Effects of ADP on different inhibitory properties of brain glutamate dehydrogenase isoproteins by perphenazine.

Incubation of glutamate dehydrogenase isoproteins (GDH I and GDH II) from b ovine brains with perphenazine resulted in a time-dependent loss of enzyme activity. 2-Oxoglutarate and NADH, separately or together, gave partial but not complete protection against the inhibition. Although there were no det ectable differences between GDH I and GDH II in inhibition by perphenazine in the absence of ADP, the sensitivities to the inhibition by the drug were significantly distinct for the two isoproteins in the presence of ADP. Low concentrations of ADP (0.05-0.20 mM) did not interfere with the inhibition of GDH I and GDH Il by perphenazine. However, in the presence of high conc entrations of ADP (0.5-1.0 mM) inhibitory effects of perphenazine on GDH is oproteins were significantly diminished as determined by enzyme kinetics an d quantitative affinity chromatography on perphenazine-Sepharose. GDH I was more sensitively reacted with ADP than GDH II on the inhibition by perphen azine. Since physiological ADP levels can vary from 0.05 to > 1.0 mM depend ing on the rate of oxidative phosphorylation, our results suggest a possibi lity that two types of GDHs are differently regulated by the antipsychotic actions of perphenazine depending on the physiological concentrations of AD P. GTP and L-leucine, other well-known allosteric regulators, did not affec t the inhibitory actions of perphenazine on bovine brain GDH isoproteins. ( C) 2001 Societe francaise de biochimie et biologie moleculaire / Editions s cientifiques et medicales Elsevier SAS. All rights reserved.