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

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Abstract

The chronic administration of disulfiram (DS) to rats resulted in significant decrease of synaptosomal Ca2+, Mg2+-ATPase activity. In vitro studies indicated that DS (ID50=20 μM) produced a dose-dependent inhibition of Ca2+, Mg2+-ATPase. However, diethyldithio-carbamate, a metabolite of DS, failed to modify Ca2+, Mg2+-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 μM) 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+, Mg2+-ATPase specific activity was observed when treated with DS (30 μM) and EGTA (100 μM) respectively. The remaining 25–30% of total activity is suggested to be of Mg2+-dependent ATPase activity. This indicates that both these drugs may act on a common target, calmodulin component that represents 70–75% of total Ca2+, Mg2+-ATPase activity. Therefore, DS-mediated modulation of synaptosomal Ca2+, Mg2+-ATPase activity could affect its function of maintaining intracellular Ca2+ concentration. This could contribute to the deleterious effects on CNS.

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Authors and Affiliations

  1. Dept. of Neurochemistry, National Institute of Mental Health and Neurosciences, 560 029, Bangalore, India

    S. N. Nagendra, K. Mamatha Rao, M. N. Subhash & K. Taranath Shetty

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  1. S. N. Nagendra
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  2. K. Mamatha Rao
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  3. M. N. Subhash
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  4. K. Taranath Shetty
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Nagendra, S.N., Mamatha Rao, K., Subhash, M.N. et al. Disulfiram lowers Ca2+, Mg2+-ATPase activity of rat brain synaptosomes. Neurochem Res 19, 1509–1513 (1994). https://doi.org/10.1007/BF00968998

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