Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A

Nat Neurosci. 2001 Sep;4(9):894-901. doi: 10.1038/nn0901-894.


Fast desensitization is an important regulatory mechanism of neuronal NMDA receptor function. Only recombinant NMDA receptors composed of NR1/NR2A exhibit a fast component of desensitization similar to neuronal NMDA receptors. Here we report that the fast desensitization of NR1/NR2A receptors is caused by ambient zinc, and that a positive allosteric interaction occurs between the extracellular zinc-binding site located in the amino terminal domain and the glutamate-binding domain of NR2A. The relaxation of macroscopic currents reflects a shift to a new equilibrium due to increased zinc affinity after binding of glutamate. We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors. These data raise the possibility that there is an allosteric interaction between the amino terminal domain and the ligand-binding domain of other glutamate receptors. Our findings may provide insight into how zinc and other extracellular modulators regulate NMDA receptor function.

Publication types

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

MeSH terms

  • Allosteric Regulation / physiology
  • Animals
  • Binding Sites / drug effects
  • Cell Line
  • Edetic Acid / pharmacology
  • Electric Conductivity
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Space / metabolism
  • Glutamic Acid / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Ligands
  • Peptide Fragments / physiology*
  • Piperidines / pharmacology
  • Protein Structure, Tertiary / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Zinc / metabolism
  • Zinc / pharmacology


  • Excitatory Amino Acid Antagonists
  • Ligands
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • Peptide Fragments
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Edetic Acid
  • Zinc
  • ifenprodil