The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction.
A variety of contractile agonists trigger activation of the small GTPase RhoA. An important target of activated RhoA in smooth muscle is Rho-associated kinase (ROK), one of the downstream targets that is the myosin binding subunit (MYPT1) of myosin light chain phosphatase (MLCP). Phosphorylation of MYPT1 at T695 by activated ROK results in a decrease in phosphatase activity of MLCP and an increase in myosin light chain (LC(20)) phosphorylation catalyzed by Ca(2)(+)/calmodulin-dependent myosin light chain kinase and/or a distinct Ca(2)(+)-independent kinase. LC(20) phosphorylation in turn triggers cross-bridge cycling and force development. ROK also phosphorylates the cytosolic protein CPI-17 (at T38), which thereby becomes a potent inhibitor of MLCP. The RhoA/ROK pathway has been implicated in the tonic phase of force maintenance in response to various agonists, with no evident role in the phasic response, suggesting this pathway as a potential target for antihypertensive therapy. Indeed, ROK inhibitors restore normal blood pressure in several rat hypertensive models.
Swärd
Karl
K
Smooth Muscle Research Group and Department of Biochemistry and Molecular Biology, University of Calgary Faculty of Medicine, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Mita
Mitsuo
M
Wilson
David P
DP
Deng
Jing Ti
JT
Susnjar
Marija
M
Walsh
Michael P
MP
D000818:Animals; D002118:Calcium / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D043263:Myosin-Light-Chain Phosphatase; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; D043263:Myosin-Light-Chain Phosphatase; D020742:rhoA GTP-Binding Protein; D002118:Calcium