Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
NMDA receptor activity is modulated by various compounds, including sulfhydryl redox agents and Zn(2+). In addition to a slow and persistent component of redox modulation common to all NMDA receptors, NR1/NR2A receptors uniquely have a rapid and reversible component that has been variously attributed to redox or Zn(2+) effects. Here we show that this rapid modulatory effect can be described by two time constants with relatively fast ( approximately 6 sec) and intermediate (60 sec) half lives, and it is likely to be attributable to both redox agents and Zn(2+). Using site-directed mutagenesis, we identified three pairs of cysteine residues that underlie the various kinetic components of redox modulation of NMDA-evoked currents in Xenopus oocytes expressing NR1/NR2A receptors: (1) Cys 87 and Cys 320 in NR2A underlie the fast component, (2) Cys 79 and Cys 308 in NR1 underlie the intermediate component, and (3) Cys 744 and Cys 798 in NR1 underlie the persistent component. Mutation of these redox-sensitive cysteine residues also affects high-affinity, voltage-independent Zn(2+) inhibition that is specific to NR1/NR2A receptors. Exposure to methanethiosulfonate agents that modify cysteine residues did not block the Zn(2+) inhibition. Thus, these cysteine residues do not appear to coordinate Zn(2+) directly. Instead, the redox status of these cysteine residues may modulate the sensitivity of the receptor to Zn(2+).
Aizenman,
Selective modulation of NMDA responses by reduction and oxidation.
1989, Pubmed
Aizenman,
Selective modulation of NMDA responses by reduction and oxidation.
1989,
Pubmed Akabas,
Acetylcholine receptor channel structure probed in cysteine-substitution mutants.
1992,
Pubmed
,
Xenbase Anson,
Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors.
1998,
Pubmed Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed Bliss,
A synaptic model of memory: long-term potentiation in the hippocampus.
1993,
Pubmed Chen,
Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition.
1997,
Pubmed Choi,
Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor.
1999,
Pubmed
,
Xenbase Choi,
Glutamate neurotoxicity and diseases of the nervous system.
1988,
Pubmed Christianson,
Structural biology of zinc.
1991,
Pubmed Christine,
Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.
1990,
Pubmed Constantine-Paton,
NMDA receptor as a mediator of activity-dependent synaptogenesis in the developing brain.
1990,
Pubmed Cornell,
Stability constant for the zinc-dithiothreitol complex.
1972,
Pubmed Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed Fayyazuddin,
Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors.
2000,
Pubmed
,
Xenbase Gilbert,
Oxidized glutathione modulates N-methyl-D-aspartate- and depolarization-induced increases in intracellular Ca2+ in cultured rat forebrain neurons.
1991,
Pubmed Gozlan,
In CA1 hippocampal neurons, the redox state of NMDA receptors determines LTP expressed by NMDA but not by AMPA receptors.
1995,
Pubmed Hirai,
The glycine binding site of the N-methyl-D-aspartate receptor subunit NR1: identification of novel determinants of co-agonist potentiation in the extracellular M3-M4 loop region.
1996,
Pubmed Hollmann,
Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
1993,
Pubmed
,
Xenbase Hollmann,
N-glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1.
1994,
Pubmed
,
Xenbase Köhr,
NMDA receptor channels: subunit-specific potentiation by reducing agents.
1994,
Pubmed Kuryatov,
Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins.
1994,
Pubmed
,
Xenbase Laube,
Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit.
1997,
Pubmed Legendre,
The inhibition of single N-methyl-D-aspartate-activated channels by zinc ions on cultured rat neurones.
1990,
Pubmed Leonard,
Apparent desensitization of NMDA responses in Xenopus oocytes involves calcium-dependent chloride current.
1990,
Pubmed
,
Xenbase Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Lipton,
Redox modulation of the NMDA receptor by NO-related species.
1998,
Pubmed Lipton,
Excitatory amino acids as a final common pathway for neurologic disorders.
1994,
Pubmed Low,
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
2000,
Pubmed
,
Xenbase Mayer,
Modulation of excitatory amino acid receptors by group IIB metal cations in cultured mouse hippocampal neurones.
1989,
Pubmed Meldrum,
Excitatory amino acid neurotoxicity and neurodegenerative disease.
1990,
Pubmed Monyer,
Heteromeric NMDA receptors: molecular and functional distinction of subtypes.
1992,
Pubmed Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase Peters,
Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons.
1987,
Pubmed Rock,
The polyamine spermine has multiple actions on N-methyl-D-aspartate receptor single-channel currents in cultured cortical neurons.
1992,
Pubmed Sucher,
Redox modulatory site of the NMDA receptor-channel complex: regulation by oxidized glutathione.
1991,
Pubmed Sullivan,
Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor.
1994,
Pubmed
,
Xenbase Tang,
The modulation of N-methyl-D-aspartate receptors by redox and alkylating reagents in rat cortical neurones in vitro.
1993,
Pubmed Tang,
Allosteric modulation of the NMDA receptor by dihydrolipoic and lipoic acid in rat cortical neurons in vitro.
1993,
Pubmed Traynelis,
Pharmacological properties and H+ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones.
1991,
Pubmed Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase Vallee,
The biochemical basis of zinc physiology.
1993,
Pubmed Vyklický,
Modulation of N-methyl-D-aspartic acid receptor desensitization by glycine in mouse cultured hippocampal neurones.
1990,
Pubmed Wafford,
Preferential co-assembly of recombinant NMDA receptors composed of three different subunits.
1993,
Pubmed
,
Xenbase Wafford,
Identification of amino acids in the N-methyl-D-aspartate receptor NR1 subunit that contribute to the glycine binding site.
1995,
Pubmed
,
Xenbase Westbrook,
Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons.
,
Pubmed Williams,
Separating dual effects of zinc at recombinant N-methyl-D-aspartate receptors.
1996,
Pubmed
,
Xenbase Wo,
Transmembrane topology of two kainate receptor subunits revealed by N-glycosylation.
1994,
Pubmed Wood,
Structural conservation of ion conduction pathways in K channels and glutamate receptors.
1995,
Pubmed
,
Xenbase Zheng,
Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition.
1998,
Pubmed
