New insights into the regulation of Na+,K+-ATPase by ouabain

Cardiac glycosides have been widely used in the treatment of congestive heart failure and cardiac arrhythmias. The mechanism of their positive ionotropic effect is well characterized and is based on the inhibition of Na(+),K(+)-ATPase. However, recently it has been discovered that circulating endogenous cardiotonic steroids bind to Na(+),K(+)-ATPase, activate cell signaling pathways, and regulate diverse cellular functions. Thus, they play an important role in both physiological and pathological processes. Circulating endogenous ouabain has been reported to activate several signaling pathways upon binding to Na(+),K(+)-ATPase, and altered plasma levels of this endogenous cardiotonic steroid have been found in several pathologies. This review focuses on ouabain-mediated activation of cell signaling pathways and secondary messengers that conversely may modulate Na(+),K(+)-ATPase function.