Cerebellar granule cells are preferentially targeted during methylmercury (MeHg) poisoning. Following acute MeHg exposure, granule cells in culture undergo an increase in intracellular Ca 2+ concentration ((Ca 2+ ) i ) that apparently contributes to cell death. This effect consists of several temporally and kinetically distinct phases. The initial elevation arises from release of Ca 2+ i stores; the second phase results from entry of Ca 2+ e . In these experiments, we tested the hypothesis that release of mitochondrial Ca 2+ through the mitochondrial permeability transition pore (MTP) contributes to the initial release of Ca 2+ i . Neonatal rat cerebellar granule cells in culture and single cell microfluorimetry were used to examine MeHg-induced changes in (Ca 2+ ) i and mitochondrial membrane potential (Ψ m ). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 μM) delayed the initial phase of increased (Ca 2+ ) i induced by 0.2 and 0.5 μM MeHg, but not 1.0 μM MeHg. CsA (5 μM) also delayed the irreversible loss of Ψ m induced by 0.5 μM MeHg. Ca 2+ e was not required for either effect, because the effect of CsA on the first phase increase in (Ca 2+ ) i and loss of Ψ m was not altered in nominally Ca 2+ -free buffer. Increasing concentrations of MeHg (0.2–2.0 μM) caused increasing incidence of cell death at 24 h postexposure. Treatment with CsA provided protection against cytotoxicity at lower MeHg concentrations (0.2–0.5 μM), but not at higher MeHg concentrations (1.0–2.0 μM). Thus, the MTP appears to play a significant role in the cellular effects following acute exposure of cerebellar granule neurons to MeHg.
Toxicology and Applied Pharmacology – Elsevier
Published: Jan 1, 2002
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