human platelet ADP receptor activates Gi2 proteins. ; citation_author=P Ohlmann; citation_volume=312; citation_publication_date=1995; citation_pages=775-779 ; citation_doi=10.1042/bj3120775; citation_id=CR12

citation_journal_title=J. Clin. Invest.; citation_title=B. 2-Methylthioadenosine[β-32P]diphosphate: an agonist and radioligand for the receptor that inhibits the accumulation of cyclic AMP in intact blood platelets.; citation_author=DE MacFarlane, PC Srivastava, DC Mills; citation_volume= 71; citation_publication_date=1983; citation_pages=420-428; citation_doi=10.1172/JCI110786; citation_id=CR13

citation_journal_title=Trends Pharmacol. Sci.; citation_title=Receptors for ADP on human blood platelets.; citation_author=SMO Hourani, D Hall; citation_volume=15 ; citation_publication_date=1994; citation_pages=103-108; citation_doi=10.1016/0165-6147(94)90045-0; citation_id=CR14

citation_journal_title=Blood; citation_title=Evidence for two distinct G protein-coupled ADP receptors mediating platelet activation.; citation_author=H-M Jantzen; citation_volume=92; citation_publication_date=1998; citation_pages= 303a; citation_id=CR15

citation_journal_title=Mol. Pharmacol.; citation_title=Identification of competitive antagonists of the P2Y1 receptor. ; citation_author=JL Boyer, T Romero-Avila, JB Schachter, TK Harden; citation_volume=50; citation_publication_date=1996; citation_pages=1323- 1329; citation_id=CR16

citation_journal_title= Mol. Pharmacol.; citation_title=Agonist action of adenosine triphosphates at the human P2Y1 receptor.; citation_author=RK Palmer, JL Boyer, JB Schachter, RA Nicholas, TK Harden; citation_volume=54; citation_publication_date=1998; citation_pages=1118-1123; citation_doi=10.1124/mol.54.6.1118; citation_id=CR17

citation_journal_title=Br. J. Pharmacol.; citation_title=The P2Y1 receptor closes the N-type Ca2+ channel in neurones, with both adenosine triphosphates and diphosphates as potent agonists.; citation_author=AK Filippov, DA Brown, EA Barnard; citation_volume=129; citation_publication_date=2000; citation_pages= 1063-1066; citation_doi=10.1038/sj.bjp.0703185; citation_id=CR18

citation_journal_title=J. Pharmacol. Exp. Ther.; citation_title=Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase. ; citation_author=JL Boyer, ER Lazarowski, XH Chen, TK Harden; citation_volume=267; citation_publication_date=1993; citation_pages=1140- 1146; citation_id=CR19

citation_journal_title= Genome Res.; citation_title=An STS-based radiation hybrid map of the human genome.; citation_author=E Stewart; citation_volume=7; citation_publication_date=1997; citation_pages=422-433; citation_doi=10.1101/gr.7.5.422; citation_id=CR20

citation_journal_title= J. Biol. Chem.; citation_title=A G protein-coupled receptor for UDP-glucose.; citation_author=JK Chambers; citation_volume=275; citation_publication_date=2000; citation_pages=10767-10771; citation_doi=10.1074/jbc.275.15.10767; citation_id=CR21

Savi, P. et al. Identification and biological activity of the active metabolite of Clopidogrel. Thromb. Haemost. (in the press)

citation_journal_title=Arterioscler. Thromb. Vasc. Biol.; citation_title=ADP receptors and clinical bleeding disorders.; citation_author=M Cattaneo, C Gachet; citation_volume=19; citation_publication_date=1999; citation_pages= 2281-2285; citation_doi=10.1161/01.ATV.19.10.2281; citation_id=CR23

citation_journal_title=Br. J. Pharmacol.; citation_title=ADP can induce aggregation of human platelets via both P2Y(1) and P(2T) receptors. ; citation_author=GE Jarvis, RG Humphries, MJ Robertson, P Leff; citation_volume=129; citation_publication_date=2000; citation_pages=275- 282; citation_doi=10.1038/sj.bjp.0703046; citation_id=CR24

citation_journal_title=Br. J. Haematol.; citation_title=The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel.; citation_author=B Hechler, A Eckly, P Ohlmann, J-P Cazenave, C Gachet; citation_volume=103; citation_publication_date=1998; citation_pages= 858-866; citation_doi=10.1046/j.1365-2141.1998.01056.x; citation_id=CR25

citation_journal_title=Arterioscler. Thromb. Vasc. Biol.; citation_title=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.; citation_author=M Humbert; citation_volume=16; citation_publication_date=1996; citation_pages=1532-1543; citation_doi=10.1161/01.ATV.16.12.1532; citation_id=CR26

citation_journal_title=N. Engl. J. Med.; citation_title=Thrombotic thrombocytopenic purpura associated with clopidogrel. ; citation_author=CL Bennett; citation_volume=325; citation_publication_date=2000; citation_pages=1371- 1372; citation_id=CR27

citation_journal_title=Nature; citation_title=The capsaicin receptor: a heat-activated ion channel in the pain pathway.; citation_author=MJ Caterina; citation_volume=389; citation_publication_date=1997; citation_pages=816- 824; citation_doi=10.1038/39807; citation_id=CR28

Thông tin
Thông tin xuất bản

Nature

Tập 409 Số 6817

202-207

Thông tin tác giả