Mechanism of phenothiazine inhibition of Ca2+-dependent guanosine 3',5'- (cyclic) monophosphate phosphodiesterase of brain

Filburn, C.R.; Colpo, F.T.; Sacktor, B.

Molecular Pharmacology 15(2): 257-262

1979


ISSN/ISBN: 0026-895X
PMID: 38390
Accession: 068518687

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Abstract
Trifluoperazine GMP was studied. Trifluoperazine (50 .mu.M) completely blocked the Ca2+ .cntdot. CDR-stimulated activity but had no effect on the basal activity. The magnitude of the inhibition depended on the concentrations of both inhibitor and activator. With increasing concentration of CDR, the enzyme became less sensitive to the phenothiazine. Plots of 1/V vs. 1/CDR and 1/V vs. trifluoperazine concentration were nonlinear with upward curvature, in contrast to a previous report. Decreasing the pH of the reaction mixture from 8.0 to 6.8 enhanced inhibition while reducing the Km for cGMP and produced no change in affinity of the enzyme for Ca2+ .cntdot. CDR. Ca2+ .cntdot. CDR-phenothiazine binding and the mechanism in which trifluoperazine, upon binding to Ca2+. CDR, renders the latter ineffective in stmulating the enzyme, thus depleting the level of active CDR and inhibiting the activator-dependent phosphodiesterase was supported. This reduction in active CDR may be involved in a mode of phenothiazine action on the activities of other Ca2+ .cntdot. CDR-dependent enzymes.