Abstract
TRPC6 (a canonical subfamily member of transient receptor potential protein) is a predominant isoform expressed in vascular smooth muscle and likely serves as an integrative non-voltage-gated Ca2+ entry channel regulating the vascular tone and remodeling. Activation of this channel occurs polymodally by stimulation of PLC-linked, G-protein-coupled and tyrosine kinase receptors and mechanical forces. Although store depletion and diacylglycerol have been proposed to be important activating signals, we have recently found that two novel mechanisms, i.e., Ca2+/calmodulin (CaM)-dependent phosphorylation and generation of an arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), strongly affect TRPC6 channel activities. Assuming a similar membrane topology to TRPC1, the former may involve the phosphorylation of T487 on the II-III intracellular loop of TRPC6 channel presumably via CaM-dependent kinases bound to its C-terminus, which leads to priming of the channel for opening in response to receptor stimulation. In contrast, the latter requires the preceding activation of TRPC6 channel by receptor stimulation, which appears to render the channel mechanosensitive through mechanical activation of phosphopliase A2 and subsequent metabolization of AA into 20-HETE via vascular smooth muscle specific cytochrome P450 enzymes having ω-hydroxylase activities. The both mechanisms seem to contribute to maintaining the vascular tone. [J Physiol Sci. 2006;56 Suppl:S12]
