1. Department of Cellular and Molecular Pharmacology and Program in Neuroscience, University of California, San Francisco , San Francisco, California 94143, USA
2. COR Therapeutics, Inc., South San Francisco, California 94080, USA
3. UMR 5533 CNRS, Hôpital Cardiologique , 33605 Pessac, France
4. Present addresses: Advanced Medicine , South San Francisco, California 94080, USA (G.L.); FibroGen, South San Francisco, California 94080, USA (L.E.).

Correspondence to: Pamela B. Conley² Correspondence and requests for materials should be addressed to P.B.C. (e-mail: Email: pconley@corr.com).

Abstract

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 subtypes^{2, 3}. The P2Y ₁ receptor couples to G_q and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation^{4, 5}. The second ADP receptor required for aggregation (variously called P2Y_ADP , P2Y_AC, P2Ycyc or P2T_AC) is coupled to the inhibition of adenylyl cyclase through G_i. The molecular identity of the G _i-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel^{6, 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.

1. Department of Cellular and Molecular Pharmacology and Program in Neuroscience, University of California, San Francisco , San Francisco, California 94143, USA
2. COR Therapeutics, Inc., South San Francisco, California 94080, USA
3. UMR 5533 CNRS, Hôpital Cardiologique , 33605 Pessac, France
4. Present addresses: Advanced Medicine , South San Francisco, California 94080, USA (G.L.); FibroGen, South San Francisco, California 94080, USA (L.E.).

Correspondence to: Pamela B. Conley² Correspondence and requests for materials should be addressed to P.B.C. (e-mail: Email: pconley@corr.com).