Acidification of the gastric lumen poses a barrier to transit of potentially pathogenic bacteria and enables activation of pepsin to complement nutrient proteolysis initiated by salivary proteases. Histamine-induced activation of the protein kinase A signaling pathway in gastric corpus parietal cells causes insertion of proton pumps into their apical plasma membranes. Parietal cell secretion and homeostasis are regulated by signaling pathways that control cytoskeletal changes required for apical membrane remodeling and organelle and proton pump activities.