Differential involvement of intracellular Ca2+ in 1-methyl-4-phenylpyridinium- or 6-hydroxydopamine-induced cell viability loss in PC12 cells

Abstract

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 Ca2+ 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 Ca2+ levels and calmodulin action. In contrast, the 6-OHDA-induced cell death seems to be mediated by Ca2+-independent manner.