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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 16, 2006; DOI: 10.1124/jpet.106.111443

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Received for publication July 24, 2006.
Revised October 29, 2006.
Accepted for publication November 15, 2006.

Ca2+-independent, inhibitory effects of cyclic AMP on Ca2+ regulation of phosphoinositide 3-kinase C2{alpha}, Rho and myosin phosphatase in vascular smooth muscle

Mohammed Ali Azam 1, Kazuaki Yoshioka 1, Shinsuke Ohkura 2, Noriko Takuwa 3, Naotoshi Sugimoto 1, Koichi Sato 2, Yoh Takuwa 1*

1 Kanazawa University 2 Yamaguchi University 3 Ishikawa Prefectural University

* Address correspondence to: E-mail: ytakuwa{at}med.kanazawa-u.ac.jp

Abstract

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 MYPT1 and CPI-17. In the present study, we investigated whether and how cyclic AMP affected Ca2+-dependent MLCP inhibiton by examining the effects of forskolin, cell permeable dibutyryl cyclic AMP (dbcAMP) and isoproterenol. Forskolin, but not its inactive analogue 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 {alpha}-isoform of phosphoinositide 3-kinase (PI3K-C2{alpha}). Forskolin inhibited KCl-induced stimulation of PI3K-C2{alpha} activity. KCl-induced membrane depolarization stimulated Rho in a manner dependent on a PI3K but not PKC (protein kinase C), and stimulated phosphorylation of MYPT1 at Thr850 and CPI-17 at Thr38 in manners dependent on both PI3K and Rho-kinase, but not PKC. Forskolin, dbcAMP and isoproterenol inhibited KCl-induced Rho activation and phosphorylation of MYPT1 and CPI-17. Consistent with these data, either forskolin, isoproterenol, a PI3K inhibitor, or a Rho kinase inhibitor, but not a PKC inhibitor, abolished KCl-induced di-phosphorylation of MLC. These observations indicate that cyclic AMP inhibits Ca2+-mediated activation of the MLCP-regulating signaling pathway comprising PI3K-C2{alpha}, Rho, and Rho kinase in a manner independent of Ca2+, and point to the novel mechanism of the cyclic AMP actions in the regulation of vascular smooth muscle contraction.


Key words: Calcium, Rho, Vascular smooth muscle, cyclic AMP, myosin phosphatase, phosphoinositide 3-kinase


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