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.
Proc Natl Acad Sci U S A
2000 Sep 26;9720:11062-7. doi: 10.1073/pnas.180307497.
Show Gene links
Show Anatomy links
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
Low CM, Zheng F, Lyuboslavsky P, Traynelis SF.
???displayArticle.abstract???
Modulation of the N-methyl-d-aspartate (NMDA)-selective glutamate receptors by extracellular protons and Zn(2+) may play important roles during ischemia in the brain and during seizures. Recombinant NR1/NR2A receptors exhibit a much higher apparent affinity for voltage-independent Zn(2+) inhibition than receptors with other subunit combinations. Here, we show that the mechanism of this apparent high-affinity, voltage-independent Zn(2+) inhibition for NR2A-containing receptors results from the enhancement of proton inhibition. We also show that the N-terminal leucine/isoleucine/valine binding protein (LIVBP)-like domain of the NR2A subunit contains critical determinants of the apparent high-affinity, voltage-independent Zn(2+) inhibition. Mutations H42A, H44G, or H128A greatly increase the Zn(2+) IC(50) (by up to approximately 700-fold) with no effect on the potencies of glutamate and glycine or on voltage-dependent block by Mg(2+). Furthermore, the amino acid residue substitution H128A, which mediates the largest effect on the apparent high-affinity Zn(2+) inhibition among all histidine substitutions we tested, is also critical to the pH-dependency of Zn(2+) inhibition. Our data revealed a unique interaction between two important extracellular modulators of NMDA receptors.
Aniksztejn,
Selective release of endogenous zinc from the hippocampal mossy fibers in situ.
1987, Pubmed
Aniksztejn,
Selective release of endogenous zinc from the hippocampal mossy fibers in situ.
1987,
Pubmed Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed Balestrino,
Concentration of carbon dioxide, interstitial pH and synaptic transmission in hippocampal formation of the rat.
1988,
Pubmed Bers,
A practical guide to the preparation of Ca2+ buffers.
1994,
Pubmed Brooks,
Bound and determined: a computer program for making buffers of defined ion concentrations.
1992,
Pubmed Charton,
Spontaneous and evoked release of endogenous Zn2+ in the hippocampal mossy fiber zone of the rat in situ.
1985,
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 Christine,
Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.
1990,
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 Giffard,
Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures.
1990,
Pubmed Harrison,
Zn2+: an endogenous modulator of ligand- and voltage-gated ion channels.
1994,
Pubmed Harvey,
Identification of an inhibitory Zn2+ binding site on the human glycine receptor alpha1 subunit.
1999,
Pubmed Kashiwagi,
An aspartate residue in the extracellular loop of the N-methyl-D-aspartate receptor controls sensitivity to spermine and protons.
1996,
Pubmed
,
Xenbase Köhr,
NMDA receptor channels: subunit-specific potentiation by reducing agents.
1994,
Pubmed Krupp,
N-terminal domains in the NR2 subunit control desensitization of NMDA receptors.
1998,
Pubmed Legendre,
The inhibition of single N-methyl-D-aspartate-activated channels by zinc ions on cultured rat neurones.
1990,
Pubmed Lynch,
Zinc potentiation of the glycine receptor chloride channel is mediated by allosteric pathways.
1998,
Pubmed Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed Mott,
Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.
1998,
Pubmed
,
Xenbase O'Hara,
The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins.
1993,
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 Slomianka,
Labeling of the neurons of origin of zinc-containing pathways by intraperitoneal injections of sodium selenite.
1990,
Pubmed Smart,
Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc.
1994,
Pubmed Stern-Bach,
Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins.
1994,
Pubmed
,
Xenbase Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase 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,
Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons.
1990,
Pubmed Villarroel,
Glycine-independent NMDA receptor desensitization: localization of structural determinants.
1998,
Pubmed Vogt,
The actions of synaptically released zinc at hippocampal mossy fiber synapses.
2000,
Pubmed 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 Xiong,
Src potentiation of NMDA receptors in hippocampal and spinal neurons is not mediated by reducing zinc inhibition.
1999,
Pubmed Zheng,
Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition.
1998,
Pubmed
