Differential involvement of intracellular Ca2+ in 1-methyl-4-phenylpyridinium- or 6-hydroxydopamine-induced cell viability loss in PC12 cells.
1-Methyl-4-phenylpyridinium (MPP(+)) or 6-hydroxydopamine (6-OHDA) caused a nuclear damage, the mitochondrial membrane permeability changes, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in PC12 cells. Nicardipine (a calcium channel blocker), EGTA (an extracellular calcium chelator), BAPTA-AM (a cell permeable calcium chelator) and calmodulin antagonists (W-7 and calmidazolium) attenuated the MPP(+)-induced mitochondrial damage and cell death. In contrast, the compounds did not reduce the toxicity of 6-OHDA. Treatment with MPP(+ )or 6-OHDA evoked the elevation of intracellular Ca(2+) levels. Unlike cell injury, addition of nicardipine, BAPTA-AM and calmodulin antagonists prevented the elevation of intracellular Ca(2+) levels due to both toxins. The results show that the MPP(+)-induced formation of the mitochondrial permeability transition seems to be mediated by elevation of intracellular Ca(2+) levels and calmodulin action. In contrast, the 6-OHDA-induced cell death seems to be mediated by Ca(2+)-independent manner.
Lee
Dong Hee
DH
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea.
Han
Young Su
YS
Han
Eun Sook
ES
Bang
Hyoweon
H
Lee
Chung Soo
CS
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004533:Egtazic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D005978:Glutathione / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009529:Nicardipine / Q000008:administration & dosage; D016627:Oxidopamine / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D002147:Calmodulin; D002614:Chelating Agents; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C017967:W 7; D016627:Oxidopamine; D045304:Cytochromes c; D009529:Nicardipine; D005978:Glutathione; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium