Cytokines & Cells Online Pathfinder Encyclopaedia
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Gastrin has been identified originally as a factor produced in the antrum of the stomach that stimulates gastric acid secretion (Edkins and Cantab, 1905). It has been purified first from hog antral mucosa and sequenced (Gregory and Tracy, 1964). The gastrin gene is a single-copy gene (Wiborg et al, 1984). Different gastrin peptides are derived from a single progastrin molecule, which in mammals has the same overall structure and size (Yoo et al, 1982; Boel et al, 1983; Fuller et al, 1987; Lund et al, 1989; Gantz et al, 1990).
Progastrin is processed in antral G cells to a number of bioactive gastrins of different length, which share the same alpha-amidated C-terminus containing the active site. The active site of gastrin is the carboxyterminal tetrapeptide amide Trp-Met-Asp-Phe-NH2 (Morley et al, 1965) and all bioactive fragments have the carboxyterminal hexasequence Tyr (SO4)-Gly-Trp-Met-Asp-Phe-NH2. The lengths of the aminoterminal extensions govern metabolism and clearance of the circulating hormone forms (Morley et al, 1965).
Gastrin circulates in at least twenty different components that arise by proteolytic processing. All gastrin peptides with this C-terminal tetrapeptide are gastrin receptor agonists that stimulate gastric acid secretion. All bioactive gastrin peptides are carboxyamidated and exist in nonsulfated and sulfated forms (Gregory et al, 1964; Gregory and Tracy, 1964; Andersen, 1984).
Gastrin is a hormone of 17 amino acids (termed gastrin-17; called also Gastrin component 3 or little Gastrin), called also Cholecystokinin B. Gastrin-17 amide corresponds to Progastrin-(55-71). Glycine-extended nonsulfated gastrin-17 corresponds to Progastrin-(55-72). Progastrin is synthesized in antral G cells and processed into a number of bioactive peptides. The heptadecapeptide gastrin-17 is the main product (Gregory and Tracy, 1964; Rehfeld and Johnsen, 1994; Gregory et al, 1964). A minor fraction of gastrin-17 is cleaved in G cells and released as short COOH-terminal peptides (Rehfeld and Larsson, 1979) as a mixture of gastrin-7, gastrin-6, and gastrin-5. The sulfated gastrin-6 is the predominant form released to antral venous blood (Rehfeld et al, 1995; Gregory et al, 1983). Hansen et al (2000) have reported that gastrin 6 has a higher potency but a lower efficacy than gastrin-17. The efficacy of gastrin-6 is increased by tyrosine O-sulfation, which also enhances the protection against elimination.
Cryptagastrin corresponds to progastrin-(1-35). Cryptagastrin-(6-35) (progastrin-(6-35) is a shorter form of this peptide (Huebner et al, 1991).
Human Gastrin-1 differs from Gastrin-2 by the absence of a sulfate ester group on a tyrosine residue in position 12 (Bentley et al, 1996). Multiple active products are generated from the progastrin precursor (Rehfeld et al, 1994). Posttranslational processing of progastrin yields a carboxyterminally amidated form (G-NH2) the immediate biosynthetic precursor of which is glycine-extended gastrin (G-Gly; abbr. gastrin G, gastrin-Gly, G-Gly). Gastrin-34 consists of an N-terminal pentadecapeptide linked via two lysine residues to a C-terminal heptadecapeptide identical with gastrin-17. Among the gastrins, gastrin-34 (called also Gastrin component 2 or big Gastrin) (Walsh et al, 1974) and gastrin-17 are the two dominating forms of gastrin in serum and constitute the primary forms that show high-affinity binding to the gastrin receptor (Rehfeld et al, 2004). The sequence of murine gastrin-34 is 94 % identical to rat gastrin-34 and 76 % identical to human gastrin-34 (Friis-Hansen et al, 1996). The two largest alpha-carboxyamidated progastrin products are gastrin-71 and gastrin-52. Gastrin-52 is bioactive with an efficacy close to or similar to that of gastrin-17 (Hansen et al, 1995). Gastrin component 1 is the largest hormonally active form of gastrin and has been shown to correspond to gastrin-71 (Rehfeld and Johnsen, 1994). Gastrin-14 has been termed gastrin component 4 or minigastrin (Gregory et al, 1979). Pentagastrin corresponds to the five C-terminal amino acids of gastrin and is the same as CCK-5 [cholecystokinin-5], which acts mainly through the type B cholecystokinin receptor.
Gastrin is synthesized in the gastric antrum mucosa (G cells) in response to alkaline pH, mechanical stimulation, or vagus stimulation. It is produced also by D cells of the pancreatic islets (Dockray et al, 1999). Large amounts of Gastrin-1 and Gastrin-2 are secreted by pancreatic tumors in the Zollinger-Ellison syndrome (Gregory et al, 1969).
Gastrin promotes the release of hydrochloric acid in the stomach and of digestive enzymes in the pancreas. The synthesis is inhibited by acidic stomach juice. Posttranslational processing of progastrin to G-NH2 is essential for its effect on gastric acid secretion and other biological effects mediated by gastrin receptors. G-Gly does not stimulate gastric acid secretion at physiological concentrations but is found in high concentrations during development. Cholecystokinin is a competitive inhibitor of gastrin.
Antral gastrin secretion and gene expression is inhibited by the paracrine release of Somatostatin from antral D cells. TGF-alpha and EGF stimulate gastrin reporter gene constructs when transfected into pituitary GH4 cells. Somatostatin inhibits EGF stimulation of gastrin gene expression, which is in part mediated at the level of transcriptional regulation as somatostatin inhibits EGF stimulation of gastrin reporter gene constructs (Bachwich et al, 1992).
Apart from its pharmacological activities gastrin also displays activities of cytokines. It has been shown that gastrin and TGF-alpha can act synergistically to stimulate pancreatic islet growth, although neither peptide alone is sufficient (Blackmore and Hirst, 1992).
G-NH2 and G-Gly have potent growth stimulatory effects on gastrointestinal tissues. Both proteins are detected in serum-free conditioned medium of human embryonic kidney cells (HEK293 cells). They act cooperatively via distinct receptors and stimulate growth in an autocrine fashion (Stepan et al, 1999).
Gastrin has been shown to promote the growth of some colonic tumor cell lines and it has been suggested that aberrant expression of gastrin may contribute to deregulated proliferation of many colorectal carcinomas (Finley et al, 1993). Gastrin has been shown also to act as a growth factor for some pancreatic cancer cell lines. Negre et al (1996) have reported that gastrin-Gly is an autocrine growth factor for the pancreatic tumor cell line AR4-2J. Gastrin may play a role also as a local growth factor in the developing colon. Gastrin also stimulates calcium ion mobilization and clonal growth in small cell lung cancer cells (Sethi and Rozengurt, 1992). It has been suggested that gastrin receptor antagonists may be a therapeutic option for gastrin receptor-positive, gastro-intestinal tumors (Watson et al, 1992).
de la Fuente et al (1996) have reported that gastrin is a negative modulator of several macrophage functions (adherence to substrate, chemotaxis, ingestion of inert particles or cells). De la Fuente et al (1997) have reported that gastrin is a negative modulator of the phagocytic process of human neutrophils.
In transgenic mice pancreatic coexpression of both gastrin and TGF-alpha significantly increases islet mass in mice expressing both transgenes (Wang et al, 1993).
Mutant knock-out mouse strains lacking expression of gastrin have been generated (Friis-Hansen et al, 1998; Koh et al, 1997). Studies with these mice show that gastrin is not a vital hormone. These animals are born in normal numbers, develop without visible abnormalities, exhibit normal weight gain, are fertile, and have a normal life span. Cholecystokinin, which also binds to the gastrin receptor, does not compensate for the loss of gastrin, and mice deficient in both gastrin and cholecystokinin are viable without obvious abnormalities (Lacourse et al, 1999). Boushey et al (2003) have reported hypoglycemia and defective islet glucagon secretion in mice with a disruption of the gastrin gene, demonstrating an essential physiologic role for gastrin in glucose homeostasis. Islet of Langerhans cell mass is normal in these mice, showing that the gastrin gene is not essential for murine islet development or the adaptive islet proliferative response to beta-cell injury. Gastrin is required for the functional maturation of the acid secretory system. Gastrin knock-out mice show a severe reduction in gastric acid secretion. Cellular changes in the stomach include thinning of the gastric mucosa, with a reduction in parietal cells and reduced expression of markers of parietal cell and ECL cell differentiated functions.
For other entries pertaining to low molecular weight substances that are not classified as cytokines or growth factors but that possess activities of cytokines see also: regulatory peptide factors.
LAST MODIFIED: September 2008
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