Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors

Neuron. 2000 Mar;25(3):683-94. doi: 10.1016/s0896-6273(00)81070-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Amino Acid Sequence
  • Animals
  • Binding Sites / physiology
  • Chimera
  • Extracellular Space / chemistry
  • Ion Channel Gating / genetics*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed / physiology
  • Oocytes / physiology
  • Point Mutation
  • Protein Structure, Tertiary
  • Rats
  • Receptors, N-Methyl-D-Aspartate* / chemistry
  • Receptors, N-Methyl-D-Aspartate* / genetics
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Xenopus
  • Zinc / metabolism*
  • Zinc / pharmacology


  • NR2A NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Zinc