Mechanisms by which Li + stimulates the (Na ++K +)-dependent ATPase

Abstract

The addition of LiCl stimulated the ( Na ++ K +)-dependent ATPase activity of a rat brain enzyme preparation. Stimulation was greatest in high Na +/low K + media and at low Mg. ATP concentrations. Apparent affinities for Li + were estimated at the α-sites (moderate-affinity sites for K + demonstrable in terms of activation of the associated K +-dependent phosphatase reaction), at the β-sites (high-affinity sites for K + demonstrable in terms of activation of the overall ATPase reaction), and at the Na + sites for activation. The relative efficacy of Li + was estimated in terms of the apparent maximal velocity of the phosphatase and ATPase reactions when Li + was substituted for K +, and also in terms of the relative effect of Li + on the apparent K M for Mg· ATP. With these data, and previously determined values for the apparent affinities of K + and Na + at these same sites, quantitative kinetic models for the stimulation were examined. A composite model is required in which Li + stimulates by relieving inhibition due to K + and Na + (i) by competing with K + for the α-sites on the enzyme through which K + decreases the apparent affinity for Mg·ATP and (ii) by competing with Na + at low-affinity inhibitory sites, which may represent the external sites at which Na + is discharged by the membrane NA +/K + pump that this enzyme represents. Both these sites of action for Li + would thus lie, in vivo, on the cell exterior.