Gene transfer of a reserpine-sensitive mechanism of resistance to N-methyl-4-phenylpyridinium.
The toxin N-methyl-1,2,3,6-tetrahydropyridine produces a model of neural degeneration very similar to idiopathic Parkinson disease. To understand the cellular mechanisms that modulate susceptibility to its active metabolite N-methyl-4-phenylpyridinium (MPP+), we have transfected a cDNA expression library from the relatively MPP(+)-resistant rat pheochromocytoma PC12 cells into MPP(+)-sensitive Chinese hamster ovary (CHO) fibroblasts. Selection of the stable transformants in high concentrations of MPP+ has yielded a clone extremely resistant to the toxin. Reserpine reverses the resistance to MPP+, suggesting that a transport activity protects against this form of toxicity, perhaps by sequestering the toxin within an intracellular compartment. In support of this hypothesis, dopamine loaded into the CHO transformant shows a localized distribution that is distinct from the pattern observed in wild-type cells and is also reversed by reserpine.
Liu
Y
Y
Department of Neurology, University of California, Los Angeles School of Medicine 90024-1769.
Roghani
A
A
Edwards
R H
RH
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007700:Kinetics; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D016716:PC12 Cells; D012110:Reserpine / Q000494:pharmacology*; D012402:Rotenone / Q000494:pharmacology; D014162:Transfection
D012402:Rotenone; D012110:Reserpine; D010088:Oxidoreductases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine