Abstract

Blood platelets produced by bone marrow megakaryocytes play a fundamental role in the initiation of endogenous hemostasis and effective endothelial repair following vascular injury. Although most platelets are found circulating inactivated in the intact vasculature, they rapidly become activated on vessel wall injury and adhere to the exposed extracellular matrix to form a platelet plug, thereby preventing blood loss. Although the activation of platelets is mediated by diverse agonists including subendothelial collagens, thromboxane A2, adenosine diphosphate (ADP), and thrombin, which act on different platelet receptors and initiate distinct signaling pathways, they all converge to an elevation of the intracellular calcium (Ca2+) concentration ([Ca]i) that drives platelet conformational change, degranulation, and insideout activation of integrin αIIbβ3 essential for platelet aggregation.1 Numerous studies have investigated the signaling pathways and molecular players contributing to Ca2+ mobilization during platelet activation. Whereas the release of Ca2+ from intracellular stores via inositol 1,4,5trisphosphate (IP3) receptors (IP3Rs) plays a major role in the elevation of [Ca ]i during platelet activation, several studies have reported on the importance of extracellular Ca2+ entry through the plasma membrane. For instance, it is established that IP3mediated Ca 2+ release from internal stores in turns triggers storeoperated Ca2+ (SOC) entry through Orai1 channels in the plasma membrane.2 In addition, a significant influx of Ca2+ also occurs via ATPgated purinergic P2X1 receptors3 and canonical transient receptor potential TRPC6 channels.4 In contrast, the implication of plasma membrane voltagegated Ca2+ channels (VGCCs) in platelet Ca2+ homeostasis has remained elusive. Early studies using pharmacological blockers and radioligand binding assays have ruled out on the implication of Ltype VGCCs in human platelets.5– 7