Calcium signaling in platelets

Summary.  Agonist-induced elevation in cytosolic Ca²⁺ concentrations is essential for platelet activation in hemostasis and thrombosis. It occurs through Ca²⁺ release from intracellular stores and Ca²⁺ entry through the plasma membrane (PM). Ca²⁺ store release is a well-established process involving phospholipase (PL)C-mediated production of inositol-1,4,5-trisphosphate (IP₃), which in turn releases Ca²⁺ from the intracellular stores through IP₃ receptor channels. In contrast, the mechanisms controlling Ca²⁺ entry and the significance of this process for platelet activation have been elucidated only very recently. In platelets, as in other non-excitable cells, the major way of Ca²⁺ entry involves the agonist-induced release of cytosolic sequestered Ca²⁺ followed by Ca²⁺ influx through the PM, a process referred to as store-operated calcium entry (SOCE). It is now clear that stromal interaction molecule 1 (STIM1), a Ca²⁺ sensor molecule in intracellular stores, and the four transmembrane channel protein Orai1 are the key players in platelet SOCE. The other major Ca²⁺ entry mechanism is mediated by the direct receptor-operated calcium (ROC) channel, P2X₁. Besides these, canonical transient receptor potential channel (TRPC) 6 mediates Ca²⁺ entry through the PM. This review summarizes the current knowledge of platelet Ca²⁺ homeostasis with a focus on the newly identified Ca²⁺ entry mechanisms.