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Departments of Physiology and Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298
The role of RhoA in myosin
light-chain (MLC)20 dephosphorylation and smooth muscle
relaxation by PKA and PKG was examined in freshly dispersed and
cultured smooth muscle cells expressing wild-type RhoA, constitutively
active RhoV14, and phosphorylation site-deficient
RhoA188. Activators of PKA
(5,6-dichloro-1-
-ribofuranosyl benzimidazole 3',5'-cyclic
monophosphothionate, Sp-isomer; cBIMPS) or PKG
[8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate
(8-pCPT-cGMP), sodium nitroprusside (SNP)] or both PKA and PKG (VIP)
induced phosphorylation of constitutively active RhoV14 and
agonist (ACh)- or GTP
S-stimulated wild-type RhoA but not RhoA188. Phosphorylation was accompanied by translocation
of membrane-bound wild-type RhoA and RhoV14 to the cytosol
and complete inhibition of ACh-stimulated Rho kinase and phospholipase
D activities, RhoA/Rho kinase association, MLC20
phosphorylation, and sustained muscle contraction. Each of these events
was blocked depending on the agent used, by the PKG inhibitor KT5823 or
the PKA inhibitor myristoylated PKI. Inhibitors were used at a
concentration (1 µM) previously shown by direct measurement of kinase
activity to selectively inhibit the corresponding kinase. In muscle
cells overexpressing the active phosphorylation site-deficient mutant
RhoA188, MLC20 phosphorylation was partly
inhibited by SNP, VIP, cBIMPS, and 8-pCPT-cGMP, suggesting the
existence of an independent inhibitory mechanism downstream of RhoA.
Results demonstrate that dephosphorylation of MLC20 and
smooth muscle relaxation are preferentially mediated by PKG- and
PKA-dependent phosphorylation and inactivation of RhoA.
myosin light chain; myosin light chain phosphatase; regulatory myosin light chain; relaxation
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