Cyclic GMP-dependent Protein Kinase Signaling Pathway Inhibits RhoA-induced Ca2+ Sensitization of Contraction in Vascular Smooth Muscle

The potent vasodilator action of cyclic GMP-dependent protein kinase (cGK) involves decreasing the Ca2+ sensitivity of contraction of smooth muscle via stimulation of myosin light chain phosphatase through unknown mechanisms (Wu, X., Somlyo, A. V., and Somlyo, A. P. (1996)Biochem. Biophys. Res. Comm...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-07, Vol.275 (28), p.21722-21729
Main Authors: Sauzeau, Vincent, Le Jeune, Hélène, Cario-Toumaniantz, Chrystelle, Smolenski, Albert, Lohmann, Suzanne M., Bertoglio, Jacques, Chardin, Pierre, Pacaud, Pierre, Loirand, Gervaise
Format: Article
Language:English
Subjects:
Actins - drug effects
Actins - metabolism
Animals
Aorta - physiology
Calcium - physiology
Calcium Signaling - physiology
Cells, Cultured
Cyclic GMP - analogs & derivatives
Cyclic GMP - pharmacology
Cyclic GMP-Dependent Protein Kinases - metabolism
Cytoskeleton - drug effects
Cytoskeleton - physiology
Gallopamil - pharmacology
Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology
Guinea Pigs
In Vitro Techniques
Isometric Contraction - physiology
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Nitroprusside - pharmacology
Phenylephrine - pharmacology
Phosphorylation
Portal Vein - physiology
Pulmonary Artery - physiology
Rabbits
Rats
Rats, Wistar
rhoA GTP-Binding Protein - metabolism
Signal Transduction
Thapsigargin - pharmacology
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Summary:The potent vasodilator action of cyclic GMP-dependent protein kinase (cGK) involves decreasing the Ca2+ sensitivity of contraction of smooth muscle via stimulation of myosin light chain phosphatase through unknown mechanisms (Wu, X., Somlyo, A. V., and Somlyo, A. P. (1996)Biochem. Biophys. Res. Commun. 220, 658–663). Myosin light chain phosphatase activity is controlled by the small GTPase RhoA and its target Rho kinase. Here we demonstrate cGMP effects mediated by cGK that inhibit RhoA-dependent Ca2+ sensitization of contraction of blood vessels and actin cytoskeleton organization in cultured vascular myocytes. Ca2+ sensitization and actin organization were inhibited by both 8-bromo-cGMP and sodium nitroprusside (SNP). SNP also caused translocation of activated RhoA from the membrane to the cytosol. SNP-induced actin disassembly was lost in vascular myocytes in culture after successive passages but was restored by transfection of cells with cGK I. Furthermore, cGK phosphorylated RhoA in vitro, and addition of cGK I inhibited RhoA-induced Ca2+ sensitization in permeabilized smooth muscle. 8-Bromo-cGMP-induced actin disassembly was inhibited in vascular myocytes expressing RhoAAla-188, a mutant that could not be phosphorylated. Collectively, these results indicate that cGK phosphorylates and inhibits RhoA and suggest that the consequent inhibition of RhoA-induced Ca2+ sensitization and actin cytoskeleton organization contributes to the vasodilator action of nitric oxide.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M000753200