Receptor-mediated inhibitory mechanisms and the regulation of platelet function.

Abstract

Platelets are derived from megakaryocytes; they circulate in mammalian blood vessels and play essential roles in hemostasis and thrombosis. When platelets encounter injury, they respond by triggering the formation of a blood clot to prevent blood loss (hemostasis). While this is vital for survival, platelets can cause blood clots inside arteries (known as thrombosis), which can trigger heart attack and stroke. Platelets express a variety of receptors, including adhesive receptors, such as glycoprotein (GP) IIb-IIIa (IIb3), GPIb-IX-V, GPIa-IIa (21), and GPVI, which can mediate the adherence of platelets to exposed collagen fibers at the sites of blood vessel injury or atherosclerosis plaque rupture [1]. These adhesive receptors initiate intracellular signals that cause platelet adhesion, spreading, and secretion. The activated platelets release several soluble agonists, such as adenosine diphosphate (ADP), prostanoid thromboxane A2 (TXA2), and thrombin. These agonists amplify the initial signals and recruit additional platelets from the circulation into a growing thrombus. The amplification of platelet activation and recruitment is mediated by G protein coupled receptors (GPCRs), such as the ADP receptors P2Y1 and P2Y12 (coupled to Gq and Gi, respectively), the TXA2 receptor Tp (coupled to Gq and G12/13) and PARs, which bind thrombin (coupled to Gi, Gq and G12/13) [2]. The functions and downstream signals of these platelet adhesive receptors in hemostasis and thrombosis have been well characterized. However, the currently most widely used anti-platelet drugs, such as the antagonists of IIb3 and P2Y12, target on the activation mechanisms and have low efficacy in many patients and are associated with serious bleeding side-effects. To develop more effective antithrombotic drugs, understanding how platelet activation is regulated is necessary. The accumulated evidence over the past decade indicates that endogenous receptor-mediated inhibitory mechanisms keep platelets quiescent and prevent excessive platelet activation. In this review, we discuss the mechanisms and therapeutic potential of inhibitory pathways in the regulation of platelet activation.