This ADAMHA Research Scientist Development Award, Type II, is sought in order to carry out research examining the relationship between energy metabolism and nerve activity and its regulation in affective disorders and alcoholism. The experimental model used will be (NA+, K+)-ATPase, the enzymatic mechanism of active cation transport and of stimulation-dependent energy metabolism in nerve, and its regulation by norepinephrine. The research will be based on my previous data describing the reaction mechanism of (Na+, K+)-ATPase, the possible presence of a nerve-specific form of enzyme, and the regulation of nerve-specific enzyme by noradrenergic innervation. Experiments on enzyme regulation and nerve activity in vivo will examine a) regulation by norepinephrine in terms of localization of regulated enzyme, specificity for nerve enzyme and for norepinephrine, and role in noradrnergic effects, b) methods of measuring nerve-specific enzyme, c) characterization of a possible endogenous sodium pump inhibitor and its interactions with norepinephrine, and d) physiology of the norepinephrine-ATPase system including peripheral-central interactions and role in energy balance. Experiments on regulation in vitro will examine the relationship between the energy of cation binding and cation transport and the effects on this of norepinephrine and electrical stimulation, and the relationship between (Na+, K+)-ATPase activity and energy production. Approaches to the study of this system in nerve cells will be developed using isolated cells from liver and from brown adipose tissue. The hypothesis being tested will be that nerve-specific enzyme is regulated by norepinephrine via cylic AMP. In clinical studies, red and white blood cell (Na+, K+)-ATPase and plasma levels of the inhibitor will be compared in normal, alcoholic, and depressed patients. Nerve-specific enzyme and norepinephrine stimulation will be compared using enzyme from postmortem brain samples from these groups. In the course of these studies, I will develop methods for measuring energy metabolism in isolated cells, measurement of ion transport in artificial vesicles, and measurement of membrane potentials in vitro.
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