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1 Departments of Molecular and Cellular Physiology and Cardiovascular Biology, University of Tokyo School of Medicine, Tokyo 113-0033; 2 Life Science Center, Asahi Chemical Industry, Fuji 416-0934; 3 Department of Biology, Faculty of Science, Kobe University, Kobe 657-0017; and 4 Department of Physiology, Kanazawa University School of Medicine, Kanazawa 920-8640, Japan
In smooth muscle, a Rho-regulated system
of myosin phosphatase exists; however, it has yet to be established
whether Rho kinase, one of the downstream effectors of Rho, mediates
the regulation of myosin phosphatase activity in vivo. In the present
study, we demonstrate in permeabilized vascular smooth muscle cells
(SMCs) that the vasodilator 1-(5-isoquinolinesulfonyl)-homopiperazine (HA-1077), which we show to be a potent inhibitor of Rho kinase, dose
dependently inhibits Rho-mediated enhancement of
Ca2+-induced 20-kDa myosin light
chain (MLC20) phosphorylation
due to abrogating Rho-mediated inhibition of
MLC20 dephosphorylation. By an
immune complex phosphatase assay, we found that guanosine 5'-O-(3-thiotriphosphate)
(GTP
S) stimulation of permeabilized SMCs caused a decrease in myosin
phosphatase activity with an increase in the extent of phosphorylation
of the 130-kDa myosin-binding regulatory subunit (MBS) of myosin
phosphatase in a Rho-dependent manner. HA-1077 abolished both of the
Rho-mediated events. Moreover, we observed that the pleckstrin
homology/cystein-rich domain protein of Rho kinase, a dominant negative
inhibitor of Rho kinase, inhibited GTPS-induced phosphorylation of
MBS. These results provide direct in vivo evidence that Rho kinase
mediates inhibition of myosin phosphatase activity with resultant
enhancement of MLC20
phosphorylation in smooth muscle and reveal the usefulness of HA-1077
as a Rho kinase inhibitor.
myosin light chain dephosphorylation; small G protein; calcium ion; sensitization; vascular smooth muscle; contraction
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