Transient Receptor Potential Channel 6: Role in Hemostasis and Thrombogenesis

Abstract

Although the importance of cytosolic calcium (Ca2+) elevation in the regulation of platelet activation has been widely acknowledged, the underlying mechanism of Ca2+ entry is still unclear. Previous studies have demonstrated that the transient receptor potential channel 6 (TRPC6) is abundantly expressed in platelets, particularly in the plasma membrane. Thus, our goal was to characterize the role of TRPC6 in platelet function in vivo. To this end, we employed a genetic approach, subjecting TRPC6 knockout mice (KO) to the tail bleeding time test and a carotid artery injury thrombosis model. We found that TRPC6 KO mice displayed a prolonged bleeding time, and an increased time for occlusion of the injured carotid artery, compared to their wild‐type (WT) littermates. Regarding a possible mechanism for the observed defects, our preliminary in vitro studies revealed a defect in the thromboxane receptor‐mediated platelet aggregation in the TRPC6 KO mice, compared to the WT animals. On the other hand, TRPC6 KO mice exhibited no apparent aggregation defects in response to ADP or the thrombin receptor activating peptide 4. Taken together, our data demonstrate, for the first time, that TRPC6 deletion results in defects in hemostasis and protection against thrombogenesis, suggesting a vital role in platelet function. Furthermore, TRPC6 may define a new therapeutic target for managing multiple thrombosis‐based disorders.