Disulfiram lowers Ca2+, Mg2+-ATPase activity of rat brain synaptosomes

Abstract

The chronic administration of disulfiram (DS) to rats resulted in significant decrease of synaptosomal Ca2+, Mg(2+)-ATPase activity. In vitro studies indicated that DS (ID50 = 20 microM) produced a dose-dependent inhibition of Ca2+, Mg(2+)-ATPase. However, diethyldithio-carbamate, a metabolite of DS, failed to modify Ca2+, Mg(2+)-ATPase activity, implying that the decrease in ATPase activity in DS administered rats was due to the effect of parent compound. The DS-mediated inhibition (48%) of ATPase activity was comparable with a similar degree of inhibition (49%) achieved by treating the synaptosomal membranes with N-ethylmaleimide (ID50 = 20 microM) in vitro. Furthermore, the inhibition by DS was neither altered by washing the membranes with EGTA nor reversed by treatment with sulfhydryl reagents such as GSH or dithiothreitol. About 74% and 68% decrease of synaptosomal Ca2+, Mg(2+)-ATPase specific activity was observed when treated with DS (30 microM) and EGTA (100 microM) respectively. The remaining 25-30% of total activity is suggested to be of Mg(2+)-dependent ATPase activity. This indicates that both these drugs may act on a common target, calmodulin component that represents 70-75% of total Ca2+, Mg(2+)-ATPase activity. Therefore, DS-mediated modulation of synaptosomal Ca2+, Mg(2+)-ATPase activity could affect its function of maintaining intracellular Ca2+ concentration. This could contribute to the deleterious effects on CNS.