ETHANOL EFFECTS ON MEMBRANE-BOUND ENZYMES

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Ethanol perturbs the structure of neuronal membrane lipids, and its CNS effects may arise secondarily as a result of changes in the function of membrane-bound enzymes. At high concentrations ethanol inhibits brain (Na-+, K-+) ATPase activity, and we found that inhibition of mouse synaptosomal ATPase activity by alcohols does not depend solely on interactions with membrane lipids; ethanol may also interact directly with the protein. Our studies showed no potentiation by norepinephrine of ethanol-induced inhibition of ATPase in mouse or rat brain. Since substantial inhibition of activity occurs only at high ethanol concentrations, the role of enzyme inhibition per se in the CNS actions of ethanol remains open to question. However, other aspects of ATPase activity can serve as a probe of changes in membrane structure, following ethanol exposure, which may be associated with tolerance or physical dependence. ATPase exists in two forms in the brain, with high and low affinity for the inhibitor, ouabain. The high-affinity component is believed to be localized in neuronal membranes. Following chronic ethanol treatment, there was a selective increase in affinity for ouabain of this component, most likely resulting from changes in the lipid microdomain of this form of the enzyme. Another membrane-bound enzyme, monoamine oxidase (MAO), also exists in two forms, A and B. Ethanol selectively inhibited the B form of the enzyme in human brain and platelet tissue by perturbation of membrane lipids, supporting the hypothesis that the two forms of MAO are distinguished by their lipid environments. Ethanol at 50 mM significantly inhibited enzyme activity, and inhibition of MAO-B could play a role in mediating the CNS effects of ethanol. This project also included studies of glial regulation of neurotransmitter metabolism, adding to our understanding of basic mechanisms of regulation of neuronal activity.