Published online before print February 14, 2002, doi: 10.1161/01.RES.0000012822.23273.EC
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Submitted on September 26, 2001
Revised on January 31, 2002
Accepted on February 1, 2002
Differential Association and Localization of Myosin Phosphatase Subunits During Agonist-Induced Signal Transduction in Smooth Muscle
Heung-Mook Shin ;
From the Boston Biomedical Research Institute (H.-M.S., H.-D.J., C.G., T.C.T., K.G.M.), Watertown, Mass; the Department of Physiology (H.-M.S.), Dongguk University College of Oriental Medicine, Kyongju, Kyongbuk, Korea; the Department of Chemistry (T.C.T.), Tufts University School of Medicine, Boston, Mass; the Department of Neurology (T.C.T), and Department of Medicine, Beth Israel Deaconess Medical Center (K.G.M.), Harvard Medical School, Boston, Mass; the Muscle Biology Group (D.J.H.), University of Arizona, Tucson, Ariz; and the First Department of Internal Medicine (M.I.), Mie University School of Medicine, Tsu, Mie, Japan.
* To whom correspondence should be addressed. E-mail: morgan{at}BBRI.org.
It has been known for some time that agonist-induced contractions of vascular smooth muscle are often associated with a sensitization of the contractile apparatus to intracellular Ca2+. One mechanism that has been suggested to explain Ca2+ sensitization is inhibition of myosin phosphatase activity. In the present study, we tested the hypothesis that differential localization of the phosphatase might be associated with its inhibition. Quantitative confocal microscopy of freshly dissociated, fully contractile smooth muscle cells was used in parallel with measurements of myosin light chain and myosin phosphatase phosphorylation. The results indicate that, in the smooth muscle cells, the catalytic and targeting subunits of the phosphatase are dissociated from each other in an agonist-specific manner and that the dissociation is accompanied by a slower rate of myosin phosphorylation. Targeting of myosin phosphatase to the cell membrane precedes the dissociation of subunits and is associated with phosphorylation of the targeting subunit at a Rho-associated kinase (ROK) phosphorylation site. The phosphorylation and membrane translocation of the targeting subunit are inhibited by a ROK inhibitor. This dissociation of subunits may provide a mechanism for the decreased phosphatase activity of phosphorylated myosin phosphatase.
Key words: myosin phosphatase • smooth muscle • Rho-associated kinase • contractility • myosin phosphorylation
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