Calbindin-D28K prevents drug-induced dopaminergic neuronal death by inhibiting caspase and calpain activity

Calbindin-D28K protects against apoptotic and necrotic cell death; these effects have been attributed to its ability to buffer calcium. In this study, we investigated the mechanisms underlying the neuroprotective effects of calbindin-D28K in staurosporine (STS)-induced apoptosis and 1-methyl-4-phenylpyridinium (MPP⁺)-induced necrosis. Treatment of the dopaminergic neuronal cell line MN9D with STS or MPP⁺ induced cell death that was associated with increased levels of free intracellular calcium. However, only MPP⁺-induced death was inhibited by co-treatment of the cells with a calcium chelator or a sodium/calcium antiporter inhibitor. Overexpression of calbindin-D28K prevented MPP⁺-induced MN9D cell death, which occurs in the absence of any detectable caspase activation. These pro-survival effects of calbindin-D28K were associated with the inhibition of calcium-mediated calpain activation, as determined by processing of Bax. Overexpression of calbindin-D28K also blocked STS-induced MN9D death. However, this effect was accompanied by the inhibition of capase-3 cleavage, poly(ADP-ribose)polymerase cleavage, and caspase activity. These findings suggest that calbindin-D28K protects against both types of cell death by inhibiting caspase- or calcium-mediated death signaling pathway.