Abstract
Trifluoperazine inhibition of a partially purified cerebral cortical phosphodiesterase having a high stimulatory response to a Ca2+-dependent regulatory (CDR) protein and specificity toward guanosine 3',5'(cyclic) monophosphate was studied. Trifluoperazine (50 µM) completely blocked the Ca2+·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 cyclic GMP and produced no change in affinity of the enzyme for Ca2+·CDR. These results correlate well with previous reports on Ca2+·CDR-phenothiazine binding and provide further support for a mechanism in which trifluoperazine, upon binding to Ca2+· CDR, renders the latter ineffective in stimulating the enzyme, thus depleting the level of active CDR and inhibiting the activator-dependent phosphodiesterase. This reduction in active CDR may be involved in a mode of phenothiazine action on the activities of other Ca2+·CDR-dependent enzymes.
- Copyright © 1979 by Academic Press, Inc.
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