Subcellular Compartmentalization of 1-methyl-4-phenylpyridinium with Catecholamines in Adrenal Medullary Chromaffin Vesicles May Explain the Lack of Toxicity to Adrenal Chromaffin Cells

Cultures of bovine adrenomedullary chromaffin cells accumulated 1-methyl-4-phenylpyridinium (MPP+) in a time- and concentration-dependent manner by a process that was prevented by desmethylimipramine. The subcellular localization of the incorporated [methyl-3H]MPP+ was examined by differential centr...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1987-11, Vol.84 (22), p.8160-8164
Main Authors: Reinhard, John F., Diliberto, Emanuel J., Viveros, O. Humberto, Daniels, Alejandro J.
Format: Article
Language:English
Subjects:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
1-Methyl-4-phenylpyridinium
Adrenal Medulla - metabolism
Adrenal Medulla - ultrastructure
Animals
Biological and medical sciences
Brain
Calcium - pharmacology
Catecholamines
Catecholamines - analysis
Catecholamines - metabolism
Cattle
Cell Compartmentation
Cell physiology
Cells, Cultured
Chromaffin cells
Cultured cells
Desipramine - pharmacology
Digitonin - pharmacology
Drug Interactions
Fundamental and applied biological sciences. Psychology
Liquids
Miscellaneous
Molecular and cellular biology
Neurons
Nicotine - pharmacology
Norepinephrine
Pyridines - pharmacokinetics
Pyridines - toxicity
Pyridinium Compounds - metabolism
Pyridinium Compounds - pharmacokinetics
Pyridinium Compounds - toxicity
Radioactive decay
Subcellular Fractions - analysis
Tetrabenazine - pharmacology
Toxins
Tyrosine 3-Monooxygenase - antagonists & inhibitors
Ungulates
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Summary:Cultures of bovine adrenomedullary chromaffin cells accumulated 1-methyl-4-phenylpyridinium (MPP+) in a time- and concentration-dependent manner by a process that was prevented by desmethylimipramine. The subcellular localization of the incorporated [methyl-3H]MPP+ was examined by differential centrifugation and sucrose density gradient fractionation and was found to be predominantly colocalized with catecholamines in chromaffin vesicles, and negligible amounts were detected within the mitochondrial fraction. When chromaffin cell membranes were made permeable with the detergent digitonin in the absence of calcium, there was no increase in the release of [3H]MPP+, indicating that there is negligible accumulation of the neurotoxin in the cytosol. Simultaneous exposure to digitonin and calcium induced cosecretion of MPP+ and catecholamines. Stimulation of the cells with nicotine released both catecholamines and MPP+ at identical rates and percentages of cellular content in a calcium-dependent manner. Last, when cells were incubated with MPP+ in the presence of tetrabenazine (an inhibitor of vesicular uptake), the chromaffin cell toxicity of MPP+ was potentiated. We submit that the ability of the chromaffin cells to take up and store MPP+ in the chromaffin vesicle prevents the toxin's interaction with other structures and, thus, prevents cell damage. As an extension of this hypothesis, the relative resistance of some brain monoaminergic neurons to the toxic actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine may result from the subcellular sequestration of MPP+ in the storage vesicle.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.84.22.8160