Chelation of extracellular calcium-induced cell death was prevented by glycogen synthase kinase-3 inhibitors in PC12 cells.
Calcium ion is a secondary messenger that mediates a variety of physiological responses of neurons, including cell survival responses. To determine the role of calcium in regulating neuronal survival and death, we examined whether chelation of extracellular calcium with EGTA induces caspase-dependent apoptotic cell death and whether glycogen synthase kinase-3 is involved in EGTA-induced cell death in PC12 cells. EGTA increased apoptotic cell death with morphological changes characterized by cell shrinkage and nuclear condensation and fragmentation accompanied by caspase activation. EGTA increased GRP78 protein expression, suggesting that EGTA induces ER stress. Glycogen synthase kinase-3 inhibitors prevented EGTA-induced apoptosis. In addition, nerve growth factor and insulin growth factor-I completely blocked EGTA-induced cell death. Moreover, caspase-3 activation was inhibited by glycogen synthase kinase-3 inhibitors. These results suggest that chelation of extracellular calcium with EGTA induces caspase-dependent apoptosis, and the activation of glycogen synthase kinase-3 is involved in the death of PC12 cells.
Takadera
Tsuneo
T
Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan. t-takadera@hokuriku-u.ac.jp
Ohtsuka
Megumi
M
Aoki
Haruka
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001552:Benzazepines / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002614:Chelating Agents / Q000378:metabolism*; D004533:Egtazic Acid / Q000378:metabolism; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008301:Maleimides / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D000091342:Endoplasmic Reticulum Chaperone BiP
D001552:Benzazepines; D002118:Calcium; D020169:Caspases; D002614:Chelating Agents; D004533:Egtazic Acid; D038362:Glycogen Synthase Kinase 3; D006360:Heat-Shock Proteins; D007211:Indoles; D007334:Insulin-Like Growth Factor I; D008301:Maleimides; D020932:Nerve Growth Factor; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C417521:SB 216763; C120793:alsterpaullone
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