title: Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor.
abstract: We have determined the gene structure for the NMDA receptor subunit gene NMDAR1. We found eight splice variants that arise from different combinations of a single 5' terminal exon insertion and three different 3' terminal exon deletions, relative to NMDAR1. We analyzed the modulation by Zn2+ of currents through homomeric receptors assembled from these splice variants and found that, in addition to its well-known inhibitory effect at high concentrations, Zn2+ potentiates agonist-induced currents at submicromolar concentrations (EC50 = 0.50 microM). This potentiation is observed only with a subset of NMDAR1 splice variants that show additional differences in pharmacological properties. Zn2+ potentiation is rapidly reversible, noncompetitive with either glutamate or glycine, and voltage independent. Zn2+ potentiation is mimicked by Cd2+, Cu2+, and Ni2+, but not by Mn2+, Co2+, Fe3+, Sn2+, or Hg2+. Our results suggest a possible role for Zn2+ as a positive modulator of NMDA receptors in certain regions of the brain.
authors.affiliation: Molecular Neurobiology Laboratory, Salk Institute, La Jolla, California 92037.
authors.forename: M
authors.initials: M
authors.lastname: Hollmann
authors.forename: J
authors.initials: J
authors.lastname: Boulter
authors.forename: C
authors.initials: C
authors.lastname: Maron
authors.forename: L
authors.initials: L
authors.lastname: Beasley
authors.forename: J
authors.initials: J
authors.lastname: Sullivan
authors.forename: G
authors.initials: G
authors.lastname: Pecht
authors.forename: S
authors.initials: S
authors.lastname: Heinemann
mesh_terms: D000818:Animals; D001483:Base Sequence; D002412:Cations; D004247:DNA / Q000737:chemistry; D004357:Drug Synergism; D004553:Electric Conductivity; D005091:Exons; D017353:Gene Deletion; D015870:Gene Expression; D014644:Genetic Variation; D007438:Introns; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D012313:RNA / Q000235:genetics; D012326:RNA Splicing; D018075:RNA, Complementary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014981:Xenopus; D015032:Zinc / Q000494:pharmacology*
chemical_list: D002412:Cations; D018075:RNA, Complementary; D016194:Receptors, N-Methyl-D-Aspartate; D012313:RNA; D004247:DNA; D015032:Zinc