Calpain-mediated regulation of NMDA receptor structure and function

Brain Res. 1998 Apr 20;790(1-2):245-53. doi: 10.1016/s0006-8993(98)00067-5.


Calpains have been previously shown to regulate AMPA receptor properties by producing partial truncation of the C-terminal domains of several receptor subunits. We now report that NMDA receptor subunits, in particular NR2 subunits, are also subjected to calpain-mediated truncation. Treatment of synaptic membranes with calpain I resulted in truncation of both NR1 and NR2 subunits, with the appearance of NR2 species with lower mol.wt. than native subunits, but still recognized by antibodies directed at the C-terminal domain. This treatment did not modify the binding of several ligands of the NMDA receptors, such as glutamate, glycine or TCP. Incubation of thin frozen-thawed brain sections with calcium resulted in calpain-mediated selective degradation of NR2 subunits, as truncation into smaller fragments was totally blocked by calpain inhibitors. Under the same conditions, TCP binding to sections was decreased by about 50%, an effect also blocked by calpain inhibitors. Treatment of hippocampal slices in culture with the excitotoxin, kainic acid, also produced calpain-mediated truncation of the C-terminal domain of NR2 but not NR1 subunits of the NMDA receptors. The results indicate that calpain activation produces several modifications of NMDA receptors, including the truncation of the C-terminal domain of NR2 subunits, and changes in channel binding properties. They suggest that calpain-mediated regulation of NMDA receptors might represent a feed-back regulation of the receptors which could be used to limit receptor activation.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium / pharmacology
  • Calpain / antagonists & inhibitors
  • Calpain / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dipeptides / pharmacology
  • Enzyme Activation / physiology
  • Excitatory Amino Acid Agonists / pharmacology
  • Freezing
  • Glutamic Acid / pharmacology
  • Hippocampus / chemistry
  • Hippocampus / enzymology
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology*
  • Kainic Acid / pharmacology
  • Neuronal Plasticity / physiology
  • Organ Culture Techniques
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synaptic Membranes / chemistry
  • Synaptic Membranes / enzymology


  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Excitatory Amino Acid Agonists
  • Receptors, N-Methyl-D-Aspartate
  • calpeptin
  • Glutamic Acid
  • Calpain
  • Kainic Acid
  • Calcium