The Na(+),K(+)-ATPase traffics between the plasma membrane and intracellular compartments in response to acute changes in membrane receptor activation. These effects are accomplished by a time-dependent interaction of the Na(+),K(+)-ATPase alpha-subunit with specific intracellular signaling molecules either at the plasma membrane (endocytosis) or at the endosome's membranes (recruitment). Most of these studies have been performed in rat renal epithelial cells in which only the alpha(1) isoenzyme is present. Studies in neurons from the neostriatum in which all three alpha-subunit isoforms are present indicate that neurotransmitter-dependent regulation of Na(+),K(+)-ATPase activity displays isoform specificity and also suggest a more complex organization of the intracellular signaling networks controlling Na(+),K(+)-ATPase traffic in mammalian cells.