Molecular Pharmacology, Vol 12, 420-432, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Induction of Tyrosine 3-Monooxygenase Elicited by Carbamylcholine in Intact and Denervated Adrenal Medulla: Role of Protein Kinase Activation and Translocation

¹ Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D. C. 20032

In adrenal medullae of rats treated with carbamylcholine (9.2 µmoles/kg intraperitoneally) the adenosine cyclic 3',5'-monophosphate (cAMP) content increased promptly by about 10-fold. The increase lasted for about 1 hr and elicited a sequence of molecular events including the activation of cAMP-dependent protein kinase in cytosol, an increase in the protein kinase activity extracted from the particulate fraction, which is due to the transfer of catalytic subunits from cytosol (translocation), and the delayed induction of tyrosine 3-monooxygenase (tyrosine hydroxylase). The translocation of catalytic subunits of kinase always preceded the delayed induction of tyrosine hydroxylase. In rats with a unilaterally denervated adrenal, the injection of aminophylline (200 µmoles/kg) increased the cAMP content in both intact and denervated adrenals. In the cytosol of both adrenal medullae the cAMP-dependent protein kinase was activated, but the translocation of protein kinase and the delayed induction of tyrosine hydroxylase occurred only on the intact side. Gel filtration and experiments with purified regulatory subunits proved that the increase in cAMP dissociates the catalytic subunit from the holoenzyme of the cytosol. The administration of hexamethonium (45 µmoles/kg intraperitoneally) prior to carbamylcholine (9.2 µmoles/kg intraperitoneally) abated the increase in cAMP content, blocked the activation of the cytosol kinase, and prevented tyrosine hydroxylase induction, whereas the administration of atropine (4 µmoles/kg intraperitoneally) failed to block any of these responses elicited by carbamylcholine. These results strongly suggest that activation of the cAMP-dependent protein kinase and its translocation from cytosol to subcellular structures are obligatory intermediate processes triggered by the early increase in cAMP; the kinase translocation mediates the delayed induction of tyrosine hydroxylase.

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