Identification of the major transport pathway for the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium.
1-Methyl-4-phenylpyridinium is a potent parkinsonism-inducing neurotoxin which has become a valuable tool for the examination of the mechanisms and therapeutic treatment strategies for Parkinson's syndrome. Recently, it has been found that physiological levels of extracellular ATP (0.1-1 mM) stimulate dopamine uptake into both rat and bovine brain synaptosomes and rat pheochromocytoma cells in a dose-dependent manner. In this study we report that physiological levels of extracellular ATP (0.1-2 mM) stimulate the transport of 1-methyl-4-phenylpyridinium into the pheochromocytoma cell line by 270% over basal levels. Kinetically, the presence of ATP increases both the K(m) and Vmax of 1-methyl-4-phenylpyridinium transport. In addition, 1-methyl-4-phenylpyridinium is far more effective at inhibiting ATP-stimulated dopamine transport (IC50 = 11 microM) than basal dopamine transport (IC50 100 microM) into pheochromocytoma cells. These data show that the ATP-regulated 1-methyl-4-phenylpyridinium transport pathway is the major component (approximately 95%) of total 1-methyl-4-phenylpyridinium transport, and provide the first evidence for the involvement of extracellular ATP in the bulk transport of 1-methyl-4-phenylpyridinium.
Dunigan
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Department of Biological Chemistry, University of Maryland at Baltimore, School of Medicine 21201, USA.
Shamoo
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D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism* / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001693:Biological Transport, Active; D002417:Cattle; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000209:etiology*; D051381:Rats
D009498:Neurotoxins; D000255:Adenosine Triphosphate; D015655:1-Methyl-4-phenylpyridinium