Na+/K+-ATPase-mediated signal transduction and Na+/K+-ATPase regulation.

A number of studies suggest that Na(+)/K(+)-ATPase in caveolae interacts with neighboring membrane proteins and organizes cytosolic cascades of signaling proteins to send messages to intracellular organelles in different tissues, mostly in cardiac myocytes. Low concentration of ouabain binding to Na(+)/K(+)-ATPase activates Src/epidermal growth factor receptor complex to initiate multiple signal pathways, which include PLC/IP3/CICR, PI3K, reactive oxygen species (ROS), PLC/DG/PKC/Raf/MEK/ERK1/2, and Ras/Raf/MEK/ERK1/2 pathways. In cardiac myocytes, the resulting downstream events include the induction of some early response proto-oncogenes, activation of transcription factors, activator protein-1, and nuclear factor-kappaB, the regulation of a number of cardiac growth-related genes, and the stimulation of protein synthesis and myocyte hypertrophy and apoptosis. Conversely, several factors acting through signal pathways, such as protein kinases, Ca(2+), ROS, etc., can modulate the activity of the Na(+)/K(+)-ATPase.