title: Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif.
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.
authors.affiliation: Center for Neuroscience and Aging, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Takahashi
authors.forename: Yeonsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Seung-Je
authors.initials: SJ
authors.lastname: Cho
authors.forename: Wagner M
authors.initials: WM
authors.lastname: Zago
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Ma
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Furukawa
authors.forename: Robert
authors.initials: R
authors.lastname: Liddington
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: Huei-Sheng Vincent
authors.initials: HS
authors.lastname: Chen
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D018360:Crystallography, X-Ray; D004220:Disulfides; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D009865:Oocytes; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*; D026403:S-Nitrosothiols / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D004220:Disulfides; D009569:Nitric Oxide; D010100:Oxygen; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds