Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif

Takahashi, H., Shin, Y., Cho, S. J., Zago, W. M., Nakamura, T., Gu, Z., Ma, Y., Furukawa, H., Liddington, R., Zhang, D., Tong, G., Chen, H. S., Lipton, S. A. (2007) Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. Neuron, 53 (1). pp. 53-64. ISSN 0896-6273 (Print)0896-6273 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/17196530
DOI: 10.1016/j.neuron.2006.11.023

Abstract

Under ambient air conditions, NO inhibits NMDAR activity by reacting with the NR2A subunit C399 along with two additional cysteine pairs if their disulfide bonds are reduced to free thiol groups [NR1(C744,C798); NR2(C87,C320)]. Here we demonstrate that relative hypoxia enhances S-nitrosylation of NMDARs by a unique mechanism involving an "NO-reactive oxygen sensor motif" whose determinants include C744 and C798 of the NR1 subunit. Redox reactions involving these two thiol groups sensitize other NMDAR sites to S-nitrosylation and consequent receptor inhibition, while their own nitrosylation has little effect on NMDAR activity. The crystal structure of the ligand-binding domain of NR1 reveals a flexible disulfide bond (C744-C798), which may account for its susceptibility to reduction and subsequent reaction with NO that is observed with biochemical techniques. These thiols may be nitrosylated preferentially during increasing hypoxia or stroke conditions, thus preventing excessive activity associated with cytotoxicity while avoiding blockade of physiologically active NMDARs.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Motifs physiology Animals Binding Sites physiology Cell Line Cerebral Cortex metabolism physiopathology Crystallography X-Ray Disulfides Down-Regulation physiology Female Humans Hypoxia, Brain metabolism physiopathology Neurons/ metabolism Nitric Oxide metabolism Oocytes Oxidation Reduction Oxygen metabolism Rats Reactive Oxygen Species metabolism Receptors N-Methyl-D-Aspartate chemistry metabolism S-Nitrosothiols metabolism Sulfhydryl Compounds metabolism Xenopus laevis
Subjects: bioinformatics > genomics and proteomics > small molecules > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein structure rendering
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Leigh Johnson
Date Deposited: 26 Mar 2012 17:56
Last Modified: 28 Feb 2013 17:50
PMCID: PMC1855274
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25164

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