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 M, 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 Nmethyl-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.

Multiple death pathways in retina-derived 661W cells following growth factor deprivation: crosstalk between caspases and calpains

“…Accordingly, caspase-3 underwent cleavage into a 17-kDa active form that could be identified by immunoblot from 24 h of starving. An additional 29-kDa band, previously described as a calpainmediated breakdown product, 21,34 was detectable at 96 h, suggesting crosstalk between these two families of proteases ( Figure 2b). We also determined the activation status of caspase-12, an endoplasmic reticulum-associated caspase, previously related to serum deprivation-induced apoptosis in other systems.…”

CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells

“…Calpains have been shown to be often associated with caspase activation in different apoptotic pathways (Neumar et al, 2003;Altznauer et al, 2004). However, caspase-independent cell death mediated by calpains has also been described in several models, including neuronal cell death (Lankiewicz et al, 2000) and vitamine-D-induced apoptosis in breast cancer cells (Mathiasen et al, 2002). Although calpain has a large number of substrates, its exact role in cell death remains unclear.…”

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

“…27 In the same way, RARaÀ/À mice exhibit caspase-independent spermatid loss. 28 Late differentiating male germ cells share similarities with various postmitotic/terminally differentiating models of caspase-independent cell death: p53-expressing or NMDAtreated neurons, 17,18 ischemic mature brain, 29 light-injured mature photoreceptor cells 19 or differentiating PC12 cells. 30 So in terminally maturing cells, calpain activation bypasses an inhibition or a block in the caspase pathway generally related to a decrease in apoptotic effectors like Apaf1 or caspase-3.…”

“…These ubiquitous enzymes are involved (i) in testicular cell loss in ischemia/reperfusion models, 6 and (ii) in several models of postmitotic, differentiating cell death. [17][18][19] Calpain 2 mRNAs were observed at all differentiation stages of normal spermatogenesis without any modification in transgenic cells (Figure 7a). By contrast, calpain 1 mRNAs were only detected in normal SP cells and spermatocytes II.…”