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.
Choi
Won-Seok
WS
Department of Biology and Protein Network Research Center, Yonsei University, 134 Shincheondong Seodaemoonku, College of Science, Seoul 120-749, Republic of Korea.
Lee
Eunhee
E
Lim
Junghyun
J
Oh
Young J
YJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064092:Calbindin 1; D064026:Calbindins; D002154:Calpain / Q000037:antagonists & inhibitors*; D061945:Caspase Inhibitors; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology
C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D061945:Caspase Inhibitors; D047428:Protein Kinase Inhibitors; D064030:S100 Calcium Binding Protein G; D002154:Calpain; D019311:Staurosporine; D004298:Dopamine