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CARDIOVASCULAR

Ca²⁺-Independent, Inhibitory Effects of Cyclic Adenosine 5'-Monophosphate on Ca²⁺ Regulation of Phosphoinositide 3-Kinase C2, Rho, and Myosin Phosphatase in Vascular Smooth Muscle

Department of Physiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (M.A.A., K.Y., N.S., Y.T.); Department of Veterinary Pharmacology, Faculty of Agriculture, Yamaguchi University, Yamaguchi, Japan (S.O., K.S.); and Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University, Kahoku, Japan (N.T.)

We have recently demonstrated in vascular smooth muscle (VSM) that membrane depolarization by high KCl induces Ca²⁺-dependent Rho activation and myosin phosphatase (MLCP) inhibition (Ca²⁺-induced Ca²⁺-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 Ca²⁺-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 Ca²⁺ mobilization in rabbit aortic VSM. dbcAMP mimicked these forskolin effects. We recently suggested that Ca²⁺-mediated Rho activation is dependent on class II -isoform of phosphoinositide 3-kinase (PI3K-C2). Forskolin inhibited KCl-induced stimulation of PI3K-C2 activity. KCl-induced membrane depolarization stimulated Rho in a manner dependent on a PI3K but not PKC and stimulated phosphorylation of MYPT1 at Thr⁸⁵⁰ and CPI-17 at Thr³⁸ 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 Ca²⁺-mediated activation of the MLCP-regulating signaling pathway comprising PI3K-C2, Rho, and Rho kinase in a manner independent of Ca²⁺ and point to the novel mechanism of the cAMP actions in the regulation of vascular smooth muscle contraction.

Address correspondence to: Dr. Yoh Takuwa, Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. E-mail:ytakuwa{at}med.kanazawa-u.ac.jp

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