Abstract:
:Cerebellar granule cells are preferentially targeted during methylmercury (MeHg) poisoning. Following acute MeHg exposure, granule cells in culture undergo an increase in intracellular Ca2+ concentration ([Ca2+]i) that apparently contributes to cell death. This effect consists of several temporally and kinetically distinct phases. The initial elevation arises from release of Ca2+(i) stores; the second phase results from entry of Ca2+(e). In these experiments, we tested the hypothesis that release of mitochondrial Ca2+ through the mitochondrial permeability transition pore (MTP) contributes to the initial release of Ca2+(i). Neonatal rat cerebellar granule cells in culture and single cell microfluorimetry were used to examine MeHg-induced changes in [Ca2+]i and mitochondrial membrane potential (Psi(m)). Pretreatment with the MTP inhibitor cyclosporin A (CsA, 5 microM) delayed the initial phase of increased [Ca2+]i induced by 0.2 and 0.5 microM MeHg, but not 1.0 microM MeHg. CsA (5 microM) also delayed the irreversible loss of Psi(m) induced by 0.5 microM MeHg. Ca2+(e) was not required for either effect, because the effect of CsA on the first phase increase in [Ca2+]i and loss of Psi(m) was not altered in nominally Ca2+-free buffer. Increasing concentrations of MeHg (0.2-2.0 microM) 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 microM), but not at higher MeHg concentrations (1.0-2.0 microM). Thus, the MTP appears to play a significant role in the cellular effects following acute exposure of cerebellar granule neurons to MeHg.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Limke TL,Atchison WDdoi
10.1006/taap.2001.9327subject
Has Abstractpub_date
2002-01-01 00:00:00pages
52-61issue
1eissn
0041-008Xissn
1096-0333pii
S0041008X01993275journal_volume
178pub_type
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