1. A novel mechanism of dopamine neurotoxicity involving the peripheral extracellular and the plasma membrane dopamine transporter.
- Author
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Liu Z, Zhang J, Fei J, and Guo L
- Subjects
- Animals, Apoptosis drug effects, CHO Cells drug effects, CHO Cells metabolism, CHO Cells ultrastructure, Cell Membrane drug effects, Cell Membrane ultrastructure, Cell Survival drug effects, Cell Survival physiology, Colforsin pharmacology, Cricetinae, Dopamine toxicity, Dopamine Plasma Membrane Transport Proteins, Dose-Response Relationship, Drug, Drug Interactions physiology, Extracellular Space drug effects, Humans, Membrane Transport Proteins drug effects, Microscopy, Electron, Neurons drug effects, Neurons ultrastructure, Neurotoxins toxicity, Parkinson Disease metabolism, Parkinson Disease pathology, Parkinson Disease physiopathology, Substantia Nigra metabolism, Substantia Nigra pathology, Substantia Nigra physiopathology, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured metabolism, Tumor Cells, Cultured ultrastructure, Apoptosis physiology, Cell Membrane metabolism, Dopamine metabolism, Extracellular Space metabolism, Membrane Glycoproteins, Membrane Transport Proteins metabolism, Nerve Tissue Proteins, Neurons metabolism, Neurotoxins metabolism
- Abstract
Chinese hamster ovary cells stably expressing a rat dopamine transporter (designated D8 cells) and neuroblastoma SK-N-SH cells were used as two model systems to study dopamine neurotoxicity. Within 24 h, 1-10 mM dopamine induced D8 cells into apoptosis while 20-200 microM dopamine induced SK-N-SH cells into cell death. The viability of both cell types decreased in a dose-dependent manner. However, the dopamine uptake activity of D8 cells at 10 mM was not significantly higher than the uptake at 100 microM, suggesting that it was not the high concentration of intracellular dopamine that induced D8 cells into apoptosis, but rather dopamine found in the extracellular space. Furthermore, cocaine, an inhibitor of dopamine uptake, could not block cell death induced by dopamine. Forskolin, an agonist of protein kinase A (PKA), stimulated dopamine uptake in D8 cells and blocked apoptosis induced by the drug. These results suggest that the dopamine transporter mediates a dopamine-dependant apoptotic signal transduction pathway that is independent of dopamine uptake into the cell.
- Published
- 2001
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