PT - JOURNAL ARTICLE AU - R Siman AU - JC Noszek AU - C Kegerise TI - Calpain I activation is specifically related to excitatory amino acid induction of hippocampal damage AID - 10.1523/JNEUROSCI.09-05-01579.1989 DP - 1989 May 01 TA - The Journal of Neuroscience PG - 1579--1590 VI - 9 IP - 5 4099 - http://www.jneurosci.org/content/9/5/1579.short 4100 - http://www.jneurosci.org/content/9/5/1579.full SO - J. Neurosci.1989 May 01; 9 AB - 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.