The other functions of the sodium pump

Schematic presentation of the two parallel cell signaling cascades that are linked to Na/K-ATPase of cardiac myocytes, and their relations to digitalis-induced cardiac hypertrophy and positive inotropy. See Section 4 for the cumulative evidence indicating that the pathway through PI3K1A leads to hypertrophy, and suggests the redundance of the pathway through EGFR/Src. [Display omitted] •The sodium pump (Na/K-ATPase) not only transports ions across the cell membrane, but may also act as a digitalis-activated signal transducer to regulate cell growth.•The advances in the signaling function of the pump in the heart during the past 2–3 decades are reviewed here.•Two parallel cell signaling pathways are activated by digitalis in cardiac myocytes: one through PI3K1A and the other through EGFR/Src.•Cumulative evidence suggests that PI3K1A activation leads to cardiac physiological hypertrophy, and that activation of EGFR/Src is redundant. Na/K-ATPase (the sodium pump) was discovered in the 1950s as the plasma membrane enzyme that carries out the coupled active transports of Na+ and K+ across the membranes of nearly all eukaryotic cells. It was not until the 1990s when it was shown that besides pumping ions, Na/K-ATPase is also capable of stimulus-induced interactions with neighboring proteins that lead to activations of signal transduction pathways causing cell growth. This article is an attempt to review the progress of the research on these signaling functions of sodium pump during the past 2–3 decades. The covered topics include (a) the controversial digitalis-induced growth activations through the epidermal growth factor receptor and Src kinase in cardiac myocytes and several other cell types; (b) the extensive findings on digitalis-induced growth activations in cardiac myocytes and other cell types through phosphatidylinositol 3-kinases; and (c) a number of interesting but insufficiently studied signaling functions of the sodium pump.