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Physiology of gastrin

Author
Rodger A Liddle, MD
Section Editor
J Thomas Lamont, MD
Deputy Editor
Shilpa Grover, MD, MPH

INTRODUCTION

Gastrin is the major hormonal regulator of gastric acid secretion [1]. Its discovery at the turn of the century was based upon its profound effect on meal-stimulated acid secretion, making it one of the first hormones to be described [1]. The study of gastrin accelerated with the isolation and characterization of the peptide in 1964 after which it was found to promote growth of the gastric antrum and have a proliferative effect, which has implicated it as having a possible role in cancer [2,3]. The cloning and characterization of the gastrin receptor in 1992 has provided a valuable tool in the study of gastrointestinal hormones [4].

This topic will review the physiology of gastrin. Zollinger-Ellison syndrome and the physiology of gastric acid secretion are discussed elsewhere. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)" and "Physiology of gastric acid secretion".)

MOLECULAR FORMS

Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide "preprogastrin" (figure 1). Human preprogastrin contains 101 amino acids (AA) including a signal peptide (21 AA), spacer sequence (37 AA), gastrin component (34 AA) and a 9 AA extension segment at the carboxyl terminus. The enzymatic processing of preprogastrin produces all of the known physiologically active forms of gastrin.

Preprogastrin is processed into progastrin and gastrin peptide fragments of various sizes by sequential enzymatic cleavage (figure 1). Like other hormones, gastrin is synthesized on rough endoplasmic reticulum, processed in the Golgi apparatus, and packaged in secretory granules, where final modifications occur [5]. In endocrine cells, the glycine residue at the carboxyl terminus is cleaved and the terminus is amidated to form the mature gastrin peptide.

Two major forms of gastrin are secreted (G-34 and G-17), although larger G-71 and smaller G-6 forms exist (table 1). The common feature of all gastrins is an amidated tetrapeptide (Try-Met-Asp-Phe-NH2) at the carboxyl terminus that imparts full biological activity. Modification by sulfation at tyrosine residues produces alternative gastrin forms. The circulating half-life of gastrin is affected by the size of the various molecular forms. The full physiologic response is determined by the presence of the biologically active moiety and the time available for receptor interaction. (See "Overview of gastrointestinal peptides in health and disease".)

            

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Literature review current through: Nov 2016. | This topic last updated: Mon Apr 11 00:00:00 GMT+00:00 2016.
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References
Top
  1. Edkins JS. On the chemical mechanism of gastric secretion. Proc R Soc Lond B Biol Sci 1905; 76:376.
  2. GREGORY RA, TRACY HJ. THE CONSTITUTION AND PROPERTIES OF TWO GASTRINS EXTRACTED FROM HOG ANTRAL MUCOSA. Gut 1964; 5:103.
  3. Joshi SN, Gardner JD. Gastrin and colon cancer: a unifying hypothesis. Dig Dis 1996; 14:334.
  4. Kopin AS, Lee YM, McBride EW, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A 1992; 89:3605.
  5. Rehfeld JF. Processing of precursors of gastroenteropancreatic hormones: diagnostic significance. J Mol Med (Berl) 1998; 76:338.
  6. Rehfeld JF. The new biology of gastrointestinal hormones. Physiol Rev 1998; 78:1087.
  7. Hellmich MR, Rui XL, Hellmich HL, et al. Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem 2000; 275:32122.
  8. Harris JC, Clarke PA, Awan A, et al. An antiapoptotic role for gastrin and the gastrin/CCK-2 receptor in Barrett's esophagus. Cancer Res 2004; 64:1915.
  9. Smith JP, Verderame MF, McLaughlin P, et al. Characterization of the CCK-C (cancer) receptor in human pancreatic cancer. Int J Mol Med 2002; 10:689.
  10. Meek CL, Lewis HB, Reimann F, et al. The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones. Peptides 2016; 77:28.
  11. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995; 75:155.
  12. Sachs G, Prinz P. Gastric enterochromaffin-like cells and the regulation of acid secretion. News in Physiological Sci 1996; 11:57.
  13. Rehfeld JF. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides. Acta Physiol (Oxf) 2011; 201:405.
  14. Wang TC, Dockray GJ. Lessons from genetically engineered animal models. I. Physiological studies with gastrin in transgenic mice. Am J Physiol 1999; 277:G6.
  15. Koh TJ, Goldenring JR, Ito S, et al. Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice. Gastroenterology 1997; 113:1015.
  16. Chen D, Zhao CM, Dockray GJ, et al. Glycine-extended gastrin synergizes with gastrin 17 to stimulate acid secretion in gastrin-deficient mice. Gastroenterology 2000; 119:756.
  17. Nagata A, Ito M, Iwata N, et al. G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo. Proc Natl Acad Sci U S A 1996; 93:11825.
  18. Langhans N, Rindi G, Chiu M, et al. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 1997; 112:280.
  19. Friis-Hansen L. Lessons from the gastrin knockout mice. Regul Pept 2007; 139:5.
  20. Calam J, Gibbons A, Healey ZV, et al. How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin physiology. Gastroenterology 1997; 113:S43.
  21. Okosdinossian ET, Munshid HA, Wasfi AI, et al. Fasting plasma-gastrin in vitiligo. Lancet 1978; 1:997.
  22. Netter P, Faure G, Brassine A, et al. Hypergastrinemia in rheumatoid arthritis is related to Sjögren's syndrome. J Rheumatol 1985; 12:651.
  23. Korman MG, Laver MC, Hansky J. Hypergastrinaemia in chronic renal failure. Br Med J 1972; 1:209.
  24. Song 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.
  25. Winbo A, Sandström O, Palmqvist R, Rydberg A. Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome. Cardiol Young 2013; 23:325.
  26. Clerc P, Dufresne M, Saillan C, et al. Differential expression of the CCK-A and CCK-B/gastrin receptor genes in human cancers of the esophagus, stomach and colon. Int J Cancer 1997; 72:931.
  27. de Weerth A, von Schrenck T, Löhr M, et al. Human pancreatic cancer cell lines express the CCKB receptor. Hepatogastroenterology 1999; 46:472.
  28. Jensen RT. Involvement of cholecystokinin/gastrin-related peptides and their receptors in clinical gastrointestinal disorders. Pharmacol Toxicol 2002; 91:333.
  29. Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 1986; 35 Suppl 1:42.
  30. Waldum HL, Hauso Ø, Fossmark R. The regulation of gastric acid secretion - clinical perspectives. Acta Physiol (Oxf) 2014; 210:239.
  31. Bordi C, D'Adda T, Azzoni C, et al. Hypergastrinemia and gastric enterochromaffin-like cells. Am J Surg Pathol 1995; 19 Suppl 1:S8.
  32. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore) 2004; 83:43.
  33. Cadiot G, Laurent-Puig P, Thuille B, et al. Is the multiple endocrine neoplasia type 1 gene a suppressor for fundic argyrophil tumors in the Zollinger-Ellison syndrome? Gastroenterology 1993; 105:579.
  34. Nakata H, Wang SL, Chung DC, et al. Oncogenic ras induces gastrin gene expression in colon cancer. Gastroenterology 1998; 115:1144.
  35. Renga M, Brandi G, Paganelli GM, et al. Rectal cell proliferation and colon cancer risk in patients with hypergastrinaemia. Gut 1997; 41:330.
  36. Thorburn CM, Friedman GD, Dickinson CJ, et al. Gastrin and colorectal cancer: a prospective study. Gastroenterology 1998; 115:275.
  37. Grabowska AM, Watson SA. Role of gastrin peptides in carcinogenesis. Cancer Lett 2007; 257:1.
  38. Bold RJ, Ishizuka J, Townsend CM Jr. Progress toward hormonal therapy of gastrointestinal cancer. Ann Surg 1996; 223:4.
  39. Stepan VM, Sawada M, Todisco A, Dickinson CJ. Glycine-extended gastrin exerts growth-promoting effects on human colon cancer cells. Mol Med 1999; 5:147.
  40. Litvak DA, Hellmich MR, Iwase K, et al. JMV1155: a novel inhibitor of glycine-extended progastrin-mediated growth of a human colon cancer in vivo. Anticancer Res 1999; 19:45.
  41. Kelly A, Hollande F, Shulkes A, Baldwin GS. Expression of progastrin-derived peptides and gastrin receptors in a panel of gastrointestinal carcinoma cell lines. J Gastroenterol Hepatol 1998; 13:208.
  42. Van Solinge WW, Nielsen FC, Friis-Hansen L, et al. Expression but incomplete maturation of progastrin in colorectal carcinomas. Gastroenterology 1993; 104:1099.
  43. Ciccotosto GD, McLeish A, Hardy KJ, Shulkes A. Expression, processing, and secretion of gastrin in patients with colorectal carcinoma. Gastroenterology 1995; 109:1142.
  44. Bombski G, Gasiorowska A, Orszulak-Michalak D, et al. Elevated plasma gastrin, CEA, and CA 19-9 levels decrease after colorectal cancer resection. Int J Colorectal Dis 2003; 18:148.
  45. Smith AM, Watson SA. Gastrin and gastrin receptor activation: an early event in the adenoma-carcinoma sequence. Gut 2000; 47:820.
  46. Ramamoorthy S, Stepan V, Todisco A. Intracellular mechanisms mediating the anti-apoptotic action of gastrin. Biochem Biophys Res Commun 2004; 323:44.
  47. Clarke PA, Dickson JH, Harris JC, et al. Gastrin enhances the angiogenic potential of endothelial cells via modulation of heparin-binding epidermal-like growth factor. Cancer Res 2006; 66:3504.
  48. Orlando LA, Lenard L, Orlando RC. Chronic hypergastrinemia: causes and consequences. Dig Dis Sci 2007; 52:2482.
  49. Smith JP, Shih A, Wu Y, et al. Gastrin regulates growth of human pancreatic cancer in a tonic and autocrine fashion. Am J Physiol 1996; 270:R1078.
  50. Smith JP, Verderame MF, Zagon IS. Antisense oligonucleotides to gastrin inhibit growth of human pancreatic cancer. Cancer Lett 1999; 135:107.
  51. el-Zimaity HM, Jackson FW, Graham DY. Fundic gland polyps developing during omeprazole therapy. Am J Gastroenterol 1997; 92:1858.
  52. Chowers MY, Keller N, Tal R, et al. Human gastrin: a Helicobacter pylori--specific growth factor. Gastroenterology 1999; 117:1113.
  53. Payne NA, Gerber JG. Differential effects of somatostatin and prostaglandins on gastric histamine release to pentagastrin. J Pharmacol Exp Ther 1992; 263:520.
  54. Brunt LM, Mazoujian G, O'Dorisio TM, Wells SA Jr. Stimulation of vasoactive intestinal peptide and neurotensin secretion by pentagastrin in a patient with VIPoma syndrome. Surgery 1994; 115:362.