Disulfiram lowers Ca2+, Mg2+-ATPase activity of rat brain synaptosomes |
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Authors: | S N Nagendra K Mamatha Rao M N Subhash K Taranath Shetty |
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Institution: | (1) Dept. of Neurochemistry, National Institute of Mental Health and Neurosciences, 560 029 Bangalore, India;(2) Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Malott 5040, 66045 Lawrence, Kansas |
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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 M) 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 M) 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 M) and EGTA (100 M) 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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Keywords: | Synaptosomes Ca2+ Mg2+ ATPase inhibition disulfiram diethyldithiocarbamate calmodulin |
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