Cell signaling mediated by nitrated cyclic guanine nucleotide.
We recently clarified the physiological formation of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) and its critical roles in nitric oxide (NO) signal transductions. This discovery of 8-nitro-cGMP is the first demonstration of a nitrated cyclic nucleotide functioning as a new second messenger in mammals since the identification of cGMP more than 40 years ago. By means of chemical analyses, e.g., liquid chromatography-tandem mass spectrometry, we unequivocally identified 8-nitro-cGMP formation, which depended on NO production, in several types of cultured cells, including macrophages and glial cells. Most important, we previously showed that 8-nitro-cGMP as an electrophile reacted with particular sulfhydryls of proteins to generate a unique post-translational modification that we called protein S-guanylation. In fact, certain specific intracellular proteins, such as the redox-sensor protein Keap1, readily underwent S-guanylation induced by 8-nitro-cGMP. 8-Nitro-cGMP activated the Nrf2 signaling pathway by triggering dissociation of Keap1, via S-guanylation of its highly nucleophilic cysteine sulfhydryls. We also determined that S-guanylation of Keap1 was involved in cytoprotective actions of NO and 8-nitro-cGMP by inducing oxidative stress response genes such as heme oxygenase-1. Such unique chemical properties of 8-nitro-cGMP shed light on new areas of NO and cGMP signal transduction. Protein S-guanylation induced by 8-nitro-cGMP may thus have important implications in NO-related physiology and pathology, pharmaceutical chemistry, and development of therapeutics for many diseases.
Akaike
Takaaki
T
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. takakaik@gpo.kumamoto-u.ac.jp
Fujii
Shigemoto
S
Sawa
Tomohiro
T
Ihara
Hideshi
H
D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction
C525106:8-nitroguanosine 3',5'-cyclic monophosphate; D009569:Nitric Oxide; D006152:Cyclic GMP