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+ a nd K+ found in most mammalian cells and is inhibited specifically by cardia c glycosides such as ouabain. Recently, we have shown that partial inhibiti on of Na/K-ATPase by non-toxic concentrations of ouabain causes hypertrophi c growth and transcriptional regulation of several growth-related marker ge nes in neonatal rat cardiac myocytes. These ouabain effects involve the act ivation of multiple signal transduction pathways, including the activation of Src kinase and tyrosine phosphorylation of the epidermal growth factor r eceptors 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 c ontractility, 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 e ffects on cardiac contractility and growth. Significantly the effects of ou abain on several early signaling events including stimulation of tyrosine p hosphorylation and production of reactive oxygen species are independent of changes in intracellular Na+ and Ca2+ concentrations. Taken together, thes e new findings have led us to propose that when ouabain binds to Na/K-ATPas e, it converts the enzyme to a signal transducer and initiates multiple gen e regulatory pathways through either direct or indirect interactions with t yrosine kinases in cardiac myocytes.