Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage

J Neurosci. 1989 May;9(5):1579-90. doi: 10.1523/JNEUROSCI.09-05-01579.1989.


Sustained stimulation of receptors for excitatory amino acids leads to both activation of the calcium-dependent cysteine protease calpain I and to the death of receptive neurons. Here, we have examined the relationship between the calpain I activation and neurodegeneration. Calpain I activation was manifested as increased levels of the major proteolytic fragments of the calpain substrate spectrin, detected and quantified by immunoblotting. Intraventricular administration of the excitatory amino acids kainate or N-methyl-D-aspartate (NMDA) produced calpain I-mediated spectrin degradation and hippocampal neuronal loss. The NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid selectively blocked NMDA- but not kainate-induced protease activation and hippocampal damage. Temporally, spectrin degradation preceded the onset of pyramidal cell degeneration monitored by silver-impregnation histochemistry. Only those doses of kainate (0.15-1 microgram) or NMDA (40-80 micrograms) sufficient to cause hippocampal damage markedly increased spectrin breakdown. Both the neuronal damage and calpain I activation induced by kainate occurred primarily in area CA3. Degeneration of hippocampal neurons evoked by colchicine was not accompanied by calpain activation, indicating that proteolysis is not stimulated simply as a secondary response to neuronal destruction. Thus, a close correspondence exists between excitatory amino acid induction of neuronal degeneration and of calpain I-mediated spectrin degradation. The results suggest that calpain I may be an intracellular mediator of excitatory amino acid action, and further, they support the hypothesis that calcium influx and calpain I activation are obligatory events in the initiation of excitatory amino acid neurotoxicity.

MeSH terms

  • Animals
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / antagonists & inhibitors
  • Aspartic Acid / pharmacology
  • Calpain / antagonists & inhibitors
  • Calpain / physiology*
  • Colchicine / pharmacology
  • Dose-Response Relationship, Drug
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Kainic Acid / pharmacology*
  • Male
  • N-Methylaspartate
  • Neurotoxins / pharmacology
  • Peptide Hydrolases / metabolism
  • Rats
  • Rats, Inbred Strains
  • Spectrin / metabolism
  • Time Factors
  • Tissue Distribution


  • Neurotoxins
  • Spectrin
  • Aspartic Acid
  • N-Methylaspartate
  • Peptide Hydrolases
  • Calpain
  • Kainic Acid
  • Colchicine