The Na+, K+-ATPase: more than just a sodium pump

Abstract

This editorial refers to ‘Cardioprotection induced by Na+/K+-ATPase activation involves extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/Akt pathway’ by J. Zheng et al ., doi:10.1093/cvr/cvq263. Cardiotonic steroids (CTS) such as digitalis were introduced as medicine for the treatment of congestive heart failure by William Withering more than 200 years ago. Their beneficial effect in stimulating heart muscle contractility (positive inotropy) via their inhibition of the cardiac sodium pump (Na+, K+-ATPase) is often overshadowed by serious toxic effects resulting in cardiac arrhythmias and a variety of neuronal irritations. Because of a rather fluid transition between therapeutic and toxic concentrations of CTS, i.e. a narrow therapeutic window, severe toxicity as a result of overdose is not uncommon. The investigation of Zheng et al .1 might provide the basis for a new approach in the treatment of congestive heart failure while avoiding the danger of toxicity. These authors demonstrate that an antibody directed against the L7/8 extracellular domain of the α-subunit of the sodium pump not only activates the enzyme, but also generates multiple cardioprotective events and induces positive inotropy in cardiac myocytes. This very intriguing observation might result in a new therapeutic concept; nevertheless, how does it fit into our knowledge about the function and physiological significance of the sodium pump? Schatzman's2 discovery in 1953 that the sodium pump of animal plasma membranes is the receptor for CTS and the identification of the Na+, K+-ATPase by Skou3 in 1957 as the biochemical equivalent of the sodium pump, in conjunction with the discovery of the Na+/Ca2+-exchanger (NCX) in the late 1960s, helped to develop a model for the CTS-induced positive inotropic effect on the heart muscle.4 This model couples the function of the sodium pump to that of …