The role of dopamine transporter in selective toxicity of manganese and rotenone

Toxicology
Yoko HirataKazutoshi Kiuchi

Abstract

The dopamine transporter has been shown to be the most relevant target site for the specificity of 1-methyl-4-phenylpyridinium ion (MPP+), a neurotoxin for dopaminergic neurons. In contrast, the mechanisms underlying the selective toxicity of manganese and rotenone, potentially toxic agents implicated in dopaminergic neuronal cell death, remain unknown. The aim of this study was to determine the cellular mechanisms of manganese or rotenone uptake in dopaminergic cells via the dopamine transporter. PC12 cells overexpressing the dopamine transporter, which were exposed to 10microM MPP+, showed extensive DNA fragmentation, a biochemical hallmark of apoptosis, whereas wild-type PC12 cells or vector-transfected PC12 cells, which were exposed to 5mM MPP+, did not show DNA fragmentation. In contrast, manganese and rotenone induced DNA fragmentation at slightly lower concentrations in PC12 cells overexpressing the dopamine transporter compared to control cells. Dopamine transporter inhibitors, such as mazindol, nomifensine, or GBR12909, inhibited MPP+-induced DNA fragmentation but did not affect manganese- and rotenone-induced DNA fragmentation in PC12 cells overexpressing the dopamine transporter. Finally, manganese accumulated to sim...Continue Reading

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Citations

Jun 26, 2012·Toxicology·Adrian LupescuFlorian Lang
Mar 31, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Thomas M JeitnerGraham R Moran
Oct 2, 2008·Biological & Pharmaceutical Bulletin·Jungmin Nam, Kisok Kim
Jul 20, 2016·Neuromolecular Medicine·Supin ChompoopongThongchai Taechowisan

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