G-protein dependent platelet signaling--perspectives for therapy.

Platelet activation and aggregation is an integral component of the pathophysiology that leads to thrombotic and ischemic diseases such as cerebral stroke, peripheral vascular disease and myocardial infarction. Anti-platelet agents (such as aspirin, ADP receptor antagonists, and GPIIb/IIIa antagonists), phosphodiesterase inhibitors and anti-coagulants are major part of the current treatment towards treating ischemic diseases. However, their limited efficacy in the setting of arterial thrombosis, unfavorable side effect profile and cost-to-benefit issues substantiate the need for the development of newer and more efficacious antithrombotic drugs. Various platelet agonists like adenosine diphosphate (ADP), thrombin and thromboxane A2 (TXA2) activate platelets by acting via their respective surface receptors, which couple to one or more distinct G-proteins belonging to either the G(i), G(q), G(12/13) or G(s) families. Upon activation, each of these G-proteins trigger a series of intracellular signaling cascades, causing the platelets to undergo shape change, secrete their granular contents, generate positive feedback mediators and form stable platelet aggregates. In addition, various G-protein-mediated signaling cascades act in synergy with one another to amplify the magnitude of the platelet responses. The significance of G-proteins as key mediators of the platelet function and normal hemostasis is further corroborated by extensive gene knockout studies. In this review we will limit our discussion to understanding the role of G-proteins in the process of platelet activation and discuss some of the anti-thrombotic drugs that mediate their beneficial effects by interfering with or preventing the initiation of the G-protein signaling pathway.

Nucleotide receptor signaling in platelets.

Upon injury to a vessel wall the exposure of subendothelial collagen results in the activation of platelets. Platelet activation culminates in shape change, aggregation, release of granule contents and generation of lipid mediators. These secreted and generated mediators trigger a positive feedback mechanism potentiating the platelet activation induced by physiological agonists such as collagen and thrombin. Adenine nucleotides, adenosine diphosphate (ADP) and adenosine triphosphate (ATP), released from damaged cells and that are secreted from platelet-dense granules, contribute to the positive feedback mechanism by acting through nucleotide receptors on the platelet surface. ADP acts through two G protein-coupled receptors, the Gq-coupled P2Y1 receptor, and the Gi-coupled P2Y12 receptor. ATP, on the other hand, acts through the ligand-gated channel P2X1. Stimulation of platelets by ADP leads to shape change, aggregation and thromboxane A2 generation. ADP-induced dense granule release depends on generated thromboxane A2. Furthermore, costimulation of both P2Y1 and P2Y12 receptors is required for ADP-induced platelet aggregation. ATP stimulation of P2X1 is involved in platelet shape change and helps to amplify platelet responses mediated by agonists such as collagen. Activation of each of these nucleotide receptors results in unique signal transduction pathways that are important in the regulation of thrombosis and hemostasis.