Molecular Determinants for Cardiovascular TRPC6 Channel Regulation by Ca2+/calmodulin‐dependent Kinase II

•  Ca2+/calmodulin (CaM)‐dependent kinase II (CaMKII) plays pivotal roles in diverse Ca2+‐mediated cellular functions including the physiology/pathophysiology of the cardiovascular system, through modulation of a variety of Ca2+‐permeable channels such as a non‐voltage‐gated Ca2+ channel TRPC6. •  In this study, we investigated the molecular mechanism underlying its positive regulation by CaMKII with chimera, deletion and site‐directed mutagenesis approaches. •  The results indicate that two spatially separated sites of TRPC6 channel, i.e. a distal part of the C‐terminal inositol‐1,4,5‐trisphosphate receptor/CaM binding domain and Thr487 located on the putative first intracellular loop, are crucial for the CaMKII‐mediated regulation of TRPC6 channels. •  This mechanism may serve as an effective positive feedback regulation of Ca2+ influx through TRPC6 channels, in concert with intracellular and transmembrane Ca2+ mobilization upon phospholipase C‐coupled receptor stimulation by neurohormonal factors, thereby fine‐tuning the cardiovascular functions. •  Disruption of these could lead to pathological states such as cardiac hypertrophy and arrhythmia, hypertension and atherosclerosis.