A novel mechanism underlying the susceptibility of neuronal cells to nitric oxide: the occurrence and regulation of protein S-nitrosylation is the checkpoint.

Abstract

The susceptibility of neuronal cells to nitric oxide (NO) is a key issue in NO-mediated neurotoxicity. However, the underlying mechanism remains unclear. As a cyclic guanosine monophosphate (cGMP)-independent NO signaling pathway, S-nitrosylation (or S-nitrosation) has been suggested to occur as a post-translational modification in parallel with O-phosphorylation. The underlying mechanism of the involvement of protein S-nitrosylation in the susceptibility of neuronal cells to NO has been little investigated. In this study, we focused on the role of S-nitrosothiols (RSNO) in the susceptibility of a cerebellar cell line R2 to NO. Our results showed the following: (i) S-nitrosoglutathione (GSNO) induced a burst of RSNO in GSH-depleted R2 cells, the majority of which were primarily contributed by the S-nitrosylation of proteins (Pro-SNOs), and was followed by severe neuronal necrosis; (ii) the elevation in the level of Pro-SNOs resulted from a dysfunction of S-nitroglutathione reductase (GSNOR) as a result of its substrate, GSNO, being unavailable in GSH-depleted cells. In the meantime, the suppression of GSNOR increased NO-mediated neurotoxicity in R2 cells, as well as in cerebellar granule neurons; (iii) Our results also demonstrate that the burst of RSNO is the "checkpoint" of cell fate: if RSNO can be reduced to free thiol proteins, cells will survive; if they are further oxidized, cells will die; and (iv) GSH-ethyl ester and Vitamin C protected R2 cells against GSNO neurotoxicity through two distinct mechanisms: by inhibiting the elevation of Pro-SNOs and by reducing Pro-SNOs to free thiol proteins, respectively. A novel mechanism underlying the susceptibility of neuronal cells to NO is proposed and some potential strategies to prevent the NO-mediated neurotoxicity are discussed.

• Authors: J He, T Wang, P Wang, P Han, Q Yin, C Chen
• Journal: Journal of neurochemistry (J Neurochem) Vol. 102 Issue 6 Pg. 1863-1874 (Sep 2007) ISSN: 0022-3042 [Print] England
• PMID: 17767703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Nitro Compounds
• Sulfhydryl Compounds
• Nitric Oxide
• S-Nitrosoglutathione
• Glutathione

Topics

• Animals
• Animals, Newborn
• Brain (metabolism, physiopathology)
• Cell Death (drug effects, physiology)
• Cell Line
• Cell Survival (physiology)
• Cells, Cultured
• Cytoprotection (drug effects, physiology)
• Glutathione (metabolism)
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects, metabolism)
• Nitric Oxide (metabolism, toxicity)
• Nitro Compounds (metabolism)
• Oxidation-Reduction
• Oxidative Stress (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• S-Nitrosoglutathione (metabolism)
• Signal Transduction (drug effects, physiology)
• Sulfhydryl Compounds (metabolism)