Skip to main content
NCBI home page
The Yale Journal of Biology and Medicine logoLink to The Yale Journal of Biology and Medicine
. 1994 May-Aug;67(3-4):81–95.

Gastric acid secretion: activation and inhibition.

G Sachs 1, C Prinz 1, D Loo 1, K Bamberg 1, M Besancon 1, J M Shin 1
PMCID: PMC2588922  PMID: 7502535

Abstract

Peripheral regulation of gastric acid secretion is initiated by the release of gastrin from the G cell. Gastrin then stimulates the cholecystokinin-B receptor on the enterochromaffin-like cell beginning a calcium signaling cascade. An exocytotic release of histamine follows with concomitant activation of a C1- current. The released histamine begins the H2-receptor mediated sequence of events in the parietal cell, which results in activation of the gastric H+/K+ - ATPase. This enzyme is the final common pathway of acid secretion. The H+/K+ - ATPase is composed of two subunits: the larger alpha-subunit couples ion transport to hydrolysis of ATP, the smaller beta-subunit is required for appropriate assembly of the holoenzyme. Both the membrane and extracytoplasmic domain contain the ion transport pathway, and therefore, this region is the target for the antisecretory drugs of the post-H2 era. The 100 kDa alpha-subunit has probably 10 membrane spanning segments with, therefore, five extracytoplasmic loops. The 35 kDA beta-subunit has a single membrane spanning segment, and most of this protein is extracytoplasmic with the six or seven N glycosylation consensus sequences occupied. Omeprazole is an acid-accumulated, acid-activated, prodrug that binds covalently to two cysteine residues at positions 813 (or 822) and 892, accessible from the acidic face of the pump. Lansoprazole binds to cys321, 813 (or 822) and 892; pantoprazole binds to cys813 and 822. The common binding site for these drugs (cys813 or 822) is responsible for the inhibition of acid transport. Covalent inhibition of the acid pump improves control of acid secretion, but since the effective half life of the inhibition in man is about 48 hr, full inhibition of acid secretion, perhaps necessary for eradication of Helicobacter pylori in combination with a single antibiotic, will require prolongation of the effect of this class of drug.

Full text

PDF
81

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bamberg K., Sachs G. Topological analysis of H+,K(+)-ATPase using in vitro translation. J Biol Chem. 1994 Jun 17;269(24):16909–16919. [PubMed] [Google Scholar]
  2. Besancon M., Shin J. M., Mercier F., Munson K., Miller M., Hersey S., Sachs G. Membrane topology and omeprazole labeling of the gastric H+,K(+)-adenosinetriphosphatase. Biochemistry. 1993 Mar 9;32(9):2345–2355. doi: 10.1021/bi00060a028. [DOI] [PubMed] [Google Scholar]
  3. Black J. W., Duncan W. A., Durant C. J., Ganellin C. R., Parsons E. M. Definition and antagonism of histamine H 2 -receptors. Nature. 1972 Apr 21;236(5347):385–390. doi: 10.1038/236385a0. [DOI] [PubMed] [Google Scholar]
  4. Brzezinski P., Malmström B. G., Lorentzon P., Wallmark B. The catalytic mechanism of gastric H+/K+-ATPase: simulations of pre-steady-state and steady-state kinetic results. Biochim Biophys Acta. 1988 Jul 21;942(2):215–219. doi: 10.1016/0005-2736(88)90022-3. [DOI] [PubMed] [Google Scholar]
  5. Burget D. W., Chiverton S. G., Hunt R. H. Is there an optimal degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology. 1990 Aug;99(2):345–351. doi: 10.1016/0016-5085(90)91015-x. [DOI] [PubMed] [Google Scholar]
  6. Canessa C. M., Horisberger J. D., Rossier B. C. Mutation of a tyrosine in the H3-H4 ectodomain of Na,K-ATPase alpha subunit confers ouabain resistance. J Biol Chem. 1993 Aug 25;268(24):17722–17726. [PubMed] [Google Scholar]
  7. Canfield S. P., Price C. A. A comparison of the effects of sympathomimetic agents on gastric acid secretion by the rat stomach in vivo and in vitro. J Physiol. 1981 Jul;316:11–21. doi: 10.1113/jphysiol.1981.sp013768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chew C. S., Brown M. R. Release of intracellular Ca2+ and elevation of inositol trisphosphate by secretagogues in parietal and chief cells isolated from rabbit gastric mucosa. Biochim Biophys Acta. 1986 Aug 29;888(1):116–125. doi: 10.1016/0167-4889(86)90077-7. [DOI] [PubMed] [Google Scholar]
  9. Clarke D. M., Loo T. W., MacLennan D. H. Functional consequences of alterations to polar amino acids located in the transmembrane domain of the Ca2(+)-ATPase of sarcoplasmic reticulum. J Biol Chem. 1990 Apr 15;265(11):6262–6267. [PubMed] [Google Scholar]
  10. Crothers J. M., Jr, Chow D. C., Forte J. G. Omeprazole decreases H(+)-K(+)-ATPase protein and increases permeability of oxyntic secretory membranes in rabbits. Am J Physiol. 1993 Aug;265(2 Pt 1):G231–G241. doi: 10.1152/ajpgi.1993.265.2.G231. [DOI] [PubMed] [Google Scholar]
  11. Dimaline R., Sandvik A. K. Histidine decarboxylase gene expression in rat fundus is regulated by gastrin. FEBS Lett. 1991 Apr 9;281(1-2):20–22. doi: 10.1016/0014-5793(91)80348-7. [DOI] [PubMed] [Google Scholar]
  12. Edkins J. S. The chemical mechanism of gastric secretion. J Physiol. 1906 Mar 13;34(1-2):133–144. doi: 10.1113/jphysiol.1906.sp001146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Farley R. A., Faller L. D. The amino acid sequence of an active site peptide from the H,K-ATPase of gastric mucosa. J Biol Chem. 1985 Apr 10;260(7):3899–3901. [PubMed] [Google Scholar]
  14. Forte T. M., Machen T. E., Forte J. G. Ultrastructural changes in oxyntic cells associated with secretory function: a membrane-recycling hypothesis. Gastroenterology. 1977 Oct;73(4 Pt 2):941–955. [PubMed] [Google Scholar]
  15. Helander H. F. The cells of the gastric mucosa. Int Rev Cytol. 1981;70:217–289. doi: 10.1016/s0074-7696(08)61133-x. [DOI] [PubMed] [Google Scholar]
  16. Hersey S. J., Steiner L., Mendlein J., Rabon E., Sachs G. SCH28080 prevents omeprazole inhibition of the gastric H+/K+-ATPase. Biochim Biophys Acta. 1988 Aug 31;956(1):49–57. doi: 10.1016/0167-4838(88)90296-8. [DOI] [PubMed] [Google Scholar]
  17. Håkanson R., Böttcher G., Ekblad E., Panula P., Simonsson M., Dohlsten M., Hallberg T., Sundler F. Histamine in endocrine cells in the stomach. A survey of several species using a panel of histamine antibodies. Histochemistry. 1986;86(1):5–17. doi: 10.1007/BF00492340. [DOI] [PubMed] [Google Scholar]
  18. Håkanson R., Tielemans Y., Chen D., Andersson K., Mattsson H., Sundler F. Time-dependent changes in enterochromaffin-like cell kinetics in stomach of hypergastrinemic rats. Gastroenterology. 1993 Jul;105(1):15–21. doi: 10.1016/0016-5085(93)90005-w. [DOI] [PubMed] [Google Scholar]
  19. Jewell-Motz E. A., Lingrel J. B. Site-directed mutagenesis of the Na,K-ATPase: consequences of substitutions of negatively-charged amino acids localized in the transmembrane domains. Biochemistry. 1993 Dec 14;32(49):13523–13530. doi: 10.1021/bi00212a018. [DOI] [PubMed] [Google Scholar]
  20. Jørgensen P. L., Andersen J. P. Structural basis for E1-E2 conformational transitions in Na,K-pump and Ca-pump proteins. J Membr Biol. 1988 Jul;103(2):95–120. doi: 10.1007/BF01870942. [DOI] [PubMed] [Google Scholar]
  21. Kopin A. S., Lee Y. M., McBride E. W., Miller L. J., Lu M., Lin H. Y., Kolakowski L. F., Jr, Beinborn M. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3605–3609. doi: 10.1073/pnas.89.8.3605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Larsson H., Carlsson E., Mattsson H., Lundell L., Sundler F., Sundell G., Wallmark B., Watanabe T., Håkanson R. Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology. 1986 Feb;90(2):391–399. doi: 10.1016/0016-5085(86)90938-8. [DOI] [PubMed] [Google Scholar]
  23. Lewin M. J., Cheret A. M. Cell isolation techniques: use of enzymes and chelators. Methods Enzymol. 1989;171:444–461. doi: 10.1016/s0076-6879(89)71024-7. [DOI] [PubMed] [Google Scholar]
  24. Mercier F., Bayle D., Besancon M., Joys T., Shin J. M., Lewin M. J., Prinz C., Reuben M. A., Soumarmon A., Wong H. Antibody epitope mapping of the gastric H+/K(+)-ATPase. Biochim Biophys Acta. 1993 Jun 18;1149(1):151–165. doi: 10.1016/0005-2736(93)90036-y. [DOI] [PubMed] [Google Scholar]
  25. Mercier F., Reggio H., Devilliers G., Bataille D., Mangeat P. Membrane-cytoskeleton dynamics in rat parietal cells: mobilization of actin and spectrin upon stimulation of gastric acid secretion. J Cell Biol. 1989 Feb;108(2):441–453. doi: 10.1083/jcb.108.2.441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mezey E., Palkovits M. Localization of targets for anti-ulcer drugs in cells of the immune system. Science. 1992 Dec 4;258(5088):1662–1665. doi: 10.1126/science.1333642. [DOI] [PubMed] [Google Scholar]
  27. Munson K. B., Gutierrez C., Balaji V. N., Ramnarayan K., Sachs G. Identification of an extracytoplasmic region of H+,K(+)-ATPase labeled by a K(+)-competitive photoaffinity inhibitor. J Biol Chem. 1991 Oct 5;266(28):18976–18988. [PubMed] [Google Scholar]
  28. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 1994 Jul 6;272(1):65–69. [PubMed] [Google Scholar]
  29. Naesdal J., Bodemar G., Walan A. Effect of omeprazole, a substituted benzimidazole, on 24-h intragastric acidity in patients with peptic ulcer disease. Scand J Gastroenterol. 1984 Oct;19(7):916–922. [PubMed] [Google Scholar]
  30. Nelson N. Structure and pharmacology of the proton-ATPases. Trends Pharmacol Sci. 1991 Feb;12(2):71–75. doi: 10.1016/0165-6147(91)90501-i. [DOI] [PubMed] [Google Scholar]
  31. Nwokolo C. U., Smith J. T., Gavey C., Sawyerr A., Pounder R. E. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine. Aliment Pharmacol Ther. 1990;4 (Suppl 1):29–45. [PubMed] [Google Scholar]
  32. Pegg A. E., McCann P. P. S-adenosylmethionine decarboxylase as an enzyme target for therapy. Pharmacol Ther. 1992 Dec;56(3):359–377. doi: 10.1016/0163-7258(92)90025-u. [DOI] [PubMed] [Google Scholar]
  33. Pfeiffer A., Rochlitz H., Noelke B., Tacke R., Moser U., Mutschler E., Lambrecht G. Muscarinic receptors mediating acid secretion in isolated rat gastric parietal cells are of M3 type. Gastroenterology. 1990 Jan;98(1):218–222. doi: 10.1016/0016-5085(90)91314-v. [DOI] [PubMed] [Google Scholar]
  34. Price E. M., Rice D. A., Lingrel J. B. Structure-function studies of Na,K-ATPase. Site-directed mutagenesis of the border residues from the H1-H2 extracellular domain of the alpha subunit. J Biol Chem. 1990 Apr 25;265(12):6638–6641. [PubMed] [Google Scholar]
  35. Prinz C., Sachs G., Walsh J. H., Coy D. H., Wu S. V. The somatostatin receptor subtype on rat enterochromaffinlike cells. Gastroenterology. 1994 Oct;107(4):1067–1074. doi: 10.1016/0016-5085(94)90231-3. [DOI] [PubMed] [Google Scholar]
  36. Prinz C., Scott D. R., Hurwitz D., Helander H. F., Sachs G. Gastrin effects on isolated rat enterochromaffin-like cells in primary culture. Am J Physiol. 1994 Oct;267(4 Pt 1):G663–G675. doi: 10.1152/ajpgi.1994.267.4.G663. [DOI] [PubMed] [Google Scholar]
  37. Rabon E. C., Reuben M. A. The mechanism and structure of the gastric H,K-ATPase. Annu Rev Physiol. 1990;52:321–344. doi: 10.1146/annurev.ph.52.030190.001541. [DOI] [PubMed] [Google Scholar]
  38. Rabon E., Sachs G., Bassilian S., Leach C., Keeling D. A K(+)-competitive fluorescent inhibitor of the H,K-ATPase. J Biol Chem. 1991 Jul 5;266(19):12395–12401. [PubMed] [Google Scholar]
  39. Rabon E., Sachs G., Bassilian S., Leach C., Keeling D. A K(+)-competitive fluorescent inhibitor of the H,K-ATPase. J Biol Chem. 1991 Jul 5;266(19):12395–12401. [PubMed] [Google Scholar]
  40. Rabon E., Wilke M., Sachs G., Zampighi G. Crystallization of the gastric H,K-ATPase. J Biol Chem. 1986 Jan 25;261(3):1434–1439. [PubMed] [Google Scholar]
  41. Rapoport T. A. Protein transport across the ER membrane. Trends Biochem Sci. 1990 Sep;15(9):355–358. doi: 10.1016/0968-0004(90)90076-n. [DOI] [PubMed] [Google Scholar]
  42. Sachs G., Chang H. H., Rabon E., Schackman R., Lewin M., Saccomani G. A nonelectrogenic H+ pump in plasma membranes of hog stomach. J Biol Chem. 1976 Dec 10;251(23):7690–7698. [PubMed] [Google Scholar]
  43. Sachs G., Shin J. M., Besancon M., Prinz C. The continuing development of gastric acid pump inhibitors. Aliment Pharmacol Ther. 1993;7 (Suppl 1):4-12, discussion 29-31. doi: 10.1111/j.1365-2036.1993.tb00582.x. [DOI] [PubMed] [Google Scholar]
  44. Scott D. R., Helander H. F., Hersey S. J., Sachs G. The site of acid secretion in the mammalian parietal cell. Biochim Biophys Acta. 1993 Feb 23;1146(1):73–80. doi: 10.1016/0005-2736(93)90340-6. [DOI] [PubMed] [Google Scholar]
  45. Scott D. R., Hersey S. J., Prinz C., Sachs G. Actions of antiulcer drugs. Science. 1993 Nov 26;262(5138):1453–1455. doi: 10.1126/science.8248786. [DOI] [PubMed] [Google Scholar]
  46. Scott D. R., Munson K., Modyanov N., Sachs G. Determination of the sidedness of the C-terminal region of the gastric H,K-ATPase alpha subunit. Biochim Biophys Acta. 1992 Dec 9;1112(2):246–250. doi: 10.1016/0005-2736(92)90398-6. [DOI] [PubMed] [Google Scholar]
  47. Shin J. M., Besancon M., Simon A., Sachs G. The site of action of pantoprazole in the gastric H+/K(+)-ATPase. Biochim Biophys Acta. 1993 Jun 5;1148(2):223–233. doi: 10.1016/0005-2736(93)90133-k. [DOI] [PubMed] [Google Scholar]
  48. Shin J. M., Sachs G. Identification of a region of the H,K-ATPase alpha subunit associated with the beta subunit. J Biol Chem. 1994 Mar 25;269(12):8642–8646. [PubMed] [Google Scholar]
  49. Shull G. E., Schwartz A., Lingrel J. B. Amino-acid sequence of the catalytic subunit of the (Na+ + K+)ATPase deduced from a complementary DNA. Nature. 1985 Aug 22;316(6030):691–695. doi: 10.1038/316691a0. [DOI] [PubMed] [Google Scholar]
  50. Tamura S., Tagaya M., Maeda M., Futai M. Pig gastric (H+ + K+)-ATPase. Lys-497 conserved in cation transporting ATPases is modified with pyridoxal 5'-phosphate. J Biol Chem. 1989 May 25;264(15):8580–8584. [PubMed] [Google Scholar]
  51. Tielemans Y., Axelson J., Sundler F., Willems G., Håkanson R. Serum gastrin concentration affects the self replication rate of the enterochromaffin like cells in the rat stomach. Gut. 1990 Mar;31(3):274–278. doi: 10.1136/gut.31.3.274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Toyoshima C., Sasabe H., Stokes D. L. Three-dimensional cryo-electron microscopy of the calcium ion pump in the sarcoplasmic reticulum membrane. Nature. 1993 Apr 1;362(6419):467–471. doi: 10.1038/362469a0. [DOI] [PubMed] [Google Scholar]
  53. Walderhaug M. O., Post R. L., Saccomani G., Leonard R. T., Briskin D. P. Structural relatedness of three ion-transport adenosine triphosphatases around their active sites of phosphorylation. J Biol Chem. 1985 Mar 25;260(6):3852–3859. [PubMed] [Google Scholar]
  54. Wallmark B., Stewart H. B., Rabon E., Saccomani G., Sachs G. The catalytic cycle of gastric (H+ + K+)-ATPase. J Biol Chem. 1980 Jun 10;255(11):5313–5319. [PubMed] [Google Scholar]
  55. Wilkes J. M., Kajimura M., Scott D. R., Hersey S. J., Sachs G. Muscarinic responses of gastric parietal cells. J Membr Biol. 1991 Jun;122(2):97–110. doi: 10.1007/BF01872634. [DOI] [PubMed] [Google Scholar]
  56. Wolosin J. M., Forte J. G. Stimulation of oxyntic cell triggers K+ and Cl- conductances in apical H+-K+-ATPase membrane. Am J Physiol. 1984 May;246(5 Pt 1):C537–C545. doi: 10.1152/ajpcell.1984.246.5.C537. [DOI] [PubMed] [Google Scholar]
  57. Xu K. Y. Any of several lysines can react with 5'-isothiocyanatofluorescein to inactivate sodium and potassium ion activated adenosinetriphosphatase. Biochemistry. 1989 Jul 11;28(14):5764–5772. doi: 10.1021/bi00440a010. [DOI] [PubMed] [Google Scholar]

Articles from The Yale Journal of Biology and Medicine are provided here courtesy of Yale Journal of Biology and Medicine

RESOURCES