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Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding.
Mol Pharmacol. 1990 Jul; 38(1):14-9.MP

Abstract

Zinc noncompetitively antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in cultured neurons. We investigated the mechanism of this inhibition by examining the effect of zinc on ligand binding to three distinct sites on the NMDA receptor in rat hippocampal membranes. Zinc dose-dependently inhibited both the association and dissociation of the NMDA channel blocker [3H]N-(1-[thienyl]cyclohexyl)piperidine ([3H]TCP) but had no effect on steady state levels of [3H]TCP binding. This suggests that zinc inhibits the receptor-gated access of [3H]TCP to its site in the ion channel but has no effect on the binding site itself. Zinc inhibition of [3H]TCP association was not mediated by an action at the NMDA recognition site, because zinc had no effect on NMDA-displaceable L-[3H]glutamate binding. On the other hand, zinc dose-dependently inhibited [3H]glycine binding by a noncompetitive interaction. Stoichiometric analysis of equilibrium binding data indicated the presence of two [3H]glycine binding sites/[3H]TCP binding site. Comparison of the potencies of zinc in inhibiting glycine-dependent [3H]TCP association and [3H]glycine binding suggests that blockade of only one of the two glycine sites is sufficient to prevent [3H]TCP association. We hypothesize that synaptically released zinc inhibits NMDA receptor-mediated responses by binding to a site on the receptor/channel complex, reducing glycine binding, and thereby decreasing what would otherwise be a tonically present action of endogenous extracellular glycine.

Authors+Show Affiliations

Department of Medicine, Duke University Medical Center, Durham, North Carolina.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1695316

Citation

Yeh, G C., et al. "Evidence That Zinc Inhibits N-methyl-D-aspartate Receptor-gated Ion Channel Activation By Noncompetitive Antagonism of Glycine Binding." Molecular Pharmacology, vol. 38, no. 1, 1990, pp. 14-9.
Yeh GC, Bonhaus DW, McNamara JO. Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding. Mol Pharmacol. 1990;38(1):14-9.
Yeh, G. C., Bonhaus, D. W., & McNamara, J. O. (1990). Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding. Molecular Pharmacology, 38(1), 14-9.
Yeh GC, Bonhaus DW, McNamara JO. Evidence That Zinc Inhibits N-methyl-D-aspartate Receptor-gated Ion Channel Activation By Noncompetitive Antagonism of Glycine Binding. Mol Pharmacol. 1990;38(1):14-9. PubMed PMID: 1695316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence that zinc inhibits N-methyl-D-aspartate receptor-gated ion channel activation by noncompetitive antagonism of glycine binding. AU - Yeh,G C, AU - Bonhaus,D W, AU - McNamara,J O, PY - 1990/7/1/pubmed PY - 1990/7/1/medline PY - 1990/7/1/entrez SP - 14 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 38 IS - 1 N2 - Zinc noncompetitively antagonizes N-methyl-D-aspartate (NMDA) receptor-mediated responses in cultured neurons. We investigated the mechanism of this inhibition by examining the effect of zinc on ligand binding to three distinct sites on the NMDA receptor in rat hippocampal membranes. Zinc dose-dependently inhibited both the association and dissociation of the NMDA channel blocker [3H]N-(1-[thienyl]cyclohexyl)piperidine ([3H]TCP) but had no effect on steady state levels of [3H]TCP binding. This suggests that zinc inhibits the receptor-gated access of [3H]TCP to its site in the ion channel but has no effect on the binding site itself. Zinc inhibition of [3H]TCP association was not mediated by an action at the NMDA recognition site, because zinc had no effect on NMDA-displaceable L-[3H]glutamate binding. On the other hand, zinc dose-dependently inhibited [3H]glycine binding by a noncompetitive interaction. Stoichiometric analysis of equilibrium binding data indicated the presence of two [3H]glycine binding sites/[3H]TCP binding site. Comparison of the potencies of zinc in inhibiting glycine-dependent [3H]TCP association and [3H]glycine binding suggests that blockade of only one of the two glycine sites is sufficient to prevent [3H]TCP association. We hypothesize that synaptically released zinc inhibits NMDA receptor-mediated responses by binding to a site on the receptor/channel complex, reducing glycine binding, and thereby decreasing what would otherwise be a tonically present action of endogenous extracellular glycine. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/1695316/Evidence_that_zinc_inhibits_N_methyl_D_aspartate_receptor_gated_ion_channel_activation_by_noncompetitive_antagonism_of_glycine_binding_ DB - PRIME DP - Unbound Medicine ER -