抄録
We have recently demonstrated in VSM that membrane depolarization (KCl stimulation) induces Ca2+-dependent Rho activation and MP inhibition through the mechanisms involving Rho kinase (ROK). ROK is shown to mediate MP inhibition by phosphorylating 110-kDa myosin targeting regulatory subunit MYPT1 of MP and/or MP-inhibitory phosphoprotein CPI-17 in receptor agonist-stimulated VSM. Protein kinase C (PKC) might also phosphorylate CPI-17, thus contributing to MP inhibition. However, it is unknown whether and how cyclic AMP, which induces inhibition of contraction, affects Ca2+-dependent Rho activation and MP inhibition. KCl induced phosphorylation of both MYPT1 and CPI-17 in a ROK inhibitor-sensitive manner, suggesting that Rho kinase mediated phosphorylation of CPI-17 as well as MYPT1. Forskolin, an adenylate cyclase activator, inhibited KCl-induced contraction with inhibition of MLC phosphorylation. Forskolin also suppressed KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17. KCl-induced Rho activation and contraction was inhibited by phosphoinositide 3-kinase (PI3K) inhibitors. KCl induced stimulation of the activity of a PI3K isoform. We are now investigating the effect of forskolin on KCl-induced PI3K activation. Thus, membrane depolarization induces not only Ca2+-dependent MLC kinase activation, but also Ca2+-dependent MP inhibition through a PI3K, Rho and Rho kinase. Cyclic AMP effectively inhibits Rho activation and thereby MP inhibition. [Jpn J Physiol 55 Suppl:S74 (2005)]
