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 Zn 2+ ions in a voltage-independent manner. The apparent affinity for Zn 2+ of the heteromeric NMDA receptors is determined by the subtype of NR2 subunit expressed, with NR2A-containing receptors being the most sensitive (IC 50 , ∼20 nM) and NR2C-containing receptors being the least sensitive (IC 50 , ∼30 μM). 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 Zn 2+ inhibition. Mutations at four residues in this domain markedly reduce Zn 2+ affinity (by up to >500-fold) without affecting either receptor activation by glutamate and glycine or inhibition by extracellular protons and Ni 2+ ions, indicating that these residues most likely participate in high-affinity Zn 2+ binding.