Identified and potential internalization signals involved in trafficking and regulation of Na⁺/K⁺ ATPase activity

The sodium-potassium pump (NKA) or Na⁺/K⁺ ATPase consumes around 30-40% of the total energy expenditure of the animal cell on the generation of the sodium and potassium electrochemical gradients that regulate various electrolyte and nutrient transport processes. The vital role of this protein entails proper spatial and temporal regulation of its activity through modulatory mechanisms involving its expression, localization, enzymatic activity, and protein-protein interactions. The residence of the NKA at the plasma membrane is compulsory for its action as an antiporter. Despite the huge body of literature reporting on its trafficking between the cell membrane and intracellular compartments, the mechanisms controlling the trafficking process are by far the least understood. Among the molecular determinants of the plasma membrane proteins trafficking are intrinsic sequence-based endocytic motifs. In this review, we (i) summarize previous reports linking the regulation of Na⁺/K⁺ ATPase trafficking and/or plasma membrane residence to its activity, with particular emphasis on the endocytic signals in the Na⁺/K⁺ ATPase alpha-subunit, (ii) map additional potential internalization signals within Na⁺/K⁺ ATPase catalytic alpha-subunit, based on canonical and noncanonical endocytic motifs reported in the literature, (iii) pinpoint known and potential phosphorylation sites associated with NKA trafficking, (iv) highlight our recent studies on Na⁺/K⁺ ATPase trafficking and PGE2-mediated Na⁺/K⁺ ATPase modulation in intestine, liver, and kidney cells.