Calmodulin inhibitor-induced apoptosis was prevented by glycogen synthase kinase-3 inhibitors in PC12 cells.
Calmodulin is known to transduce Ca(2+) signals by interacting with specific target proteins. In order to determine the role of calmodulin in regulating neuronal survival and death, we examined, whether calmodulin inhibitors induce caspase-dependent apoptotic cell death, and whether glycogen synthase kinase-3 is involved in calmodulin inhibitor-induced cell death in PC12 cells. W13, a calmodulin specific inhibitor increased apoptotic cell death with morphological changes characterized by cell shrinkage and nuclear condensation of fragmentation. Glycogen synthase kinase-3 inhibitors prevented calmodulin inhibitor-induced apoptosis. In addition, nerve growth factor and cycloheximide, a protein synthesis inhibitor, completely blocked cell death. Moreover, caspase-3 activation was accompanied by calmodulin inhibitor-induced cell death and inhibited by nerve growth factor. These results suggest that calmodulin inhibitors induce 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
Ohyashiki
Takao
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology*; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*
D001552:Benzazepines; D002147:Calmodulin; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D013449:Sulfonamides; C120793:alsterpaullone; C033772:N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide; D007770:L-Lactate Dehydrogenase; D038362:Glycogen Synthase Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3