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• W2918315477 abstract "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 PKA 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. Helicobacter pylori colonization of human gastric mucosa affects gastric epithelial cell plasticity and homeostasis, promoting epithelial progression to neoplasia. By intervening in proton pump expression, H pylori regulates the abundance and diversity of microbiota that populate the intestinal lumen. We review stimulation–secretion coupling and renewal mechanisms in parietal cells and the mechanisms by which H pylori toxins and effectors alter cell secretory pathways (constitutive and regulated) and organelles to establish and maintain their inter- and intracellular niches. Studies of bacterial toxins and their effector proteins have provided insights into parietal cell physiology and the mechanisms by which pathogens gain control of cell activities, increasing our understanding of gastrointestinal physiology, microbial infectious disease, and immunology. 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 PKA 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. Helicobacter pylori colonization of human gastric mucosa affects gastric epithelial cell plasticity and homeostasis, promoting epithelial progression to neoplasia. By intervening in proton pump expression, H pylori regulates the abundance and diversity of microbiota that populate the intestinal lumen. We review stimulation–secretion coupling and renewal mechanisms in parietal cells and the mechanisms by which H pylori toxins and effectors alter cell secretory pathways (constitutive and regulated) and organelles to establish and maintain their inter- and intracellular niches. Studies of bacterial toxins and their effector proteins have provided insights into parietal cell physiology and the mechanisms by which pathogens gain control of cell activities, increasing our understanding of gastrointestinal physiology, microbial infectious disease, and immunology. Infection with Helicobacter pylori is the most clearly identified risk factor for gastric cancer—the third leading cause of cancer mortality worldwide in men, and the fifth in women.1Torre L.A. Bray F. Siegel R.L. et al.Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Crossref PubMed Scopus (17170) Google Scholar In 2017, there were an estimated 950,000 cases worldwide, and 723,000 deaths.2Lederman L. Gastric cancer: local and global burden.Am J Manag Care. 2017; 4Google Scholar The risk of gastric cancer involves interactions among H pylori strain–specific virulence factors, patient genotype, and environmental factors. Perturbation of gastric acid secretion is an acute and chronic outcome of H pylori infection that promotes gastric carcinogenesis.3Hagiwara T. Mukaisho K.I. Nakayama T. et al.Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori.Gut. 2011; 60: 624-630Crossref PubMed Scopus (64) Google Scholar, 4Judd L.M. Andringa A. Rubio C.A. et al.Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors.J Gastroenterol Hepatol. 2005; 20: 1266-1278Crossref PubMed Scopus (0) Google Scholar, 5Ahn J.S. Eom C.S. Jeon C.Y. et al.Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies.World J Gastroenterol. 2013; 19: 2560-2568Crossref PubMed Scopus (51) Google Scholar The acute inhibitory effects of H pylori on acid secretion are transitory and normal acid secretion can be restored after H pylori is eradicated.6Furuta T. Baba S. Takashima M. et al.H+/K+-adenosine triphosphatase mRNA in gastric fundic gland mucosa in patients infected with Helicobacter pylori.Scand J Gastroenterol. 1999; 34: 384-390Crossref PubMed Scopus (17) Google Scholar In contrast to acute H pylori infection, which induces hypochlorhydria, chronic infection can induce an antrum-predominant phenotype associated with gastrin-mediated acid hypersecretion or a corpus-predominant phenotype associated with acid hyposecretion—this results from H pylori–induced proton pump suppression and activities of cytokines produced by infiltrating immune cells.7Dixon M.F. Genta R.M. Yardley J.H. et al.Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.Am J Surg Pathol. 1996; 20: 1161-1181Crossref PubMed Scopus (3837) Google Scholar H pylori's ability to reduce proton pump expression allows it to regulate gastric luminal acidity and alter the persistence or transit of other gastrointestinal microbes.7Dixon M.F. Genta R.M. Yardley J.H. et al.Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994.Am J Surg Pathol. 1996; 20: 1161-1181Crossref PubMed Scopus (3837) Google Scholar Acid secretion is regulated by differentiated parietal cells located in secretory glands formed by invagination of the epithelial monolayer that lines the fundus and body of the mammalian stomach. The secretory glands also contain other highly differentiated cell types that protect the stomach and support its function. These include mucus neck cells, which secrete mucus; chief cells, which secrete pepsinogen; and oxyntic enterochromaffin-like (ECL) cells, which regulate acid secretion by secreting histamine in response to paracrine gastrin stimulation originating in antral G cells. Acid secretion by parietal cells is mediated by the membrane-bound enzyme H+,K+-ATPase, found in high density on intracellular tubulovesicular and secretory canalicular membranes.8Forte J.G. Hanzel D.K. Urushidani T. et al.Pumps and pathways for gastric HCl secretion.Ann N Y Acad Sci. 1989; 574: 145-158Crossref PubMed Google Scholar, 9Sachs G. The gastric proton pump: the H+, K+-ATPase.in: Johnson L.R. Physiology of the Gastrointestinal Tract. 2nd ed. Raven, New York1987: 865-881Google Scholar The enzyme is a heterotetramer of 2 ATP4A subunits, which have catalytic ATPase and cation transport activity, and 2 ATP4B subunits, which are smaller and glycosylated. In parietal cells, ATP4A and ATP4B are translated on endoplasmic reticulum–bound ribosomes into integral membrane polypeptides that localize to cytoplasmic tubulovesicles with limited K+ permeability.10Lee H.C. Breitbart H. Berman M. et al.Potassium-stimulated ATPase activity and hydrogen transport in gastric microsomal vesicles.Biochim Biophys Acta. 1979; 553: 107-131Crossref PubMed Scopus (0) Google Scholar, 11Yao X. Forte J.G. Cell biology of acid secretion by the parietal cell.Annu Rev Physiol. 2003; 65: 103-131Crossref PubMed Scopus (189) Google Scholar ATP4B subunits facilitate assembly of functional proton pumps and migration of the nascent enzyme complex to tubulovesicular and canalicular membranes and protect the complex from degradation.12Spicer Z. Miller M.L. Andringa A. et al.Stomachs of mice lacking the gastric H,K-ATPase alpha-subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia.J Biol Chem. 2000; 275: 21555-21565Crossref PubMed Scopus (0) Google Scholar, 13Asano S. Kawada K. Kimura T. et al.The roles of carbohydrate chains of the beta-subunit on the functional expression of gastric H(+),K(+)-ATPase.J Biol Chem. 2000; 275: 8324-8330Crossref PubMed Scopus (0) Google Scholar, 14Bakkelund K.E. Waldum H.L. Nordrum I.S. et al.Long-term gastric changes in achlorhydric H(+)/K(+)-ATPase beta subunit deficient mice.Scand J Gastroenterol. 2010; 45: 1042-1047Crossref PubMed Scopus (8) Google Scholar The relative K+ impermeability of tubulovesicular membranes ensures that ATP4A activity, responsible for the H+-K+ counter-transport functions of the enzyme, remains latent.10Lee H.C. Breitbart H. Berman M. et al.Potassium-stimulated ATPase activity and hydrogen transport in gastric microsomal vesicles.Biochim Biophys Acta. 1979; 553: 107-131Crossref PubMed Scopus (0) Google Scholar A distinct set of intracytoplasmic RAB11-positive vesicles express the K+ voltage–gated channels KCNQ1 and KCNE2.15Nguyen N. Kozer-Gorevich N. Gliddon B.L. et al.Independent trafficking of the KCNQ1 K+ channel and H+/K+ ATPase in gastric parietal cells from mice.Am J Physiol. 2013; 304: G157-G166Google Scholar Nutrient-induced neural, hormonal, and paracrine stimulation of parietal cells, in the form of acetylcholine activation of calcium-dependent signaling pathways, gastrin activation of histamine release from ECL cells, and histamine-mediated increases in intracellular adenosine 3′,5′-cyclic monophosphate (cAMP), activates protein kinases. These kinases cause fusion of H,K-ATPase–containing tubulovesicles and K+ channel–containing vesicles with collapsed invaginations of the parietal cell apical membrane. The resulting expanded membrane-delimited pan-cellular microvillous secretory canalicular compartment is characteristic of actively secreting parietal cells. Delivery of K+ channels (KCNQ1, KCNE2, KCNJ10, and KCNJ15)16Roepke T.K. Anantharam A. Kirchhoff P. et al.The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion.J Biol Chem. 2006; 281: 23740-23747Crossref PubMed Scopus (108) Google Scholar, 17Song P. Groos S. Riederer B. et al.KCNQ1 is the luminal K+ recycling channel during stimulation of gastric acid secretion.J Physiol. 2009; 587: 3955-3965Crossref PubMed Scopus (0) Google Scholar, 18Song P. Groos S. Riederer B. et al.Kir4.1 channel expression is essential for parietal cell control of acid secretion.J Biol Chem. 2011; 286: 14120-14128Crossref PubMed Scopus (0) Google Scholar, 19He W. Liu W. Chew C.S. et al.Acid secretion-associated translocation of KCNJ15 in gastric parietal cells.Am J Physiol Gastrointest Liver Physiol. 2011; 301: G591-G600Crossref PubMed Scopus (17) Google Scholar to canalicular membranes provides access of cytoplasmic K+ to luminally oriented K+-binding sites on ATP4A, initiating ATP binding and hydrolysis on its cytoplasmic side, which promotes electroneutral exchange of luminal K+ for cytoplasmic protons with unitary H+:K+:ATP stoichiometry.20Rabon E.C. McFall T.L. Sachs G. The gastric [H,K]ATPase:H+/ATP stoichiometry.J Biol Chem. 1982; 257: 6296-6299PubMed Google Scholar Under maximal secretory conditions, H,K-ATPase activity establishes a million-fold proton gradient across the canalicular membrane.21Black J.A. Forte T.M. Forte J.G. Structure of oxyntic cell membranes during conditions of rest and secretion of HCl as revealed by freeze-fracture.Anat Rec. 1980; 196: 163-172Crossref PubMed Google Scholar, 22Smolka A. Helander H.F. Sachs G. Monoclonal antibodies against gastric H+ + K+ ATPase.Am J Physiol. 1983; 245: 589-596PubMed Google Scholar, 23Soroka C.J. Chew C.S. Hanzel D.K. et al.Characterization of membrane and cytoskeletal compartments in cultured parietal cells: immunofluorescence and confocal microscopic examination.Eur J Cell Biol. 1993; 60: 76-87PubMed Google Scholar Recent high-resolution (2.8 Å) crystal structures of H,K-ATPase complexed with the K+-competitive acid secretory inhibitors vonoprazan or SCH28080 indicate that the conformational change of the cation-binding site, induced by ATP hydrolysis, lowers the pKa value of Glu820 in ATP4A, enabling release of protons into the pH 1.0 environment of the stomach.24Abe K. Irie K. Nakanishi H. et al.Crystal structures of the gastric proton pump.Nature. 2018; 556: 214-218Crossref PubMed Scopus (8) Google Scholar Stimulants of parietal cell acid secretion include gastrin, secreted by antral G cells (hormonal pathway)25Beales I. Blaser M.J. Srinivasan S. et al.Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G cells.Gastroenterology. 1997; 113: 465-471Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 26DelValle J. Sugano K. Yamada T. Progastrin and its glycine-extended posttranslational processing intermediates in human gastrointestinal tissues.Gastroenterology. 1987; 92: 1908-1912Abstract Full Text PDF PubMed Scopus (57) Google Scholar; histamine, secreted from oxyntic ECL cells (paracrine pathway)27Bitziou E. Patel B.A. Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach.Am J Physiol. 2012; 303: G396-G403Google Scholar; and acetylcholine, secreted from oxyntic (gastric body and fundus) and antral intramural postganglionic neurons (neural pathway).28Wilkes J.M. Kajimura M. Scott D.R. et al.Muscarinic responses of gastric parietal cells.J Membr Biol. 1991; 122: 97-101Crossref PubMed Scopus (0) Google Scholar Parietal cells express specific receptors for each of these secretagogues (gastrin or CCK2, H2, and M3, respectively). Gastrin is the major hormonal stimulant secreted during meal ingestion, inducing release of histamine from ECL cells. Gastrin also stimulates the parietal cell directly, acting via CCK2 receptors coupled to an increase in [Ca2+]i. Parietal cell histamine H2 receptors are coupled to adenylate cyclase, which catalyzes formation of cAMP. In rat hepatoma-derived cells transfected with canine histamine H2 receptor, histamine elicited transient increases in intracellular calcium ([Ca2+]i) with generation of inositol trisphosphate.29DelValle J. Wang L. Gantz I. et al.Characterization of H2 histamine receptor: linkage to both adenylate cyclase and [Ca2+](i) signaling systems.Am J Physiol. 1992; 263: G967-G972PubMed Google Scholar Acetylcholine stimulates parietal cells directly through M3 muscarinic receptors coupled to an increase in [Ca2+]i, and indirectly by inhibiting M4 muscarinic receptor-mediated somatostatin secretion from oxyntic D cells.30Takeuchi K. Endoh T. Hayashi S. et al.Activation of muscarinic acetylcholine receptor subtype 4 is essential for cholinergic stimulation of gastric acid secretion: relation to D cell/somatostatin.Front Pharmacol. 2016; 7: 278Crossref PubMed Scopus (2) Google Scholar Somatostatin, secreted from oxyntic and antral D cells, is the primary physiological inhibitor of acid secretion. Although there are few D cells in oxyntic mucosa, compared to parietal cells, D cells are functionally coupled to parietal and ECL cells via cytoplasmic processes or via local circulation.31Larsson L.I. Goltermann N. de Magistris L. et al.Somatostatin cell processes as pathways for paracrine secretion.Science. 1979; 205: 1393-1395Crossref PubMed Scopus (361) Google Scholar, 32Martinez V. Curi A.P. Torkian B. et al.High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice.Gastroenterology. 1998; 114: 1125-1132Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Under resting conditions, somatostatin places tonic restraint on parietal cell acid secretion, ECL cell histamine secretion, and G cell gastrin secretion. Removal of this restraint (disinhibition) by activation of cholinergic neurons stimulates acid secretion. Direct evidence for Ca2+ signaling in histamine-dependent acid secretion in mice was provided by organelle-targeted Ca2+ imaging and direct patch-clamping of apical vacuolar membranes of gastric parietal cells.33Sahoo N. Gu M. Zhang X. et al.Gastric acid secretion from parietal cells is mediated by a Ca(2+) efflux channel in the tubulovesicle.Dev Cell. 2017; 41: 262-273.e6Abstract Full Text Full Text PDF PubMed Google Scholar This study revealed that a lysosome calcium channel, mucolipin 1 (MCOLN1 or TRPML1), co-localized with tubulovesicles that express ATP4A, was required for histamine-induced PKA-dependent release of Ca2+ from tubulovesicular stores and for acid secretion. Proton pump inhibitors, such as omeprazole, lansoprazole, rabeprazole, and esomeprazole, have revolutionized the treatment of gastroesophageal reflux disease, peptic ulcer disease, and Zollinger-Ellison syndrome (gastrinoma). Proton pump inhibitors are substituted benzimidazoles that inhibit gastric acid secretion by binding covalently to luminally exposed cysteine residues on ATP4A, altering its conformation. Vonoprazan is a lipophilic, weak base pyrrole derivative that blocks acid secretion by accumulating in acidic parietal cell canaliculi and prevents proton pump activation by competing with K+ on the luminal (intra-canalicular) surface of ATP4A.34Otake K. Sakurai Y. Nishida H. et al.Characteristics of the novel potassium-competitive acid blocker vonoprazan fumarate (TAK-438).Adv Ther. 2016; 33: 1140-1157Crossref PubMed Scopus (6) Google Scholar Advantages of using vonoprazan vs conventional proton pump inhibitors include rapid onset of action, longer duration of acid suppression, and less variation among individuals, at the possible cost of increased hypergastrinemia.35Sugano K. Vonoprazan fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date.Therap Adv Gastroenterol. 2018; 11 (1756283x17745776)Crossref PubMed Scopus (5) Google Scholar Parietal cells have characteristic morphology closely related to their function.36Forte T.M. Machen T.E. Forte J.G. Ultrastructural changes in oxyntic cells associated with secretory function: a membrane-recycling hypothesis.Gastroenterology. 1977; 73: 941-955Abstract Full Text PDF PubMed Google Scholar The cells are generally pyramidal in shape and are packed with mitochondria and other membrane-bound structures. The apex of the pyramid, which faces the glandular lumen, is surrounded by tight junctions to adjacent cells. Three-dimensional nanotomography analysis of mouse parietal cells revealed intricate networks of mitochondria, which are evenly distributed throughout the cytoplasm, and abundant roughly spherical lysosomes, which are mostly adjacent to mitochondria.37Lo H.G. Jin R.U. Sibbel G. et al.A single transcription factor is sufficient to induce and maintain secretory cell architecture.Genes Dev. 2017; 31: 154-171Crossref PubMed Scopus (24) Google Scholar Tubular and vesicular membrane organelles (tubulovesicles) that express ATP4A and ATP4B in high density are distributed throughout the parietal cell cytoplasm. Resting or non-secreting cells have a limited area of apical membrane in direct apposition to the gland lumen, but more extensive luminal exposure is provided by a distinctive invagination of the apical membrane deep into the cytoplasm, forming a residual collapsed secretory canaliculus. Further studies are needed to determine whether parietal cell organelle interactions involved in histamine-induced acid secretion are affected by H pylori infection. Changes in parietal cell morphology that accompany stimulation of acid secretion result from fusion of intracellular tubulovesicles with the residual secretory canalicular membranes, leading to elongation of intra-canalicular microvilli and the concomitant disappearance of cytoplasmic tubulovesicles.11Yao X. Forte J.G. Cell biology of acid secretion by the parietal cell.Annu Rev Physiol. 2003; 65: 103-131Crossref PubMed Scopus (189) Google Scholar These changes in vesicle trafficking, membrane interactions, and actin cytoskeleton arrangement are mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), which are found in different membranes and intracellular locations. Initial searches for parietal cell SNARE proteins identified 6 SNAREs: VAMP; syntaxins 1, 2, 3, and 4; and SNAP25.38Calhoun B.C. Goldenring J.R. Two Rab proteins, vesicle-associated membrane protein 2 (VAMP-2) and secretory carrier membrane proteins (SCAMPs), are present on immunoisolated parietal cell tubulovesicles.Biochem J. 1997; 325: 559-564Crossref PubMed Google Scholar, 39Peng X.R. Yao X. Chow D.C. et al.Association of syntaxin 3 and vesicle-associated membrane protein (VAMP) with H+/K(+)-ATPase-containing tubulovesicles in gastric parietal cells.Mol Biol Cell. 1997; 8: 399-407Crossref PubMed Google Scholar Live-cell imaging with fluorescently labeled VAMP2 demonstrated the translocation of VAMP2 from tubulovesicular membranes to the apical canalicular membrane of parietal cells upon stimulation of acid secretion.40Karvar S. Yao X. Duman J.G. et al.Intracellular distribution and functional importance of vesicle-associated membrane protein 2 in gastric parietal cells.Gastroenterology. 2002; 123: 281-290Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The functional importance of VAMP2 in stimulating acid secretion was demonstrated by concomitant inhibition of acid secretion by parietal cells exposed to tetanus toxin, a Zn-dependent proteinase that specifically cleaves VAMP2.40Karvar S. Yao X. Duman J.G. et al.Intracellular distribution and functional importance of vesicle-associated membrane protein 2 in gastric parietal cells.Gastroenterology. 2002; 123: 281-290Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 41Lehnardt S. Ahnert-Hilger G. Bigalke H. et al.Acid secretion of parietal cells is paralleled by a redistribution of NSF and alpha, beta-SNAPs and inhibited by tetanus toxin.Histochem Cell Biol. 2000; 114: 387-391PubMed Google Scholar Although identification of VAMP2 as a v-SNARE in parietal cells was anticipated, the identification of syntaxin 3 on tubulovesicles was unexpected. This prototypical t-SNARE localizes to vesicular membranes of parietal cells and may mediate homotypic fusion of tubulovesicles, accounting for the rapid apical morphologic changes associated with active acid secretion. Parietal cell stimulation was accompanied by translocation of co-localized syntaxin 3 and ATP4A from tubulovesicles to the apical membrane.42Calhoun B.C. Lapierre L.A. Chew C.S. et al.Rab11a redistributes to apical secretory canaliculus during stimulation of gastric parietal cells.Am J Physiol. 1998; 275: C163-C170Crossref PubMed Google Scholar The importance of syntaxin 3 in acid secretion was demonstrated in studies with streptolysin O–permeabilized gastric glands. In these studies, recombinant syntaxin 3 competed for endogenous protein.43Ammar D.A. Zhou R. Forte J.G. et al.Syntaxin 3 is required for cAMP-induced acid secretion: streptolysin O-permeabilized gastric gland model.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G23-G33Crossref PubMed Google Scholar Ezrin, a membrane-cytoskeletal linker with sequence homology to talin and erythrocyte band 4.1, has been associated with the remodeling of parietal cell apical membrane that occurs with cAMP-dependent protein kinase stimulation. Atomic force microscopy studies revealed that ezrin phosphorylation and conformational change allowed binding of syntaxin 3 to the N-terminus of ezrin.44Yu H.J. Zhou J.J. Takahashi H. et al.Spatial control of proton pump H,K-ATPase docking at the apical membrane by phosphorylation-coupled ezrin-syntaxin 3 interaction.J Biol Chem. 2014; 289: 33333-33342Crossref PubMed Scopus (10) Google Scholar SNARE proteins therefore mediate recognition and docking events, but additional mechanisms, such as partition of a hydrophobic domain of a membrane protein into an adjacent closely apposed membrane, could promote thermodynamic fusion of membranes.11Yao X. Forte J.G. Cell biology of acid secretion by the parietal cell.Annu Rev Physiol. 2003; 65: 103-131Crossref PubMed Scopus (189) Google Scholar, 45Forte J.G. Zhu L. Apical recycling of the gastric parietal cell H,K-ATPase.Annu Rev Physiol. 2010; 72: 273-296Crossref PubMed Scopus (50) Google Scholar Other molecular effectors of parietal cell morphologic transformation are Rab GTPases, which are members of the Ras GTPase superfamily that regulate many steps of membrane trafficking. Rabs are often tethered to membranes through 2 C-terminal prenyl groups,46Sanford J.C. Foster L. Kapadia Z. et al.Analysis of the stoichiometry of Rab protein prenylation.Anal Biochem. 1995; 224: 547-556Crossref PubMed Scopus (20) Google Scholar and switch between GDP-bound and GTP-bound forms depending on activation, dissociation, displacement, and exchange factors.47Deneka M. Neeft M. van der Sluijs P. Regulation of membrane transport by rab GTPases.Crit Rev Biochem Mol Biol. 2003; 38: 121-142Crossref PubMed Google Scholar RAB11 is involved in regulating recycling endosomes in transferrin recycling models and is also required for trafficking from trans-Golgi network to the plasma membrane.48Chen W. Feng Y. Chen D. et al.Rab11 is required for trans-Golgi network-to-plasma membrane transport and a preferential target for GDP dissociation inhibitor.Mol Biol Cell. 1998; 9: 3241-3257Crossref PubMed Google Scholar Initial screening of parietal cells found a high level of RAB11 mRNA49Goldenring J.R. Shen K.R. Vaughan H.D. et al.Identification of a small GTP-binding protein, Rab25, expressed in the gastrointestinal mucosa, kidney, and lung.J Biol Chem. 1993; 268: 18419-18422Abstract Full Text PDF PubMed Google Scholar and RAB11 protein localized to tubulovesicles that contain ATP4A.50Goldenring J.R. Soroka C.J. Shen K.R. et al.Enrichment of rab11, a small GTP-binding protein, in gastric parietal cells.Am J Physiol. 1994; 267: G187-G194PubMed Google Scholar Expression of a dominant-negative form of RAB11 (RAB11N124I) in parietal cells inhibited acid secretion.51Duman J.G. Tyagarajan K. Kolsi M.S. et al.Expression of rab11a N124I in gastric parietal cells inhibits stimulatory recruitment of the H+-K+-ATPase.Am J Physiol. 1999; 277: C361-C372Crossref PubMed Google Scholar Inhibition correlated with impaired membrane translocation from tubulovesicles to the apical plasma membrane. Interestingly, RAB11 interacts with another small GTPase, ARF6.52Schonteich E. Pilli M. Simon G.C. et al.Molecular characterization of Rab11-FIP3 binding to ARF GTPases.Eur J Cell Biol. 2007; 86: 417-431Crossref PubMed Scopus (0) Google Scholar Like ATP4A, native ARF6 redistributes from predominantly cytoplasmic membranes to apical canalicular membranes when cells are stimulated.53Matsukawa J. Nakayama K. Nagao T. et al.Role of ADP-ribosylation factor 6 (ARF6) in gastric acid secretion.J Biol Chem. 2003; 278: 36470-36475Crossref PubMed Scopus (21) Google Scholar In parietal cells, ARF6 is activated by an Arf-GAP containing a coiled-coil ACAP4.54Fang Z.Y. Miao Y. Ding X. et al.Proteomic identification and functional characterization of a novel ARF6 GTPase-activating protein, ACAP4.Mol Cell Proteomics. 2006; 5: 1437-1449Crossref PubMed Scopus (0) Google Scholar ACAP4 interacts with ezrin, which is regulated by protein phosphorylation.55Ding X. Deng H. Wang D.M. et al.Phospho-regulated ACAP4-ezrin interaction is essential for histamine-stimulated parietal cell secretion.J Biol Chem. 2010; 285: 18769-18780Crossref PubMed Scopus (20) Google Scholar Histamine stimulation of parietal cell acid secretion activates PKA signaling via STK26 (or MST4),56Jiang H. Wang W.W. Zhang Y. et al.Cell polarity kinase MST4 cooperates with cAMP-dependent kinase to orchestrate histamine-stimulated acid secretion in gastric parietal cells.J Biol Chem. 2015; 290: 28272-28285Crossref PubMed Scopus (6) Google Scholar leading to phosphorylation of ACAP4 at Thr545. This phosphorylation enables ACAP4 to interact with ezrin.57Yuan X. Yao P.Y. Jiang J.Y. et al.MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion.J Biol Chem. 2017; 292: 16174-16187Crossref PubMed Scopus (2) Google Scholar Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat of ACAP4, it is likely that MST4 phosphorylation induces a conformational change that allows ACAP4 to interact with ezrin (Figure 1A and B). Although somatostatin, EGF, and TGFα signals inhibit acid secretion, withdrawal of the secretory stimulus alone appears to be sufficient to turn off acid secretion.36Forte T.M. Machen T.E. Forte J.G. Ultrastructural changes in oxyntic cells associated with secretory function: a membrane-recycling hypothesis.Gastroenterology. 1977; 73: 941-955Abstract Full Text PDF PubMed Google Scholar, 58Sawaguchi A. Aoyama F. Ohashi M. et al.Ultrastructural transformation of gastric parietal cells reverting from the active to the resting state of acid secretion revealed in isolated rat gastric mucosa model processed by high-pressure freezing.J Electron Microsc (Tokyo). 2006; 55: 97-105Crossref PubMed Scopus (0) Google Scholar Initial studies of the mechanisms of ATP4A recovery from secretory membrane and its recycling led to discovery of a tyrosine-based internalization motif at the cytoplasmic, N-terminus of ATP4B.59Courtois-Coutry N. Roush D. Rajendran V. et al.A tyrosine-based signal targets H/K-ATPase to a regulated compartment and is required for the cessation of gastric acid secretion.Cell. 1997; 90: 501-510Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In studies of transgenic mice, substitution of this tyrosine with an alanine resulted in continued localization of ATP4B to the parietal cell surface and sustained secretion of acid. These mice develop gastric ulce" @default.
• W2918315477 created "2019-03-11" @default.
• W2918315477 creator A5040923571 @default.
• W2918315477 creator A5070808152 @default.
• W2918315477 date "2019-06-01" @default.
• W2918315477 modified "2023-10-14" @default.
• W2918315477 title "Gastric Parietal Cell Physiology and Helicobacter pylori–Induced Disease" @default.
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