Gastric parietal cell acid secretion in mice can be regulated independently of H+/K+ ATPase endocytosis

Background & Aims: Gastric parietal cells secrete acid into the lumen of the stomach. They express a proton pump, the gastric H+/K+ ATPase, the activity of which is tightly regulated. The H+/K+ ATPase traffics between an intracytoplasmic compartment (tubulovesicles) in quiescent parietal cells and the apical plasma membrane in activated cells. These trafficking events are considered to contribute to the control of acid secretion by modulating access to apical K+ and Cl- conductances that are required for transmembrane H+ ion transport by the H+/K+ ATPase. Here, we have determined whether the control of acid secretion in vivo requires membrane trafficking of the H+/K+ ATPase. Methods: We developed mice that only express an H+/K+ ATPase P subunit in which a putative tyrosine-based endocytosis motif in the cytoplasmic tail is mutated. Location of the H+/K+ ATPase and parietal cell ultrastructure and gastric acid secretion were then examined. Results: Parietal cells of these mice lacked a tubulovesicular compartment, and the H+/K+ ATPase was resident exclusively on the apical plasma membrane. Despite the inability of the H+/K+ ATPase to be endocytosed, the gastric acid secretory response to histamine or an antagonist was very similar to that of wild-type mice, indicating that control of H+/K+ ATPase activity can occur independently of intracellular trafficking. Conclusions: We were able to dissociate the regulation of H+/K+ ATPase activity from intracellular trafficking of the protein. Thus, it is likely that direct regulation of apical K+ and Cl- conductances are sufficient to control gastric acid secretion.