Platelets possess two receptors for ADP, P2Y1 and P2Y12. ADP is released from platelet dense granules upon platelet activation by numerous agonists and thereby amplifies platelet responses regardless of the initial stimulus. The P2Y1 receptor is one of many platelet receptors coupled to Gq and initiates ADP-induced activation. The P2Y12 receptor on the other hand is linked to Gi and plays a special role in the amplification of platelet activation initiated by numerous other pathways. Platelet activation leads to a range of responses that play a critical role in arterial thrombosis and the inflammatory responses associated with this, including platelet aggregation, dense and α granule secretion and procoagulant activity. P2Y12 receptor activation yields powerful amplification of these processes such that P2Y12 receptor antagonists may have dramatic inhibitory effects on platelet function regardless of the activating stimuli. This phenomenon, coupled with the restricted distribution of the P2Y12 receptor in humans, makes the receptor an ideal target for pharmaceutical therapy. This has already been established by the therapeutic success of clopidogrel, which acts, via an active metabolite, on this receptor. However, current therapeutic regimens of clopidogrel yield variable and incomplete P2Y12 receptor blockade and more effective strategies to block P2Y12 receptor activation offer the potential of greater clinical efficacy.
Keywords: receptor-operated cation channel, antiplatelet effects, ATP, clopidogrel, Platelet activation
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