Acid

Acid is secreted by the gastric gland parietal cells via the action of the gastric H+/K+ ATPase, a transmembrane proton pump. In nonstimulated parietal cells the pump is present in cytoplasmic vesicles (the tubulovesicles) separated from the apical membrane. Electron microscopy studies have shown that these vesicles are in fact small stacks of cisternae and should be called tubulocisternae. On stimulation the pumps are transported in vesicles to the apical membrane along the actin cytoskeleton where they fuse to and greatly increase the surface area of the apical membrane forming numerous microvilli. When physiological stimuli for acid secretion is removed the pumps are recycled back to the tubulo-cisternae. These trafficking processes involve: (1) movement to the apical membrane of vesicles containing the H+/K+ATPase; (2) fusion with the apical membrane and formation of actin filament-based scaffolds to form surface microvilli; (3) dissolution of the actin scaffolds; and (4) transport of the endo-cytotic vesicles containing the H+/K+ATPase back to the tubulocisternae. Numerous proteins have been reported to be associated with these processes; rabll (a GTPase), syntaxin 3, VAMPs (vesicle associated membrane protein), c-src (a nonreceptor tyrosine kinase), clathrin, dynamin, SCAMPs (secretory carrier membrane proteins), lasp-1, actin, ezrin, coro-nin, myosin Vb, and myosin light chain kinases. For activity the pump needs to be associated with K+ and Cl3 conductive pathways. There is a huge H+ concentration gradient across the parietal cells (the lumen has 2-4 x 106 greater H+ concentration than the blood); consequently, the cells require a great deal of energy and, as a result, mitochondria make up 34% of cell volume. The processes of HCl secretion are shown in Figure 4.

The H+/K+ pump is a noncovalent dimer of an a (catalytic subunit) and a fi glycosylated subunit. The fi subunit targets the pump to the apical membrane and protects the catalytic subunit from degradation. Acid secretion requires both subunits. The a subunit (mol. wt 100000) consists of 10 membrane-spanning

Apical membrane

Parietal cell

Basolateral membrane

HCO-Blood

Figure 4 Ion movements in HCL secretion. Thick arrows at top show apical recycling of K+. ||, ion channel; O, anion exchanger;

cation exchanger; CA, carbonic anhydrase. Na+ may be transported instead of H3O+. HCO3 transport back into the blood during acid secretion is the so-called 'alkaline tide.' Cl3 entry via the basolateral membrane may be linked to Na+ entry. Cl3 exiting across the apical membrane into the lumen may be linked to K+ efflux.

Apical membrane

Parietal cell

Basolateral membrane

HCO-Blood

Figure 4 Ion movements in HCL secretion. Thick arrows at top show apical recycling of K+. ||, ion channel; O, anion exchanger;

cation exchanger; CA, carbonic anhydrase. Na+ may be transported instead of H3O+. HCO3 transport back into the blood during acid secretion is the so-called 'alkaline tide.' Cl3 entry via the basolateral membrane may be linked to Na+ entry. Cl3 exiting across the apical membrane into the lumen may be linked to K+ efflux.

segments with the intracellular loop between membrane spans 4 and 5 forming the ATP binding and phosphorylation sites. Hydrophilic amino acids in the membrane-spanning portions form the ion pathway. Proton pump inhibitors (PPI) are used clinically to treat acid-related diseases, e.g., gastroesophageal reflux disease (GORD) and peptic ulcer disease. PPIs are protonated in the stomach producing the active drug sulfenamide, which inactivates the H+/ K+ATPase by binding to cysteine residues close to or in the extracellular loops between membrane segments 3 and 4, 5 and 6, and 7 and 8. The key cysteine for inhibition by omeprazole is in membrane segment 6 close to the extracellular loop between segments 5 and 6. Binding of sulfenamide to the cell surface prevents the movements of membrane domains relative to each other necessary to pump H+. The membrane organization of the pump is shown in Figure 5.

Control of acid secretion Four cells are key in the control of acid secretion: the parietal, the entero-chromaffin-like (ECL), the G, and the D cells. The three major stimulatory compounds are gastrin, histamine, and acetylcholine and the major inhibitory compound is somatostatin. The interaction between the four cell types and the four controlling

ATP-binding activator and catalytic site

Figure 5 Organization of the H+/K+ ATPase in the parietal cell apical membrane. The a-subunit contains 10 transmembrane spans and the 3 subunit one. In addition the a-subunit has 4 intracellular loops. There is a large mass of protein in the loop between transmembrane spans 4 and 5, which contains the ATP binding and phosphorylation sites. The Activator domain is important for the conformational transitions and may work as an anchor for the ATP-binding domain. NH2, N-terminal; COOH, C-terminal; site of Cys 822, the key residue for inhibition by the PPI omeprazole.

ATP-binding activator and catalytic site

Figure 5 Organization of the H+/K+ ATPase in the parietal cell apical membrane. The a-subunit contains 10 transmembrane spans and the 3 subunit one. In addition the a-subunit has 4 intracellular loops. There is a large mass of protein in the loop between transmembrane spans 4 and 5, which contains the ATP binding and phosphorylation sites. The Activator domain is important for the conformational transitions and may work as an anchor for the ATP-binding domain. NH2, N-terminal; COOH, C-terminal; site of Cys 822, the key residue for inhibition by the PPI omeprazole.

agents and other factors are shown in Figure 6. Acid secretion can be divided into four phases: basal, cephalic, gastric, and intestinal. Basal phase secretion makes up only 10% of the total secretion produced by all four phases, while cephalic phase secretion accounts for 45% of the total. In response to smell, taste, sight, chewing, and swallowing, the fundic and oxyntic mucosa are stimulated by the vagus (parasympathetic) nerve. Acid is secreted by the parietal cells following direct stimulation, with acetylcholine binding to M3 muscarinic receptors. Acetylcholine also stimulates histamine release from the ECL cells, which binds to H2 receptors on the parietal cells causing an increase in cAMP, which in turn stimulates acid secretion. In addition pituitary adenylate cyclase-activating polypeptide (PACAP) is released from the mucosal nerves, stimulating acid secretion by increasing histamine release from ECL cells. The vagus also stimulates G cells of the antrum to release gastrin into the blood, which further stimulates the parietal cells via binding to CCK-2 receptors and increasing intracellular Ca2+ leading to an increase in HCl secretion. During the cephalic phase gastric leptin (a hormone thought to function as a satiety signal when released from adipocytes) is also released. Gastric leptin inhibits acid secretion and is believed to act on the central nervous system presumably to suppress further food intake.

Acid secretion during the gastric phase accounts for 45% of total acid secretion. Food entering the stomach causes distension and gastrin is released from the antrum via two mechanisms: (1) local enteric and long loop parasympathetic mediated reflexes; (2) stimulation by the products of protein digestion, i.e., peptides and amino acids, of the G cells to release gastrin directly, particularly hydro-phobic amino acids. This second effect is interesting considering the fact that the G cells must be covered with a mucous gel layer and the amino acids need to diffuse through it before eliciting a response. The gastrin produced by both mechanisms stimulates the parietal cells to produce HCl directly and via histamine release from ECL cells. The intestinal phase is mainly an inhibitory phase; however, there is a small stimulatory phase via amino acids and peptides in the jejunum promoting release of gastrin from the intestine. Two groups of factors lead to the inhibitory phase. First, fat, acid, hypertonicity, and distension of the duodenum cause release of secretin from duodenal S cells, which inhibits gastrin release and thereby acid secretion. This works partly through the release of somatostatin from D cells in the stomach. In addition, a smaller effect on acid secretion results from gastric inhibitory pep-tide, released from intestinal K cells, VIP released from nerve endings, glucagon-like peptides (GLP-1 and GLP-2) from the enteroendocrine L cells in the small intestine, and CCK released by intestinal cells, again probably via a somatostatin-mediated pathway. Second, stimulation of G cells is reduced as food leaves the stomach and pH will fall as buffering from food is lost. This high H+ concentration will stimulate the D cells to release soma-tostatin further inhibiting gastrin release. As well as inhibition of gastrin secretion, gastrin is also destroyed by a neutral endopeptidase present in stomach cells. With removal of stomach distension, the vagal and intrinsic nerve stimuli for acid secretion is lost.

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