Abstract
Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-α (TGF-α) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several posttranslation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include β-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-α, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H2 receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.
References
1.
Bayliss WM, Starling EH: The mechanism of pancreatic secretion. J Physiol 1902;28:325–330.
2.
Edkins JS: On the chemical mechanism of gastric secretion. Proc R Soc Lond 1905;76:376–380.
3.
Brand S, Andersen B, Rehfeld J: Complete tyrosine-O-sulphate of gastrin in neonatal rat pancreas. Nature 1984;309:456–458.
4.
Uvnas-Wallensten K, Rehfeld J, Larsson L, Uvnas B: Heptadecapeptide gastrin in the vagal nerve. Proc Natl Acad Sci USA 1977;74:5707–5710.
5.
Powell C, Ney C, Aran P, Agarwal K: A gastrin gene is expressed in both porcine and antral mucosal tissue. Nucleic Acid Res 1985;13:7299–7305.
6.
Rehfeld J: Localization of gastrin to neuro- and adenohypophysis. Nature 1978;271:771–773.
7.
Rehfeld J, Bardram L, Hilsted L: Gastrin in human bronchogenic carcinomas: Constant expression but variable processing of progastrin. Cancer Res 1989;49:2840–2843.
8.
Schalling M, Persson H, Pelto-Huikko M, et al: Expression and localisation of gastrin messenger RNA and peptide in spermatogenic cells. J Clin Invest 1990;86:660–669.
9.
Solcia E, Capella C, Buffa R, Usellini L, Fiocca R, Sessa F: Endocrine cells of the digestive system; in Johnson LR (ed): Physiology of the Gastrointestinal Tract. New York, Raven Press, 1987.
10.
Campos R, Buchan A, Meloche R, Pederson R, Kwok Y, Coy D: Gastrin secretion from human antral G-cells in culture. Gastroenterology 1990;99:36–44.
11.
Schepp W, Soll A, Walsh J: Dual modulation by adenosine of gastrin release from canine G-cells in culture. Am J Physiol 1990;259:G556–G563.
12.
Dial E, Cooper L, Lichtenberger L: Amino acid and amine-induced gastrin release from isolated rat endocrine granules. Am J Physiol 1991;260:G175–G181.
13.
Johnsen A, Rehfeld J: Cionin: A disulphotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. J Biol Chem 1990;265: 3054–3058.
14.
Rehfeld J: Four basic characteristics of the gastrin-cholecystokinin system. Am J Physiol 1981;240:G255–G266.
15.
Merchant J, Demediuk B, Brand S: A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol 1991;11:2686–2696.
16.
Brand S, Stone D: Reciprocal regulation of antral gastrin and somatostatin gene expression by omeprazole-induced achlorhydria. J Clin Invest 1988;82:1059–1066.
17.
Wu S, Giraud A, Mogard M, Sumil K, Walsh J: Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats. Am J Physiol 1990;258:G788–G793.
18.
Harty R: Gastrointestinal hormones. Curr Opin Gastroenterol 1991;7:906–912.
19.
Daugherty D, Yamada T: Posttranslational processing of gastrin. Physiol Rev 1989;69:482–502.
20.
Varro A, Desmond H, Pauwels S, Gregory H, Young J: The human gastrin precursor. Biochem J 1988;256:951–957.
21.
Walsh J: Physiology and pathophysiology of gastrin. Mt Sinai J Med 1992;59:117–123.
22.
Seva C, Dickinson C, Yamada T: Growth-promoting effects of glycine-extended progastrin. Science 1994;265:410–412.
23.
El-Omar E, Penman I, Ardill J, Chittajulla R, Howie C, McColl K: Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 1995;109:681–691.
24.
El-Omar E, Penman I, Dorrian C, Ardill J, McColl K: Eradicating Helicobacter pylori infection lowers gastrin-mediated acid secretion by two thirds in patients with duodenal ulcer. Gut 1993;34:1060–1065.
25.
Graham D, Opekun A, Lew G, Evans D, Klein P, Evans D: Ablation of exaggerated meal-stimulated gastrin release in duodenal ulcer patients after clearance of Helicobacter (Campylobacter) pylori infection. Am J Gastroenterol 1990;85:394–398.
26.
Karnes W, Ohning G, Sytnik B, Kim S, Walsh J: Elevation of meal-stimulated gastrin release in subjects with Helicobacter pylori infection: Reversal by low intragastric pH. Rev Infect Dis 1991;13(suppl 8):665–670.
27.
Smith J, Pounder R, Nwokolo C, et al: Inappropriate hypergastrinemia in asymptomatic healthy subjects infected with Helicobacter pylori. Gut 1990;31:522–525.
28.
Nujumi A, Dorrian C, Chittajallu R, Neithercut W, McColl K: Effect of inhibition of Helicobacter pylori urease activity by acetohydroxamic acid on serum gastrin in duodenal ulcer subjects. Gut 1991;32:866–870.
29.
Chittajallu R, Dorrian C, Neithercut W, Dahill S, McColl K: Is Helicobacter pylori associated hypergastrinemia due to the bacterium’s urease activity or the antral gastritis? Gut 1991;32:1286–1290.
30.
Lichtenberger L, Dial E, Romero J, Lechago J, Jarboe L, Wolfe M: Role of luminal ammonia in the development of gastropathy and hypergastrinemia in the rat. Gastroenterology 1995;108:320–329.
31.
Weigert N, Schaffer K, Schusdziarra V, Classen M, Schepp W: Gastrin secretion from primary cultures of rabbit antral G cells: Stimulation by inflammatory cytokines. Gastroenterology 1996;110:147–154.
32.
Le A, Lambert J, Davenport P, et al: Antral mucosal gastrin and tumor necrosis factor-alpha release in patients with nonulcer dyspepsia and H. pylori infection. Gastroenterology 1993;104:A10470.
33.
Lamers C, Ruland C, Joosten H, Verkoogen H, van Tongeren J, Rehfeld J: Hypergastrinemia of antral origin in duodenal ulcer. Dig Dis Sci 1978;23:998–1002.
34.
Dockray G, Tracy H: Atropine does not abolish cephalic vagal stimulation or gastrin release. J Physiol 1980;306:473–480.
35.
Hirschowitz B, Bigson R, Molina E: Atropine suppresses gastrin release by food in intact and vagotomised dogs. Gastroenterology 1981;81:838–843.
36.
Saffouri B, Weir G, Bitar K, Makhlouf G: Gastrin and somatostatin secretion by perfused rat stomach: Functional linkage of antral peptides. Am J Physiol 1980;238:G495–G501.
37.
Wolfe M, Jain D, Reel G, McGuigan J: Effects of carbachol on gastrin and somatostatin release in rat antral tissue. Gastroenterology 1984;87:86–93.
38.
Chiba T, Yamada T: Mechanisms for muscarinic inhibition of somatostatin release from canine fundic D cells. Metabolism 1990;39:122–124.
39.
Schubert M, Hightower J, Coy D, Makhlouf G: Functional distinct muscarinic receptors on gastric somatostatin cells. Am J Physiol 1990;258:G982–G987.
40.
DeSchryver-Kechkemeti K, Greider M, Reiders E, Komyati S, McGuigan J: In vitro gastrin secretion by rat antrum: Effects of neurotransmitter agonists, antagonists and modulators of secretion. Lab Invest 1981;44:158–163.
41.
Dockray G, Vailiant C, Walsh J: The neuronal origin of bombesin-like immunoreactivity in the rat gastrointestinal tract. Neuroscience 1979;4:1561–1568.
42.
Makhlouf G, Schubert M: Antral bombesin: Physiological regulator of gastrin release. Ann NY Acad Sci 1988;547:225–233.
43.
Guo Y, Thompson J, Singh P: Role of gastrin in bombesin-stimulated somatostatin release. Gastroenterology 1990;99:1297–1302.
44.
Schubert M: Gastric somatostatin: A paracrine regulator of gastrin and acid secretion. Regul Pept Lett 1991;3:7–11.
45.
Schubert M, Makhlouf G: Regulation of acid secretion by bombesin/GRP neurons of the gastric fundus. Am J Physiol 1992;260:G156–G160.
46.
Langhans N, Rindi G, Chiu M, et al: Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin receptor-deficient mice. Gastroenterology 1997;112:280–286.
47.
Hakanson R, Sundler F: Proposed mechanisms of induction of gastric carcinoids: The gastrin hypothesis. Eur J Clin Invest 1990;20:S65–S71.
48.
Soybell D, Modlin I: Implications of sustained suppression of gastric acid secretion. Am J Surg 1992;163:613–622.
49.
Soll A, Aimirian D, Thomas L, Reedy T, Elashoff J: Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984;73:1434–1447.
50.
Gregory R: Gastrin. Adv Metab Disord 1988;11:163–198.
51.
Black J, Shankley N: How does gastrin act to stimulate oxyntic cell secretion? Trends Pharmacol Sci 1987;8:486–490.
52.
Code C: Reflections on histamine, gastric secretion and the H2 receptor. N Engl J Med 1977;296:1459–1462.
53.
Hakanson R, Owman C, Sjoberg N-O: Cellular stores of gastric histamine in the developing rat. Life Sci 1967;6:2535–2543.
54.
Bottcher G, Hakanson R, Nilsson G, Seensalu R, Sundler F: Effects of long-term hypergastrinaemia on the ultrastructure of enterochromaffin-like cells in the stomach of the rat, hamster and guinea pig. Cell Tissue Res 1989;256:247–257.
55.
Salganik RI, Bersimbaev RI, Argutinskaya SV, Kiseleva EV, Khristolyubova NB, Deribas VI: Integration of biochemical functions of different cells of rat gastric mucosa for hydrochloric acid secretion. Mol Cell Biochem 1976;12:181–191.
56.
Solcia E, Fiocca R, Sessa F, et al: Morphology and natural history of gastric endocrine tumours; in Hakanson R, Sundler F (eds): The Stomach as an Endocrine Organ. Amsterdam, Elsevier Science, 1991, pp 473–498.
57.
Panula P, Kaartinen M, Macklin M, Costa E: Histamine-containing peripheral neuronal and endocrine systems. J Histochem Cytochem 1985;33:933–941.
58.
Solcia E, Vassallo G, Capella C: Cytology and cytochemistry of hormone-producing cells of the upper gastrointestinal tract; in Creutzfeld W (ed): Origin, Chemistry, Physiology and Pathophysiology of the Gastrointestinal Hormones. Stuttgart, Schattauer, 1970, pp 3–29.
59.
Capella C, Finzi G, Cornaggia M, et al: Ultrastructural typing of gastric endocrine cells; in Hakanson R, Sundler F (eds): The Stomach as an Endocrine Organ. Fernstrom Symp No 15. Amsterdam, Elsevier, 1991, pp 27–51.
60.
Hakanson R, Owman C, Sporrong B, Sundler F: Electron microscopic identification of the histamine-storing argyrophil (enterochromaffin-like) cells in the rat stomach. Z Zellforsch 1971;122:460–466.
61.
D’Adda T, Bertele A, Pilato FP, Bordi C: Quantitative electron microscopy of endocrine cells in oxyntic mucosa of human stomach. Cell Tissue Res 1989;255:41–48.
62.
Furness JB, Padbury RTA, Baimbridge KG, Skinner JM, Lawson DEM: Calbindin immunoreactivity is a characteristic of enterochromaffin-like cells of the human stomach. Histochemistry 1989;92:449–451.
63.
Hakanson R, Owman C: Distribution and properties of amino acid decarboxylases in gastric mucosa. Biochem Pharmacol 1966;15:489–499.
64.
Aures D, Schauer A: Histidine decarboxylase and DOPA decarboxylase in the rat stomach. Properties and cellular localization. Eur J Pharmacol 1968;3:217–234.
65.
Prinz C, Scott D, Hurwitz D, Helander H, Sachs G: Gastrin effects on isolated rat enterochromaffin-like cells in primary culture. Am J Physiol 1994;267:G663–G675.
66.
Hersey S, Sachs G: Gastric acid secretion. Physiol Rev 1995;75:155–189.
67.
Kopin A, Lee Y, McBride E, et al: Expression, cloning and characterisation of canine parietal cell gastrin receptor. Proc Natl Acad Sci USA 1992;89:3605–3609.
68.
Kidd M, Sandor A, Lawton G, Tang L, O’Keefe S, Modlin I: Acetylcholine-mediated enterochromaffin-like cell modulation of the cephalic phase of acid secretion. Gastroenterology 1995;108:A627–A630.
69.
Kidd M, Sandor M, Lawton G, Tang L, O’Keefe S, Modlin I: The role of calcium channels in gastrin-driven ECL cell histamine secretion. Gastroenterology 1995;108:A627–A630.
70.
Reubi J, Waser B, Horisberger H, et al: Identification of somatostatin and gastrin receptors on enterochromaffin-like cells from mastomys gastric tumors. Endocrinology 1992;131:166–172.
71.
Sandor A, Kidd M, Lawton G, Tang L, Modlin I: Neurohormonal modulation of rat enterochromaffin-like cell histamine secretion. Gastroenterology 1996;110:1084–1092.
72.
Zeng N, Walsh J, Kang T, Wu V, Sachs G: Peptide YY inhibition of rat gastric enterochromaffin-like cell function. Gastroenterology 1997;112:127–135.
73.
Modlin I, Tang L: The gastric enterochromaffin-like cell: An enigmatic cellular lesion. Gastroenterology 1996;111:783–810.
74.
Hakanson R, Sundler F: Proposed mechanism of induction of gastric carcinoids: The gastrin hypothesis. Eur J Clin Invest 1990;20:S65–S71.
75.
Lamberts R, Creutzfeldt W, Stockmann F, Jacubaschke U, Maas S, Brunner G: Long-term omeprazole treatment in man: Effects on gastric endocrine cell populations. Digestion 1988;39:126–135.
76.
Sirinek K, Levin B, Moyer M: Pentagastrin stimulates in vitro growth of normal and malignant human colon epithelial cells. Am J Surg 1985;149:35–39.
77.
Ciccotosto G, McLeish A, Hardy K, Shulkes A: Expression, processing and secretion of gastrin in patients with colorectal carcinoma. Gastroenterology 1995;109:1142–1153.
78.
van Solinge W, Rehfeld J: Co-transcription of the gastrin and cholecystokinin genes with selective translation of gastrin mRNA in a human gastric carcinoma cell line. FEBS Lett 1992;309:47–50.
79.
Miyake A: A truncated form of human CCK-B/gastrin receptor generated by alternative usage of a novel exon. Biochem Biophys Res Commun 1995;208:230–237.
80.
Hoosein N, Kiener P, Curry R, Brattain M: Evidence for autocrine growth stimulation of cultured colon tumor cells by a gastrin/cholecystokinin-like peptide. Exp Cell Res 1990;186:15–21.
81.
Watson S: Gastrin antagonists and gastrointestinal tumors. Exp Opin Invest Drugs 1995;4:1253–1266.
82.
Dickinson C: Relationship of gastrin processing to colon cancer. Gastroenterology 1995;109:1384–1388.
83.
Varro A, Voronina S, Dockray G: Pathways of processing of the gastrin precursor in rat antral mucosa. J Clin Invest 1995;95:1642–1649.
1998
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