Monensin inhibits catecholamine synthesis in pheochromocytoma cells

The carboxylic ionophore monensin inhibits the activity of tyrosine 3-monooxygenase and decreases the rate of catecholamine synthesis in pheochromocytoma cells incubated in vitro. The ionophore inhibits dopa production in intact pheochromocytoma cells, but does not itself inhibit tyrosine 3-monooxygenase and does not produce a stable inactivation of the enzyme as assayed in cell-free extracts of the cells. The inhibition of dopa production by monensin is dependent upon extracellular Na+, but does not require extracellular Ca++. This effect of monensin is more pronounced in the presence of pargyline. In the absence of pargyline, monensin also depletes the cells of norepinephrine and increases the accumulation of the deaminated norepinephrine metabolite, dihydroxyphenylglycol. Finally, monensin increases the release of catecholamines from isolated chromaffin granules. These results are consistent with the hypothesis that monensin causes the release of norepinephrine from chromaffin granules into the cytoplasm of pheochromocytoma cells and that the increase in cytoplasmic norepinephrine inhibits tyrosine 3-monooxygenase activity.