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Molecular Pharmacology, Vol 12, 41-48, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Dopaminergic Neurons: Activation of Tyrosine Hydroxylase by a Calcium Chelator

VICTOR H. MORGENROTH III 1, MARGARET C. BOADLE-BIBER 1, and ROBERT H. ROTH 1

1 Departments of Pharmacology and Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510

Addition of the calcium-chelating agent ethylene glycol bis(beta-aminoethyl ether)-N,N’-tetraacetic acid (EGTA) to a high-speed supernatant preparation obtained from rat striatum produced a dramatic increase in the activity of tyrosine hydroxylase assayed in the presence of subsaturating concentrations of tyrosine and reduced pterin cofactor. This activation appeared to be mediated by changes in the kinetic properties of tyrosine hydroxylase. In the presence of EGTA (50 µM) the Km of the enzyme for tyrosine decreased nearly 8-fold (from 54 µM to 9 µM), the Km for 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine decreased 7-fold (from 0.89 mM to 0.13 mM), and the Ki for dopamine increased 700-fold (from 0.11 mM to 74 mM). No significant change in Vmax was observed. All these kinetic alterations could be reversed by the addition of calcium to the assay medium, while magnesium, even in high concentrations (1 mM), was ineffective. A similar activation was observed with tyrosine hydroxylase isolated from other dopamine-containing regions of rat brain (median eminence, olfactory tubercle) and in the dopamine-rich pedal ganglion of Mercenaria mercenaria (Mollusca). EGTA produced no significant change in the activity of tyrosine hydroxylase prepared from central (medulla-pons) or peripheral noradrenergic neurons. These results suggest that tyrosine hydroxylase associated with dopaminergic neurons may differ from the enzyme found in noradrenergic neurons. This unique response of the tyrosine hydroxylase present in dopaminergic neurons may serve as a useful biochemical marker for identifying these neurons.

Note:
ACKNOWLEDGMENTS Thanks are due to Ms. Anne Morrison for her expert technical assistance and enduring patience.

Submitted on March 24, 1975






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