The physiological function of an ion transport protein is determined, in part, by its subcellular localization and by the cellular mechanisms that modulate its activity. The Na⁺/K⁺-ATPase and the gastric H⁺/K⁺-ATPase are two closely related members of the P-type family of ion transporting ATPases. Despite their homology, these pumps are sorted to different domains in polarized epithelial cells and their enzymatic activities are subject to distinct regulatory pathways. The molecular signals responsible for these properties have begun to be elucidated. It appears that a complex array of inter- and intra-molecular interactions govern these proteins’ trafficking, distribution and catalytic capacities. By analysing the sorting behaviours of a number of chimeric pumps composed of complementary portions of the H⁺/K⁺-ATPase α-subunit and Na⁺/K⁺-ATPase α-subunit, we have identified an H⁺/K⁺-ATPase signal motif that is sufficient to redirect the normally basolateral Na⁺/K⁺-ATPase to the apical surface in transfected epithelial cells. This motif resides entirely within the fourth of the H⁺/K⁺-ATPase α-subunit’s ten predicted transmembrane domains. Surprisingly, apical sorting was also detected with a chimera in which the TM4 of the Na⁺/K⁺-ATPase is flanked by H⁺/K⁺-ATPase α-subunit sequences. Despite the fact that it possesses the basolateral sodium pump’s TM4 segment, this chimera accumulates at the apical surfaces of transfected epithelial cells. Neither of the flanking sequences is capable of directing apical localization when presented alone. It appears, therefore, that these discontinuous sequence domains, separated by the TM4, are able to co-operate in recapitulating the H⁺/K⁺-ATPase TM4’s apical sorting signal. Thus the apical sorting determinant appears to be the product of a conversation between the fourth transmembrane domain and the motifs that abut it.

The β-subunit of the H⁺/K⁺-ATPase contains a sorting signal that functions to internalize the pump complex from the surface of the gastric parietal cell and return it to an intracellular regulated storage compartment. This internalization is responsible for the cessation of gastric acid secretion following the removal of secretagogue stimulation. Transgenic mice that express an H⁺/K⁺-ATPase β-subunit lacking this tyrosine-based endocytosis signal are unable to re-internalize H⁺/K⁺-ATPase from the apical surfaces of their gastric parietal cells. Consequently, they produce elevated gastric acid secretion during the interdigestive period. Mice carrying the mutant β-subunit develop gastritis and gastric ulcerations with histological features that are essentially identical to those found in human disease. In recent studies we have begun to identify and characterize the epithelial proteins that interact with these putative sorting signals.