Identification of the platelet ADP receptor targeted by antithrombotic drugs

• Published in: Nature (London) Vol. 409; no. 6817; pp. 202 - 207
• Main Authors: Conley, Pamela B, Hollopeter, Gunther, Jantzen, Hans-Michael, Vincent, Diana, Li, Georgia, England, Laura, Ramakrishnan, Vanitha, Yang, Ruey-Bing, Nurden, Paquita, Nurden, Alan, Julius, David
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 11.01.2001; Nature Publishing Group
• Subjects: Adenosine Diphosphate - metabolism; Amino Acid Sequence; Animals; Biological and medical sciences; Blood Platelets - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Brain - metabolism; Calcium; Cardiovascular diseases; CHO Cells; Chromosomes, Human, Pair 3; Cloning; Cloning, Molecular; Cricetinae; Cyclic AMP - metabolism; DNA, Complementary; Erythrocytes; Female; Fibrinolytic Agents - metabolism; Frameshift Mutation; G Protein-Coupled Inwardly-Rectifying Potassium Channels; GTP-Binding Proteins - metabolism; Hematologic and hematopoietic diseases; Hemorrhage - metabolism; Humans; Ions; Male; Medical sciences; Membrane Proteins; Molecular Sequence Data; Myocardial infarction; Oocytes; Pharmacology. Drug treatments; Platelet Aggregation - physiology; Platelet diseases and coagulopathies; Potassium; Potassium - metabolism; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Protons; Rats; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2 - physiology; Receptors, Purinergic P2Y12; Tissue Distribution; Whooping cough; Xenopus; San Francisco California; South San Francisco California; California; United States > US; Amphibia; Electrophysiology; Hemopathy; ADP; Characterization; Gene; Antithrombotic agent; Genetics; Molecular cloning; G protein; Biological receptor; Human; Xenopus laevis; Salientia; Gene expression; In vitro; Cell subpopulation; Antiplatelet agent; Ticlopidine; Vertebrata; Platelet; Animal; Clopidogrel; Mutation; Coagulopathy; Oocyte
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35051599

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 activators. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes. The P2Y 1 receptor couples to Gq and mobilizes intracellular calcium ions to mediate platelet shape change and aggregation. 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 G i-linked receptor is still elusive, even though it is the target of efficacious antithrombotic agents, such as ticlopidine and clopidogrel and AR-C66096 (ref. 9). Here we describe the cloning of this receptor, designated P2Y12, and provide evidence that a patient with a bleeding disorder has a defect in this gene. Cloning of the P2Y12 receptor should facilitate the development of better antiplatelet agents to treat cardiovascular diseases.