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Biochemistry. 2016 Feb 9;55(5):751-61. doi: 10.1021/acs.biochem.5b00774. Epub 2016 Jan 29.

Persistent Activation of cGMP-Dependent Protein Kinase by a Nitrated Cyclic Nucleotide via Site Specific Protein S-Guanylation.

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Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency , Kawaguchi, Saitama 332-0012, Japan.
Department of Cardiology, Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital , London SE1 7EH, U.K.
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University , Honjo 1-1-1, Kumamoto 860-8556, Japan.


8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a nitrated derivative of guanosine 3',5'-cyclic monophosphate (cGMP) formed endogenously under conditions associated with production of both reactive oxygen species and nitric oxide. It acts as an electrophilic second messenger in the regulation of cellular signaling by inducing a post-translational modification of redox-sensitive protein thiols via covalent adduction of cGMP moieties to protein thiols (protein S-guanylation). Here, we demonstrate that 8-nitro-cGMP potentially S-guanylates thiol groups of cGMP-dependent protein kinase (PKG), the enzyme that serves as one of the major receptor proteins for intracellular cGMP and controls a variety of cellular responses. S-Guanylation of PKG was found to occur in a site specific manner; Cys42 and Cys195 were the susceptible residues among 11 Cys residues. Importantly, S-guanylation at Cys195, which is located in the high-affinity cGMP binding domain of PKG, causes persistent enzyme activation as determined by in vitro kinase assay as well as by an organ bath assay. In vivo, S-guanylation of PKG was demonstrated to occur in mice without any specific treatment and was significantly enhanced by lipopolysaccharide administration. These findings warrant further investigation in terms of the physiological and pathophysiological roles of S-guanylation-dependent persistent PKG activation.

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