title: Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors.
abstract: NMDA receptors are allosterically inhibited by Zn2+ ions in a voltage-independent manner. The apparent affinity for Zn2+ of the heteromeric NMDA receptors is determined by the subtype of NR2 subunit expressed, with NR2A-containing receptors being the most sensitive (IC50, approximately 20 nM) and NR2C-containing receptors being the least sensitive (IC50, approximately 30 microM). Using chimeras constructed from these two NR2 subtypes, we show that the N-terminal LIVBP-like domain of the NR2A subunit controls the high-affinity Zn2+ inhibition. Mutations at four residues in this domain markedly reduce Zn2+ affinity (by up to >500-fold) without affecting either receptor activation by glutamate and glycine or inhibition by extracellular protons and Ni2+ ions, indicating that these residues most likely participate in high-affinity Zn2+ binding.
authors.affiliation: Laboratoire de Neurobiologie, Ecole Normale Supérieure, Centre National de la Recherche Scientificque/Unité Mixte de Recherche 8544, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Fayyazuddin
authors.forename: A
authors.initials: A
authors.lastname: Villarroel
authors.forename: A
authors.initials: A
authors.lastname: Le Goff
authors.forename: J
authors.initials: J
authors.lastname: Lerma
authors.forename: J
authors.initials: J
authors.lastname: Neyton
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002678:Chimera; D005110:Extracellular Space / Q000737:chemistry; D015640:Ion Channel Gating / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014981:Xenopus; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D015032:Zinc