Ouabain interaction with cardiac Na/K-ATPase reveals that the enzyme can act as a pump and as a signal transducer.

Na/K-ATPase hydrolyzes ATP to maintain the transmembrane gradients of Na+ and K+ found in most mammalian cells and is inhibited specifically by cardiac glycosides such as ouabain. Recently, we have shown that partial inhibition of Na/K-ATPase by non-toxic concentrations of ouabain causes hypertrophic growth and transcriptional regulation of several growth-related marker genes in neonatal rat cardiac myocytes. These ouabain effects involve the activation of multiple signal transduction pathways, including the activation of Src kinase and tyrosine phosphorylation of the epidermal growth factor receptors and other proteins, followed by the activation of Ras, the Ras/Raf/MEK/MAPK cascade, and increased production of reactive oxygen species. The gene regulatory actions of ouabain, like its classical effect on cardiac contractility, are dependent on the net influx of Ca2+ and rise in [Ca2+]i, indicating that the latter is a shared second messenger for the ouabain effects on cardiac contractility and growth. Significantly, the effects of ouabain on several early signaling events including stimulation of tyrosine phosphorylation and production of reactive oxygen species are independent of changes in intracellular Na and Ca2+ concentrations. Taken together, these new findings have led us to propose that when ouabain binds to Na/K-ATPase, it converts the enzyme to a signal transducer and initiates multiple gene regulatory pathways through either direct or indirect interactions with tyrosine kinases in cardiac myocytes.