Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor

Neuron. 1999 May;23(1):171-80. doi: 10.1016/s0896-6273(00)80763-1.


Zinc (Zn2+) inhibition of N-methyl-D-aspartate receptor (NMDAR) activity involves both voltage-independent and voltage-dependent components. Recombinant NR1/NR2A and NR1/NR2B receptors exhibit similar voltage-dependent block, but voltage-independent Zn2+ inhibition occurs with much higher affinity for NR1/NR2A than NR1/NR2B receptors (nanomolar versus micromolar IC50, respectively). Here, we show that two neighboring histidine residues on NR2A represent the critical determinant (termed the "short spacer") for high-affinity, voltage-independent Zn2+ inhibition using the Xenopus oocyte expression system and site-directed mutagenesis. Mutation of either one of these two histidine residues (H42 and H44) in the extracellular N-terminal domain of NR2A shifted the IC50 for high-affinity Zn2+ inhibition approximately 200-fold without affecting the EC50 of the coagonists NMDA and glycine. We suggest that the mechanism of high-affinity Zn2+ inhibition on the NMDAR involves enhancement of proton inhibition.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diethyl Pyrocarbonate / pharmacology
  • Female
  • Histidine / drug effects
  • Histidine / genetics
  • Histidine / physiology*
  • Mutation / physiology
  • Oocytes
  • Patch-Clamp Techniques
  • Protein Isoforms / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Xenopus laevis
  • Zinc / antagonists & inhibitors
  • Zinc / pharmacology*


  • Protein Isoforms
  • Receptors, N-Methyl-D-Aspartate
  • Histidine
  • Zinc
  • Diethyl Pyrocarbonate