Cell signaling mediated by nitrated cyclic guanine nucleotide

T. Akaike, Shigemoto Fujii, Tomohiro Sawa, Hideshi Ihara

Research output: Contribution to journalReview articlepeer-review

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)166-174
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume23
Issue number3
DOIs
Publication statusPublished - 2010 Nov

Keywords

  • 8-Nitro-cGMP
  • Cell signaling
  • Nitrated cyclic nucleotide
  • Nitric oxide
  • S-guanylation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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