Molecular Pharmacology, Vol 15, 263-270, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

The Role of Cyclic Adenosine 3':5'-Monophosphate in the Regulation of Tyrosine 3-monooxygenase Activity

¹ Department of Physiology, Harvard Medical School, 25 Shattuck Street, Boston, Mass. 02115

The activity of tyrosine 3-monooxygenase (TH) was measured in extracts of cell suspensions prepared from a rat pheochromocytoma. Incubation of the cells with cholera toxin (0.1-1 µg/ml) or dibutyryl cAMP (1 mM) leads to an increase in TH activity in the cells. The effects of these agents are not dependent upon the presence of extracellular Ca²⁺, and are not blocked by diphenylhydantoin, an inhibitor of Ca²⁺ uptake into the cells. The activation of TH by cholera toxin occurs after a lag period of 10-15 min, and is associated with a large rise in cAMP levels in the cells. Cholera toxin and dibutyryl cAMP increase the rate of catecholamine biosynthesis in these cells, but have no effect on the secretion of catecholamine from the cells. Incubation of the cells in media containing 56 mM K⁺ also leads to the activation of TH. However, this treatment does not result in a rise in cAMP levels, nor does it increase the rate of formation of [³H]cAMP from [³H]adenine in these cells. These results are consistent with the hypothesis that TH can be regulated by two distinct pathways, one of which involves cAMP, and the other of which is independent of the nucleotide.

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ACKNOWLEDGMENTS We are grateful to Dr. Shields Warren and Ms. Rosanna Chute for supplying the pheochromocytoma used in these studies. We thank Dr. William Moyle for his help with the cAMP assays.