Calcium/calmodulin-dependent protein kinases as potential targets of nitric oxide.
Nitric oxide (NO) synthesis is controlled by Ca(2+)/calmodulin (CaM) binding with and kinase-dependent phosphorylation of constitutive NO synthases, which catalyze the formation of NO and L-citrulline from L-arginine. NO operates as a mediator of important cell signaling pathways, such as cGMP signaling cascade. Another mechanism by which NO exerts biological effects is mediated via post-translational modification of redox-sensitive cysteine thiols of proteins. The Ca(2+)/CaM-dependent protein kinases (CaM kinases) such as CaM kinase I, CaM kinase II, and CaM kinase IV, are a family of protein kinases which requires binding of Ca(2+)/CaM to and subsequent phosphorylation of the enzymes to initiate its activation process. We report other regulation mechanisms of CaM kinases, such as S-glutathionylation of CaM kinase I at Cys(179) and S-nitrosylation of CaM kinase II at Cys(6/30). Such unique post-translational modification of CaMKs by NO shed light on a new area of mutual regulation of NO- and CaM kinases-signals. Based on the novel direct regulation of these kinases, we propose that CaM kinases/NO signaling would be good targets for understanding how they can participate in neuronal physiology and disease.
Department of Pharmacology, High Technology Research Center, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Tsuyoshi
T
Takata
Jun
J
Kimura
Yukihiro
Y
Tsuchiya
Yasuhito
Y
Naito
Yasuo
Y
Watanabe
D000704:Analysis of Variance; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D003001:Cloning, Molecular; D003545:Cysteine / Q000378:metabolism; D004789:Enzyme Activation; D057075:Enzyme Assays / Q000379:methods; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005822:Genetic Vectors; D047468:Immunoprecipitation; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D002147:Calmodulin; D011993:Recombinant Fusion Proteins; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C517599:Camk1 protein, rat; D003545:Cysteine; D002118:Calcium