期刊
ANTIOXIDANTS & REDOX SIGNALING
卷 10, 期 1, 页码 87-101出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2007.1858
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资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P01HD029587] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R01EY005477, R01EY009024] Funding Source: NIH RePORTER
- NEI NIH HHS [R01 EY05477, R01 EY09024] Funding Source: Medline
- NICHD NIH HHS [P01 HD29587] Funding Source: Medline
Overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic disorders. Recent studies have suggested that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS) can mediate excitotoxicity, in part by triggering protein misfolding. S-Nitrosylation, which is a covalent reaction of a NO group with a cysteine thiol, represents one such mechanism that can contribute to NO-induced neurotoxicity. The ubiquitin-proteasome system (UPS), in conjunction with molecular chaperones, can prevent accumulation of aberrantly-folded proteins. For example, protein disulfide isomerase (PDI) can provide neuroprotection from misfolded proteins or endoplasmic reticulum stress through its molecular chaperone and thiol-disulfide oxidoreductase activities. Here, the authors present recent evidence suggesting that NO contributes to degenerative conditions by S-nitrosylating PDI (forming SNO-PDI) and the ubiquitin protein ligase, parkin (forming SNO-parkin). Moreover, it is demonstrated for the first time that inhibition of excessive NMDA receptor activity by memantine, via a mechanism of uncompetitive open-channel block with a relatively rapid off-rate, can ameliorate excessive production of NO, protein misfolding, and neurodegeneration.
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