Platelet P2 receptors: from curiosity to clinical targets

Adenosine 5′-diphosphate (ADP) is a paracrine mediator that activates human blood platelets, causing them to become adhesive and thereby contributing to their role in hemostasis. The actions of ADP were initially thought to be mediated by a unique ADP receptor termed P2_T found only on platelets and antagonized by ATP, but it appears that at least two P2Y receptor subtypes are involved, a P2Y₁ receptor linked in some way to control of intracellular-free calcium levels and another P2Y receptor linked via an inhibitory G protein to adenylate cyclase. In addition, the presence of excitatory P2X₁ receptors that mediate the influx of monovalent and divalent cations in response to both ADP and ATP has been demonstrated. The precise contribution that each of these P2 receptors make to the overall phenomena associated with platelet aggregation, adhesion and hemostasis is yet to be defined. Antithrombotic agents that interfere with the actions of ADP are marketed, and P2 receptor antagonists are entering clinical trials for acute treatments of thrombosis. This review seeks to summarize the present state of knowledge of platelet P2 receptor pharmacology and therapeutics.