Pumps and Pathways for Gastric HCl Secretion

Abstract

Data reviewed herein show that the HCl-secreting parietal cell is an exaggerated example of dynamic membrane transformation. Recruitment and recycling of membrane provide the means for the massive redistribution of the gastric proton pump, the H,K-ATPase, from one membrane domain (cytoplasmic tubulovesicles) to another (apical plasma membrane) as a function of parietal cell activation and inactivation. Functional activation of HCl secretion requires not only the redistribution of pump protein, but also the participation of pathways for the rapid flux of K+ and Cl- across the apical membrane. In apical plasma membrane vesicles from stimulated cells these pathways appear to be conductive and can operate independently. Thus, our model for the parietal cell proposes that K+ and Cl- flux from cell to lumen, operating in parallel and in concert with ATP-driven H+/K+ exchange, provides the concentration and osmotic forces required for net HCl secretion. Whether and how the K+ and Cl- pathways are activated by stimulation and/or how they get to the apical membrane domain remain important questions. With respect to mechanisms of parietal cell activation, secretagogue-coupled elevation of cAMP and activation of protein kinase A form the basis of a well-established second messenger pathway. Several laboratories have identified various proteins that are phosphorylated concomitant with parietal cell stimulation, representing numerous candidates for effectors in stimulus-secretion coupling. Here, we emphasized the possible involvement of an 80-kDa protein whose phosphorylation was correlated with the cAMP pathway of HCl secretion. Immunocytolocalization of the 80-kDa phosphoprotein to the apical membrane and associated actin microfilaments prompted our suggestion that this protein might serve as a linkage between plasma membrane and cytoskeleton. Search for a possible role for the 80-kDa phosphoprotein in apical surface organization, stability, and turnover should represent an important thrust of research. Further understanding of the mechanism of cell activation will require a more complete elaboration of the functional role of many activation-related proteins.