On the mechanism of modal regulation of cardiovascular Ca2+entry channel TRPC6

经典瞬时受体电位蛋白6（TRPC 6）是一种通过受体介导和机械敏感信号通路的协同作用激活的Ca^2+进入通道。它的过度活动有助于心血管疾病的发病机制。本研究的结果表明，受体和机械刺激对TRPC 6通道激活之间的协同作用可能是通过TRPC 6通道N-末端锚定样结构域和肌动蛋白细胞骨架之间的物理相互作用和功能偶联发生的。此外，这种协同作用被邻近这些结构域的氨基酸残基中的致病性突变放大，并被蛋白激酶G介导的TRPC 6 N-末端磷酸化抵消，分别通过加强和破坏N-末端结构域-肌动蛋白细胞骨架相互作用。

The canonical transient receptor potential protein 6(TRPC6) is a Ca^<2+> entry channel activated by synergistic operation of receptor-mediated and mechanosentive signaling pathways. Its excessive activity contributes to the pathogenesis of cardiovascular diseases. The results of the present study suggest that the synergy between receptor and mechanical stimulations on TRPC6 channel activation likely occurs through physical interaction and functional coupling between TRPC6 channel N-terminal ankyrin-like domains and actin cytoskeleton. Further, this synergy is exaggerated by pathogenic mutations in amino acid residues adjacent to these domains, and counteracted byprotein kinase G-mediated phosphorylation of TRPC6 N-terminus, by strengthening and disrupting the N-terminus domain-actin cytoskeleton interaction, respectively.