Document Detail

The role of dopamine transporter in selective toxicity of manganese and rotenone.
MedLine Citation:
PMID:  18206288     Owner:  NLM     Status:  MEDLINE    
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 similar levels in PC12 cells overexpressing the dopamine transporter and control PC12 cells following incubation with manganese chloride. These results suggested that the dopamine transporter dose not confer cytotoxicity to manganese and rotenone.
Yoko Hirata; Hiromi Suzuno; Tadamiki Tsuruta; Kentaro Oh-hashi; Kazutoshi Kiuchi
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Publication Detail:
Type:  Journal Article     Date:  2007-12-03
Journal Detail:
Title:  Toxicology     Volume:  244     ISSN:  0300-483X     ISO Abbreviation:  Toxicology     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-03-03     Completed Date:  2008-04-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  249-56     Citation Subset:  IM    
Department of Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
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MeSH Terms
1-Methyl-4-phenylpyridinium / antagonists & inhibitors,  toxicity
Blotting, Western
DNA Fragmentation / drug effects
DNA, Complementary / biosynthesis,  genetics
Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors,  physiology*
Manganese / analysis,  metabolism,  toxicity*
Manganese Poisoning / metabolism*
PC12 Cells
Rotenone / toxicity*
Uncoupling Agents / toxicity*
Reg. No./Substance:
0/DNA, Complementary; 0/Dopamine Plasma Membrane Transport Proteins; 0/Uncoupling Agents; 48134-75-4/1-Methyl-4-phenylpyridinium; 7439-96-5/Manganese; 83-79-4/Rotenone

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