Journal
CELL DEATH AND DIFFERENTIATION
Volume 14, Issue 7, Pages 1305-1314Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4402138
Keywords
S-nitrosylation; NMDA receptor; parkin; protein-disulfide isomerase; memantine; NitroMemantine
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Funding
- NEI NIH HHS [R01 EY09024, R01 EY05477] Funding Source: Medline
- NICHD NIH HHS [P01 HD29587] Funding Source: Medline
- NINDS NIH HHS [R01 NS046994] Funding Source: Medline
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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca2+ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins - can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.
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