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Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites at N-methyl-D-aspartate receptor complex.
J Pharmacol Exp Ther. 1999 Jun; 289(3):1584-91.JP

Abstract

In this study, we investigated the hypothesis that inhibition of the N-methyl-D-aspartate (NMDA) receptor complex by zinc involves a polyamine-sensitive regulatory site. We found that the specific binding of the open channel ligand [3H]MK-801 to rat hippocampal membranes 1) was inhibited by low concentrations of Zn2+ (IC50 = 5.5 microM) by 65%. 2) This high-affinity component of inhibition was reversed by the polyamine spermine to an extent that could be reconciled with competitive interaction between Zn2+ and spermine. 3) Partial inhibition by Zn2+ was additive with partial inhibition by ifenprodil, an inhibitor of the NMDA receptor complex supposed to act at a polyamine-sensitive regulatory site, and 4) in membranes prepared from several other brain regions, inhibition of [3H]MK-801 binding by Zn2+ and by ifenprodil was either less than additive, or superadditive. Our observation that ifenprodil, at concentrations saturating its high-affinity component of inhibition, prevented spermine from reversing the inhibition by Zn2+ indicates that spermine did not increase [3H]MK-801 binding by competition with Zn2+ but rather via another polyamine regulatory site not sensitive to zinc but sensitive to ifenprodil. We conclude that Zn2+ reduces channel opening of the NMDA receptor complex by allosteric inhibition of a polyamine-sensitive regulatory site different from that inhibited by ifenprodil and that these two allosteric sites influence each other in a manner dependent on the brain region investigated. The different proportions of zinc/ifenprodil inhibition in different regions could reflect different percentages of various NMDA receptor subtypes.

Authors+Show Affiliations

Institute of Biochemical Pharmacology, University of Vienna, Vienna, Austria. berger@univie.ac.atNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10336556

Citation

Berger, M L., and P Rebernik. "Zinc and Ifenprodil Allosterically Inhibit Two Separate Polyamine-sensitive Sites at N-methyl-D-aspartate Receptor Complex." The Journal of Pharmacology and Experimental Therapeutics, vol. 289, no. 3, 1999, pp. 1584-91.
Berger ML, Rebernik P. Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites at N-methyl-D-aspartate receptor complex. J Pharmacol Exp Ther. 1999;289(3):1584-91.
Berger, M. L., & Rebernik, P. (1999). Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites at N-methyl-D-aspartate receptor complex. The Journal of Pharmacology and Experimental Therapeutics, 289(3), 1584-91.
Berger ML, Rebernik P. Zinc and Ifenprodil Allosterically Inhibit Two Separate Polyamine-sensitive Sites at N-methyl-D-aspartate Receptor Complex. J Pharmacol Exp Ther. 1999;289(3):1584-91. PubMed PMID: 10336556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zinc and ifenprodil allosterically inhibit two separate polyamine-sensitive sites at N-methyl-D-aspartate receptor complex. AU - Berger,M L, AU - Rebernik,P, PY - 1999/5/21/pubmed PY - 1999/5/21/medline PY - 1999/5/21/entrez SP - 1584 EP - 91 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 289 IS - 3 N2 - In this study, we investigated the hypothesis that inhibition of the N-methyl-D-aspartate (NMDA) receptor complex by zinc involves a polyamine-sensitive regulatory site. We found that the specific binding of the open channel ligand [3H]MK-801 to rat hippocampal membranes 1) was inhibited by low concentrations of Zn2+ (IC50 = 5.5 microM) by 65%. 2) This high-affinity component of inhibition was reversed by the polyamine spermine to an extent that could be reconciled with competitive interaction between Zn2+ and spermine. 3) Partial inhibition by Zn2+ was additive with partial inhibition by ifenprodil, an inhibitor of the NMDA receptor complex supposed to act at a polyamine-sensitive regulatory site, and 4) in membranes prepared from several other brain regions, inhibition of [3H]MK-801 binding by Zn2+ and by ifenprodil was either less than additive, or superadditive. Our observation that ifenprodil, at concentrations saturating its high-affinity component of inhibition, prevented spermine from reversing the inhibition by Zn2+ indicates that spermine did not increase [3H]MK-801 binding by competition with Zn2+ but rather via another polyamine regulatory site not sensitive to zinc but sensitive to ifenprodil. We conclude that Zn2+ reduces channel opening of the NMDA receptor complex by allosteric inhibition of a polyamine-sensitive regulatory site different from that inhibited by ifenprodil and that these two allosteric sites influence each other in a manner dependent on the brain region investigated. The different proportions of zinc/ifenprodil inhibition in different regions could reflect different percentages of various NMDA receptor subtypes. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10336556/Zinc_and_ifenprodil_allosterically_inhibit_two_separate_polyamine_sensitive_sites_at_N_methyl_D_aspartate_receptor_complex_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10336556 DB - PRIME DP - Unbound Medicine ER -