Calcium-dependent regulation of Rho and myosin phosphatase in vascular smooth muscle

Calcium-dependent regulation of Rho and myosin phosphatase in vascular smooth muscle
Yoh Takuwa, Kazuaki Yoshioka, Noriko Takuwa, Yu Wang, Mohammed Ali Azam, and Naotoshi Sugimoto (Japan)

Phosphorylation of 20 kD myosin light chain (MLC) is a critical process in eliciting smooth muscle contraction. Excitatory receptor agonists increase the extent of MLC phosphorylation by both activating myosin light chain kinase (MLCK) and inhibiting myosin phosphatase (MP). Activation of MLCK is dependent on Ca2+ and calmodulin, while inhibition of MP is dependent on the small guanosine triphosphatase Rho and Rho kinase. Receptor agonists were previously shown to induce Rho activation via the heterotrimeric G12/13 protein, largely in non-muscle cells. We recently discovered the novel Ca2+-dependent activation of Rho in vascular smooth muscle. This Ca2+-dependent Rho activation mechanism operates upon stimulation of vascular smooth muscle by either membrane depolarization or Gq-coupled vasoconstrictor receptors. Thus, Ca2+ induces MLC phosphorylation through both MLCK stimulation and MP inhibition. We found that phosphoinositide 3-kinase class II . isoform (PI3K-C2.) is involved in the Ca2+-dependent Rho activation and MP inhibition. PI3K-C2. appears to participate in regulation of vascular Rho activity and tone in vivo. These observations also indicate that PI3Ks exert isoform-specificeffectsonvasculartonethrough mechanisms involving regulation of endothelial nitric oxide production and smooth muscle MP activity.
Biomed Rev 2005; 16: 13-21.

Key words: contraction, phosphoinositide 3-kinase class II ., myosin light chain phosphorylation, Rho kinase, MYPT1
Received 18 October 2005 and accepted 23 December 2005.

Correspondence and reprint requests to Dr. Yoh Takuwa, Department of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. Tel.: 81 76 265 2165, Fax: 81 76 234 4223,

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