Insights into the Regulation of Gastric Acid Secretion Through Analysis of Genetically Engineered Mice

Abstract

The regulation of acid secretion in the stomach involves a complex network of factors that stimulate secretion in response to the ingestion of a meal and maintain homeostasis of gastric pH. Genetically engineered mouse models have provided a new opportunity to investigate the importance and function of specific molecules and pathways involved in the regulation of acid secretion. Mouse mutants with disruptions in the three major stimulatory pathways for acid secretion in parietal cells, gastrin, histamine, and acetylcholine, have been generated. Disruption of the gastrin pathway results in a major impairment in both basal and induced acid secretion. Histamine and acetylcholine pathway mutants also have significant alterations in acid secretion, although the impairment does not appear to be as severe as in gastrin pathway mutants, perhaps due in part to the hypergastrinemia that occurs. Mice with a disruption in the somatostatin pathway have increased gastric acid secretion, which confirms an important negative regulatory role for this factor. This review discusses these genetically engineered mouse models, as well as others, that provide insight into the complex regulation of in vivo gastric acid secretion. The regulation of growth and cellular morphology of the stomach in these mouse models is also presented. In addition, transgene promoters that are expressed in the gastric epithelium are discussed because these promoters will be important tools to alter cellular physiology in new mouse models in the future.

Inefficient Chronic Activation of Parietal Cells in Ae2−/− Mice

“…26 Several knockout models exist with complete abrogation of gastric acid secretion and those animals are quite healthy. 2 The fact that acid secretion is only partly impaired in our targeted animals raises the question of which other mechanisms of intracellular acidification may be active. A new Na ϩ -independent electroneutral Cl Ϫ /HCO 3 Ϫ exchanger protein named Slc26a7 has been localized at the basolateral membrane of the parietal cell, 15 and it could account for the partial acid secretion capacity observed in Ae2 a,b Ϫ/Ϫ mice in their early adulthood.…”

“…Immunohistochemistry HCl is secreted at the apical membrane of the gastric parietal cell in response to gastrin, 1 histamine, and acetylcholine. [1][2][3] Parietal cell stimulation results in insertion of tubulovesicular membranes harboring the H ϩ /K ϩ -ATPase pump in the apical plasma membrane. 4,5 Cl Ϫ secretion via chloride channels ensures electroneutrality and completes the apical aspect of acid secretion.…”

Dietary acidification enhances phosphorus digestibility but decreases H+/K+-ATPase expression in rainbow trout

“…In mammals, gastric acid secretion is tightly regulated by the stimulatory effects of gastrin, histamine and acetylcholine, and the inhibitory actions of somatostatin (SST) on their respective receptors located in the basolateral membrane of parietal cells (Samuelson and Hinkle, 2003). Gastrin, histamine and an acetylcholine analog, carbamoylcholine (carbachol) induce rapid and coordinated increases of H + /K + -ATPase (ATP4A/B, proton pump) mRNA in parietal cells (Dockray, 1999).…”

Effects of Omeprazole, Famotidine, and Ranitidine on the Enzyme Activities of Carbonic Anhydrase from Bovine Stomach in Vitro and Rat Erythrocytes in Vivo

“…Thus, carbonic anhydrase isozymes perform different functions at their specific locations, and their absence or malfunction can lead to diseased states, ranging from the loss of acid production to stomach failure. 12,13) Therefore, we examined the effects of omeprazole, famotidine, and ranitidine on stomach CA and erythrocyte CA, and compared the results for the 3 drugs with each other.…”

“…Thus, carbonic anhydrase isozymes perform different functions at their specific locations, and their absence or malfunction can lead to diseased states, ranging from the loss of acid production to stomach failure. 12,13) Therefore, we examined the effects of omeprazole, famotidine, and ranitidine on stomach CA and erythrocyte CA, and compared the results for the 3 drugs with each other.It has been reported that the activity levels of CA isoenzymes in human erythrocytes vary considerably under certain pathological and physiological conditions. Changes in CA activity have been associated with metabolic diseases such as diabetes mellitus and hypertension.…”