Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage.
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.
Siman
R
R
Neuroscience Group, DuPont Company, Wilmington, Delaware 19898.
Noszek
J C
JC
Kegerise
C
C
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D003078:Colchicine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate; D009498:Neurotoxins / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013049:Spectrin / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D009498:Neurotoxins; D013049:Spectrin; D001224:Aspartic Acid; D016202:N-Methylaspartate; D010447:Peptide Hydrolases; D002154:Calpain; D007608:Kainic Acid; D003078:Colchicine