title: Activation of calpain I converts excitotoxic neuron death into a caspase-independent cell death.
abstract: Glutamate receptor overactivation contributes to neuron death after stroke, trauma, and epileptic seizures. Exposure of cultured rat hippocampal neurons to the selective glutamate receptor agonist N-methyl-d-aspartate (300 microm, 5 min) or to the apoptosis-inducing protein kinase inhibitor staurosporine (300 nm) induced a delayed neuron death. In both cases, neuron death was preceded by the mitochondrial release of the pro-apoptotic factor cytochrome c. Unlike staurosporine, the N-methyl-d-aspartate-induced release of cytochrome c did not lead to significant activation of caspase-3, the main caspase involved in the execution of neuronal apoptosis. In contrast, activation of the Ca(2+)-activated neutral protease calpain I was readily detectable after the exposure to N-methyl-d-aspartate. In a neuronal cell-free apoptosis system, calpain I prevented the ability of cytochrome c to activate the caspase cascade by inhibiting the processing of procaspase-3 and -9 into their active subunits. In the hippocampal neuron cultures, the inhibition of calpain activity restored caspase-3-like protease activity after an exposure to N-methyl-d-aspartate. Our data demonstrate the existence of signal transduction pathways that prevent the entry of cells into a caspase-dependent cell death program after the mitochondrial release of cytochrome c.
authors.affiliation: Interdisciplinary Center for Clinical Research (IZKF), Research Group "Apoptosis and Cell Death," Westphalian Wilhelms University, D-48149 Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lankiewicz
authors.forename: C
authors.initials: C
authors.lastname: Marc Luetjens
authors.forename: N
authors.initials: N
authors.lastname: Truc Bui
authors.forename: A J
authors.initials: AJ
authors.lastname: Krohn
authors.forename: M
authors.initials: M
authors.lastname: Poppe
authors.forename: G M
authors.initials: GM
authors.lastname: Cole
authors.forename: T C
authors.initials: TC
authors.lastname: Saido
authors.forename: J H
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051381:Rats
chemical_list: D003574:Cytochrome c Group; D016202:N-Methylaspartate; D002154:Calpain; D020169:Caspases