Activation of Na+/K(+)-ATPase by fatty acids, acylglycerols, and related amphiphiles: structure-activity relationship

A number of fatty acids and derivatives have been shown to activate Na+/K(+)-ATPase when ATP is suboptimal. To explore the relation of the structures of these amphiphiles to Enzyme activation, the effects of varying amphiphile concentrations on the activity of the highly purified kidney Na+/K(+)-ATPase at 50 microM ATP were determined. Among fatty acids, efficacy (maximal level of activation) and potency were found to be dependent, in different ways, on chain length and unsaturation. Compared to fatty acids, the corresponding alcohols had lower efficacies. Methyl esters of fatty acids inhibited, but CoA esters and monoacyl esters of glycerol activated the Enzyme. Relation between chain length and potency among CoA esters and monoacylglycerols was the same as that observed with acids. Diacylglycerols did not activate, but they antagonized the effects of the activator amphiphiles. The substantial specificities of the amphiphile effects support the hypothesis that these ligands bind to a distinct amphipathic peptide segment of the intracellular central loop of the alpha-subunit to regulate ATP binding to the Enzyme. The findings also suggest that direct effects of the changing intracellular levels of fatty acids and derivatives on Na+/K(+)-ATPase should be considered as a possible mechanism for the regulation of its function in the intact cell.