The sodium pump and digitalis drugs: Dogmas and fallacies

The sodium pump (Na/K-ATPase) is a plasma membrane enzyme that transports Na⁺ and K⁺ against their physiological gradients in most eukaryotic cells. Besides pumping ions, the enzyme may also interact with neighboring proteins to activate cell signaling pathways that regulate cell growth. Digitalis drugs, useful for the treatment of heart failure and atrial arrhythmias, inhibit the pumping function of Na/K-ATPase and stimulate its signaling function. In the current field of research on the sodium pump and digitalis drugs, some issues that are commonly accepted to be well established are not so, and this may impede progress. Here, several such issues are identified, their histories are discussed, and their open discussions are urged. The covered unsettled questions consist of (a) the suggested hormonal role of endogenous digitalis compounds; (b) the specificity of Na/K-ATPase as the receptor for digitalis compounds; (c) the relevance of the positive inotropic action of digitalis to its use for the treatment of heart failure; (d) the conflicting findings on digitalis-induced signaling function of Na/K-ATPase; and (e) the uncertainties about the structure of Na/K-ATPase in the native cell membrane.