Gastrin
| GAST | |||||||||||||||||
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| Aliases | GAST, GAS, gastrin | ||||||||||||||||
| External IDs | OMIM: 137250 MGI: 104768 HomoloGene: 628 GeneCards: GAST | ||||||||||||||||
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| Orthologs | |||||||||||||||||
| Species | Human | Mouse | |||||||||||||||
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| Ensembl | |||||||||||||||||
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| RefSeq (mRNA) | |||||||||||||||||
| RefSeq (protein) | |||||||||||||||||
| Location (UCSC) | Chr 17: 41.71 – 41.72 Mb | Chr 11: 100.33 – 100.34 Mb | |||||||||||||||
| PubMed search | [1] | [2] | |||||||||||||||
| Wikidata | |||||||||||||||||
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| Gastrin | |||||||||
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| Identifiers | |||||||||
| Symbol | Gastrin | ||||||||
| Pfam | PF00918 | ||||||||
| InterPro | IPR001651 | ||||||||
| PROSITE | PDOC00232 | ||||||||
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Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
Gastrin binds to cholecystokinin B receptors to stimulate the release of histamines in enterochromaffin-like cells, and it induces the insertion of K+/H+ ATPase pumps into the apical membrane of parietal cells (which in turn increases H+ release into the stomach cavity). Its release is stimulated by peptides in the lumen of the stomach.
Physiology
Genetics
In humans, the GAS gene is located on the long arm of the seventeenth chromosome (17q21).[3]
Synthesis
Gastrin is a linear peptide hormone produced by G cells of the duodenum and in the Pyloric antrum of the stomach. It is secreted into the bloodstream. Gastrin is found primarily in three forms:
- gastrin-34 ("big gastrin")
- gastrin-17 ("little gastrin")
- gastrin-14 ("minigastrin")
Also, pentagastrin is an artificially synthesized, five amino acid sequence identical to the last five amino acid sequence at the C-terminus end of gastrin. The numbers refer to the amino acid count.
Release
Gastrin is released in response to certain stimuli. These include:
- Stomach antrum distension
- vagal stimulation (mediated by the neurocrine bombesin, or GRP in humans)
- the presence of partially digested proteins, especially amino acids, in the stomach
- hypercalcemia (via Calcium-sensing receptors[4])
Gastrin release is inhibited by:[5][6]
- The presence of acid (primarily the secreted HCl) in the stomach (a case of negative feedback).
- Somatostatin also inhibits the release of gastrin, along with secretin, GIP (gastroinhibitory peptide), VIP (vasoactive intestinal peptide), glucagon and calcitonin.
Function
The presence of gastrin stimulates parietal cells of the stomach to secrete hydrochloric acid (HCl)/gastric acid. This is done both directly on the parietal cell and indirectly via binding onto CCK2/gastrin receptors on ECL cells in the stomach, which then responds by releasing histamine, which in turn acts in a paracrine manner on parietal cells stimulating them to secrete H+ ions. This is the major stimulus for acid secretion by parietal cells.
Along with the above-mentioned function, gastrin has been shown to have additional functions as well:
- Stimulates parietal cell maturation and fundal growth.
- Causes chief cells to secrete pepsinogen, the zymogen (inactive) form of the digestive enzyme pepsin.
- Increases antral muscle mobility and promotes stomach contractions.
- Strengthens antral contractions against the pylorus, and relaxes the pyloric sphincter, which increases the rate of gastric emptying.[7]
- Plays a role in the relaxation of the ileocecal valve.[8]
- Induces pancreatic secretions and gallbladder emptying.[9]
- May impact lower esophageal sphincter (LES) tone, causing it to contract,[10] - although pentagastrin, rather than endogenous gastrin, may be the cause.[11]
- Gastrin Contributes to the gastrocolic reflex.
Factors influencing secretion
Gastric lumen
- Stimulatory factors: dietary protein and amino acids (meat), hypercalcemia. (i.e. during the gastric phase)
- Inhibitory factor: acidity (pH below 3) - a negative feedback mechanism, exerted via the release of somatostatin from δ cells in the stomach, which inhibits gastrin and histamine release.
Paracrine
- Stimulatory factor: bombesin or gastrin-releasing peptide (GRP)
- Inhibitory factor: somatostatin - acts on somatostatin-2 receptors on G cells. in a paracrine manner via local diffusion in the intercellular spaces, but also systemically through its release into the local mucosal blood circulation; it inhibits acid secretion by acting on parietal cells.
Nervous
- Stimulatory factors: Beta-adrenergic agents, cholinergic agents, gastrin-releasing peptide (GRP)
- Inhibitory factor: Enterogastric reflex
Circulation
- Stimulatory factor: epinephrine
- Inhibitory factors:gastric inhibitory peptide (GIP), secretin, somatostatin, glucagon, calcitonin
Role in disease
In the Zollinger–Ellison syndrome, gastrin is produced at excessive levels, often by a gastrinoma (gastrin-producing tumor, mostly benign) of the duodenum or the pancreas. To investigate for hypergastrinemia (high blood levels of gastrin), a "pentagastrin test" can be performed.
In autoimmune gastritis, the immune system attacks the parietal cells leading to hypochlorhydria (low stomach acid secretion). This results in an elevated gastrin level in an attempt to compensate for increased pH in the stomach. Eventually, all the parietal cells are lost and achlorhydria results leading to a loss of negative feedback on gastrin secretion. Plasma gastrin concentration is elevated in virtually all individuals with mucolipidosis type IV (mean 1507 pg/mL; range 400-4100 pg/mL) (normal 0-200 pg/mL) secondary to a constitutive achlorhydria. This finding facilitates the diagnosis of patients with this neurogenetic disorder.[12] Additionally, elevated gastrin levels may be present in chronic gastritis resulting from H pylori infection.[13]
History
Its existence was first suggested in 1905 by the British physiologist John Sydney Edkins,[14][15] and gastrins were isolated in 1964 by Roderic Alfred Gregory at the University of Liverpool.[16] In 1964 the structure of gastrin was determined.[17]
References
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ Lund T, Geurts van Kessel AH, Haun S, Dixon JE (May 1986). "The genes for human gastrin and cholecystokinin are located on different chromosomes". Human Genetics. 73 (1): 77–80. PMID 3011648. doi:10.1007/BF00292669.
- ↑ Feng J, Petersen CD, Coy DH, Jiang JK, Thomas CJ, Pollak MR, Wank SA (October 2010). "Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion". Proceedings of the National Academy of Sciences of the United States of America. 107 (41): 17791–6. PMC 2955134
. PMID 20876097. doi:10.1073/pnas.1009078107. - ↑ Holst JJ, Orskov C, Seier-Poulsen S (1992). "Somatostatin is an essential paracrine link in acid inhibition of gastrin secretion". Digestion. 51 (2): 95–102. PMID 1354190. doi:10.1159/000200882.
- ↑ Johnson LR (March 1984). "Effects of somatostatin and acid on inhibition of gastrin release in newborn rats". Endocrinology. 114 (3): 743–6. PMID 6141932. doi:10.1210/endo-114-3-743.
- ↑ Tortora, G. J., & Grabowski, S. R. (1996). Principles of anatomy and physiology. New York, NY: HarperCollins College. 14th Ed. Pg 906
- ↑ Vadokas B, Lüdtke FE, Lepsien G, Golenhofen K, Mandrek K (December 1997). "Effects of gastrin-releasing peptide (GRP) on the mechanical activity of the human ileocaecal region in vitro". Neurogastroenterology and Motility. 9 (4): 265–70. PMID 9430795. doi:10.1046/j.1365-2982.1997.d01-59.x.
- ↑ Valenzuela JE, Walsh JH, Isenberg JI (September 1976). "Effect of gastrin on pancreatic enzyme secretion and gallbladder emptying in man". Gastroenterology. 71 (3): 409–11. PMID 950091.
- ↑ Castell DO (February 1978). "Gastrin and lower esophageal sphincter tone". Archives of Internal Medicine. 138 (2): 196. PMID 626547. doi:10.1001/archinte.138.2.196.
- ↑ Henderson JM, Lidgard G, Osborne DH, Carter DC, Heading RC (February 1978). "Lower oesophageal sphincter response to gastrin--pharmacological or physiological?". Gut. 19 (2): 99–102. PMC 1411818 . PMID 631634. doi:10.1136/gut.19.2.99.
- ↑ Schiffmann R, Dwyer NK, Lubensky IA, Tsokos M, Sutliff VE, Latimer JS, Frei KP, Brady RO, Barton NW, Blanchette-Mackie EJ, Goldin E (February 1998). "Constitutive achlorhydria in mucolipidosis type IV". Proceedings of the National Academy of Sciences of the United States of America. 95 (3): 1207–12. PMC 18720 . PMID 9448310. doi:10.1073/pnas.95.3.1207.
- ↑ "Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause". www.medscape.com.
- ↑ Edkins JS (March 1906). "The chemical mechanism of gastric secretion". The Journal of Physiology. 34 (1–2): 133–44. PMC 1465807 . PMID 16992839. doi:10.1113/jphysiol.1906.sp001146.
- ↑ Modlin IM, Kidd M, Marks IN, Tang LH (February 1997). "The pivotal role of John S. Edkins in the discovery of gastrin". World Journal of Surgery. 21 (2): 226–34. PMID 8995084. doi:10.1007/s002689900221.
- ↑ Gregory RA, Tracy HJ (1964). "The constitution and properties of two gastrins extracted from hog antral mucosa: Part I the isolation of two gastrins from hog antral mucosa". Gut. 5 (2): 103–107. doi:10.1136/gut.5.2.103.
- ↑ Gregory H, Hardy PM, Jones DS, Kenner GW, Sheppard RC (December 1964). "The antral hormone gastrin. Structure of gastrin.". Nature. 204: 931–3. PMID 14248711. doi:10.1038/204931a0.
Further reading
- Rozengurt E, Walsh JH (2001). "Gastrin, CCK, signaling, and cancer". Annual Review of Physiology. 63: 49–76. PMID 11181948. doi:10.1146/annurev.physiol.63.1.49.
- Dockray GJ (December 2004). "Clinical endocrinology and metabolism. Gastrin". Best Practice & Research. Clinical Endocrinology & Metabolism. 18 (4): 555–68. PMID 15533775. doi:10.1016/j.beem.2004.07.003.
- Anlauf M, Garbrecht N, Henopp T, Schmitt A, Schlenger R, Raffel A, Krausch M, Gimm O, Eisenberger CF, Knoefel WT, Dralle H, Komminoth P, Heitz PU, Perren A, Klöppel G (September 2006). "Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features". World Journal of Gastroenterology. 12 (34): 5440–6. PMID 17006979. doi:10.3748/wjg.v12.i34.5440.
- Polosatov MV, Klimov PK, Masevich CG, Samartsev MA, Wünsch E (April 1979). "Interaction of synthetic human big gastrin with blood proteins of man and animals". Acta Hepato-Gastroenterologica. 26 (2): 154–9. PMID 463490.
- Fritsch WP, Hausamen TU, Scholten T (April 1977). "[Gastrointestinal hormones. I. Hormones of the gastrin group]". Zeitschrift Fur Gastroenterologie. 15 (4): 264–76. PMID 871064.
- Higashimoto Y, Himeno S, Shinomura Y, Nagao K, Tamura T, Tarui S (May 1989). "Purification and structural determination of urinary NH2-terminal big gastrin fragments". Biochemical and Biophysical Research Communications. 160 (3): 1364–70. PMID 2730647. doi:10.1016/S0006-291X(89)80154-8.
- Pauwels S, Najdovski T, Dimaline R, Lee CM, Deschodt-Lanckman M (June 1989). "Degradation of human gastrin and CCK by endopeptidase 24.11: differential behaviour of the sulphated and unsulphated peptides". Biochimica et Biophysica Acta. 996 (1–2): 82–8. PMID 2736261. doi:10.1016/0167-4838(89)90098-8.
- Lund T, Geurts van Kessel AH, Haun S, Dixon JE (May 1986). "The genes for human gastrin and cholecystokinin are located on different chromosomes". Human Genetics. 73 (1): 77–80. PMID 3011648. doi:10.1007/BF00292669.
- Kariya Y, Kato K, Hayashizaki Y, Himeno S, Tarui S, Matsubara K (1986). "Expression of human gastrin gene in normal and gastrinoma tissues". Gene. 50 (1–3): 345–52. PMID 3034736. doi:10.1016/0378-1119(86)90338-0.
- Gregory RA, Tracy HJ, Agarwal KL, Grossman MI (August 1969). "Aminoacid constitution of two gastrins isolated from Zollinger-Ellison tumour tissue". Gut. 10 (8): 603–8. PMC 1552899 . PMID 5822140. doi:10.1136/gut.10.8.603.
- Bentley PH, Kenner GW, Sheppard RC (February 1966). "Structures of human gastrins I and II". Nature. 209 (5023): 583–5. PMID 5921183. doi:10.1038/209583b0.
- Ito R, Sato K, Helmer T, Jay G, Agarwal K (August 1984). "Structural analysis of the gene encoding human gastrin: the large intron contains an Alu sequence". Proceedings of the National Academy of Sciences of the United States of America. 81 (15): 4662–6. PMC 391550 . PMID 6087340. doi:10.1073/pnas.81.15.4662.
- Wiborg O, Berglund L, Boel E, Norris F, Norris K, Rehfeld JF, Marcker KA, Vuust J (February 1984). "Structure of a human gastrin gene". Proceedings of the National Academy of Sciences of the United States of America. 81 (4): 1067–9. PMC 344765 . PMID 6322186. doi:10.1073/pnas.81.4.1067.
- Kato K, Hayashizaki Y, Takahashi Y, Himeno S, Matsubara K (December 1983). "Molecular cloning of the human gastrin gene". Nucleic Acids Research. 11 (23): 8197–203. PMC 326575 . PMID 6324077. doi:10.1093/nar/11.23.8197.
- Boel E, Vuust J, Norris F, Norris K, Wind A, Rehfeld JF, Marcker KA (May 1983). "Molecular cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication". Proceedings of the National Academy of Sciences of the United States of America. 80 (10): 2866–9. PMC 393933 . PMID 6574456. doi:10.1073/pnas.80.10.2866.
- Kato K, Himeno S, Takahashi Y, Wakabayashi T, Tarui S, Matsubara K (December 1983). "Molecular cloning of human gastrin precursor cDNA". Gene. 26 (1): 53–7. PMID 6689486. doi:10.1016/0378-1119(83)90035-5.
- Koh TJ, Wang TC (November 1995). "Molecular cloning and sequencing of the murine gastrin gene". Biochemical and Biophysical Research Communications. 216 (1): 34–41. PMID 7488110. doi:10.1006/bbrc.1995.2588.
- Rehfeld JF, Hansen CP, Johnsen AH (January 1995). "Post-poly(Glu) cleavage and degradation modified by O-sulfated tyrosine: a novel post-translational processing mechanism". The EMBO Journal. 14 (2): 389–96. PMC 398093 . PMID 7530658.
- Rehfeld JF, Johnsen AH (August 1994). "Identification of gastrin component I as gastrin-71. The largest possible bioactive progastrin product". European Journal of Biochemistry. 223 (3): 765–73. PMID 8055952. doi:10.1111/j.1432-1033.1994.tb19051.x.
- Varro A, Dockray GJ (November 1993). "Post-translational processing of progastrin: inhibition of cleavage, phosphorylation and sulphation by brefeldin A". The Biochemical Journal. 295 (Pt 3): 813–9. PMC 1134634 . PMID 8240296. doi:10.1042/bj2950813.
External links
- Overview at colostate.edu
- Physiology: 6/6ch4/s6ch4_14 - Essentials of Human Physiology