Identification of the major transport pathway for the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium

Abstract

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 V max of 1-methyl-4-phenylpyridinium transport. In addition, 1-methyl-4-phenylpyridinium is far more effective at inhibiting ATP-stimulated dopamine transport ( ic 50 = 11 μM) than basal dopamine transport ( ic 50 > 100 μM) 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.