Ca2+-Independent, Inhibitory Effects of Cyclic Adenosine 5'-Monophosphate on Ca2+ Regulation of Phosphoinositide 3-Kinase C2{alpha}, Rho, and Myosin Phosphatase in Vascular Smooth Muscle.
We have recently demonstrated in vascular smooth muscle (VSM) that membrane depolarization by high KCl induces Ca(2+)-dependent Rho activation and myosin phosphatase (MLCP) inhibition (Ca(2+)- induced Ca(2+)-sensitization) through the mechanisms involving phosphorylation of myosin- targeting protein 1 (MYPT1) and 17-kDa protein kinase C (PKC)-potentiated inhibitory protein of PP1 (CPI-17). In the present study, we investigated whether and how cAMP affected Ca(2+)-dependent MLCP inhibition by examining the effects of forskolin, cell-permeable dibutyryl cAMP (dbcAMP), and isoproterenol. Forskolin, but not its inactive analog 1,9-dideoxyforskolin, inhibited KCl-induced contraction and the 20-kDa myosin light chain (MLC) phosphorylation without inhibiting Ca(2+) mobilization in rabbit aortic VSM. dbcAMP mimicked these forskolin effects. We recently suggested that Ca(2+)-mediated Rho activation is dependent on class II alpha-isoform of phosphoinositide 3-kinase (PI3K-C2alpha). Forskolin inhibited KCl-induced stimulation of PI3K-C2alpha activity. KCl-induced membrane depolarization stimulated Rho in a manner dependent on a PI3K but not PKC and stimulated phosphorylation of MYPT1 at Thr(850) and CPI-17 at Thr(38) in manners dependent on both PI3K and Rhokinase, but not PKC. Forskolin, dbcAMP, and isoproterenol inhibited KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17. Consistent with these data, forskolin, isoproterenol, a PI3K inhibitor, or a Rho kinase inhibitor, but not a PKC inhibitor, abolished KCl-induced diphosphorylation of MLC. These observations indicate that cAMP inhibits Ca(2+)-mediated activation of the MLCP-regulating signaling pathway comprising PI3K-C2alpha, Rho, and Rho kinase in a manner independent of Ca(2+) and point to the novel mechanism of the cAMP actions in the regulation of vascular smooth muscle contraction.[1]References
- Ca2+-Independent, Inhibitory Effects of Cyclic Adenosine 5'-Monophosphate on Ca2+ Regulation of Phosphoinositide 3-Kinase C2{alpha}, Rho, and Myosin Phosphatase in Vascular Smooth Muscle. Azam, M.A., Yoshioka, K., Ohkura, S., Takuwa, N., Sugimoto, N., Sato, K., Takuwa, Y. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
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