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

Soichiro Akashi, Khandaker Ahtesham Ahmed, Tomohiro Sawa, Katsuhiko Ono, Hiroyasu Tsutsuki, Joseph R. Burgoyne, Tomoaki Ida, Eiji Horio, Oleksandra Prysyazhna, Yuichi Oike, Mizanur Md Rahaman, Philip Eaton, Shigemoto Fujii, Takaaki Akaike

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)751-761
Number of pages11
JournalBiochemistry
Volume55
Issue number5
DOIs
Publication statusPublished - 2016 Feb 9
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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