Role of purinergic activation and TRPC3 channels in the Frank-Starling mechanism

TRPC3 channels are involved in the physiological and pathological myocardial responses to mechanical loads. However, the involvement of TRPC3 in the response to acute stretch, that is, the Frank-Starling mechanism, has not been comprehensively elucidated. To elucidate this, we analyzed the response to stretch in isolated mouse ventricular cardiomyocytes. Our analysis revealed that TRPC3-deficient cells exhibited significantly lower cellular end-systolic elastance, an index of contractility, than wild-type cells owing to the absence of acute stretch-induced reactive oxygen species (ROS) production. Subsequently, we demonstrated that ATP released from pannexin-1 during stretch activates the TRPC3-NOX2 complex via P2Y signaling, thereby increasing ROS production. The results of this study show that TRPC3 plays a role in the Frank-Starling mechanism by mediating the mechanotransduction pathway of stretch-induced ROS production, which is a novel physiological role for TRPC3 in the heart.