Identification of the platelet ADP receptor targeted by antithrombotic drugs

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 activators. ADP mediates platelet aggregation through its action on two G-protein-coupled receptor subtypes. The P2Y1 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 P2Y(ADP), P2Y(AC), P2Ycyc or P2T(AC)) 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 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.

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

“…ADP binds to the G‐protein‐coupled receptors P2Y 1 22 and P2Y 12 23, 24 located on the platelet surface membrane. For a normal ADP‐induced activation and aggregation, responses from both pathways are required 25, 26, 27.…”

The role of purinergic signalling in the musculoskeletal system

“…The P2Y12 receptor was only identified in 2001 (Hollopeter et al, 2001), the same year as the study by Hoebertz et al, and thus it was not considered in the original investigation. Expression of the P2Y12 receptor by osteoclasts has recently been reported (Orriss et al, 2011b) and P2Y12 receptor knockout mice display impaired responses to ADP, increased trabecular bone and decreased arthritis associated bone loss (Su et al, 2012).…”

Historical perspective on ADP-induced platelet activation

“…First P2 T [112], followed by P2Y cyc [123], P2Y AC [106], P2Y ADP [124], and finally, in 2001, P2Y 12 after it was cloned and analyzed by Hollopeter et al [125]. The latter investigators showed that the receptor has four extracellular cysteines and that the thiol reagent p-chloromercuriphenylsulfonic acid (pCMBS) inhibits ADP-induced P2Y 12 activation [125]. Twenty years earlier, Macfarlane and Mills [90] had already used a similar reagent to prevent ADP-induced inhibition of cyclic AMP formation in platelets.…”