A CA-DEPENDENT MODULATOR PROTEIN OF THE NA-K ATPASE

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Recent work by the author has shown that the sensitivity of the Na-K ATPase and Na-K pump of human red blood cells to inhibition by Ca is increased 20 fold by an unidentified protein present in the cytoplasm of red cells. The protein is not calmodulin, appears to bind to the membrane of human red cells in a Ca-dependent manner, and increases the sensitivity of the Na-K ATPase to the extent that 50% inhibition can occur at low micromolar concentrations of free Ca. If this protein also alters the effect of Ca on the Na-K ATPase in other cells, then it could play a fundamental role in cellular regulation of the Na-K pump under many conditions. For instance, it could be involved in the relationship between the Na-K pump and the Na/Ca exchange and the control of free Ca in smooth muscle which may underlie the inotropic effect of cardiac glycosides and the relationship between sodium metabolism and hypertension. The first aim of the proposed project is to purify and identify the protein; the second is to determine its molecular weight, amino acid composition, end terminals, and possible prosthetic groups. The third aim is to study the effect of the purified protein on Ca inhibition of the Na-K ATPase in human red cell membranes and the fourth is to establish its effect on the purified Na-K ATPase. The fifth and final aim is to investigate if the Na-K ATPase in patients with essential hypertension are more sensitive than normal to inhibition by Ca and to establish what role the purified protein may play in such differences. The proposed work will require three years to complete.