Gastrin

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.

GAST
Identifiers
AliasesGAST, GAS, gastrin
External IDsOMIM: 137250 MGI: 104768 HomoloGene: 628 GeneCards: GAST
Gene location (Human)
Chr.Chromosome 17 (human)[1]
Band17q21.2Start41,712,331 bp[1]
End41,715,969 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

2520

14459

Ensembl

ENSG00000184502

ENSMUSG00000017165

UniProt

P01350

P48757

RefSeq (mRNA)

NM_000805

NM_010257

RefSeq (protein)

NP_000796

NP_034387

Location (UCSC)Chr 17: 41.71 – 41.72 MbChr 11: 100.33 – 100.34 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Gastrin
Identifiers
SymbolGastrin
PfamPF00918
InterProIPR001651
PROSITEPDOC00232

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).[5]

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. The encoded polypeptide is preprogastrin, which is cleaved by enzymes in posttranslational modification to produce progastrin (an intermediate, inactive precursor) and then gastrin in various forms, primarily the following three:

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:

Gastrin release is inhibited by:[8][9]

Function
G cell is visible near bottom left, and gastrin is labeled as the two black arrows leading from it. Note: this diagram does not illustrate gastrin's stimulatory effect on ECL cells.

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.[10]

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.[11]
  • Plays a role in the relaxation of the ileocecal valve.[12]
  • Induces pancreatic secretions and gallbladder emptying.[13]
  • May impact lower esophageal sphincter (LES) tone, causing it to contract,[14] - although pentagastrin, rather than endogenous gastrin, may be the cause.[15]
  • Gastrin contributes to the gastrocolic reflex.

Factors influencing secretion

Factors influencing secretion of gastrin can be divided into 2 categories:[16]

Physiologic
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
Circulation

Pathophysiologic
Paraneoplastic

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.[17]

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.[18] Additionally, elevated gastrin levels may be present in chronic gastritis resulting from H pylori infection.[19]

History

Its existence was first suggested in 1905 by the British physiologist John Sydney Edkins,[20][21] and gastrins were isolated in 1964 by Hilda Tracy and Roderic Alfred Gregory at the University of Liverpool.[22] In 1964 the structure of gastrin was determined.[23]

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References
  1. GRCh38: Ensembl release 89: ENSG00000184502 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000017165 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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. doi:10.1007/BF00292669. PMID 3011648.
  6. Blanco, Antonio; Blanco, Gustavo (2017), "Biochemical Bases of Endocrinology (II) Hormones and Other Chemical Intermediates", Medical Biochemistry, Elsevier, pp. 573–644, doi:10.1016/b978-0-12-803550-4.00026-4, ISBN 9780128035504
  7. 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. doi:10.1073/pnas.1009078107. PMC 2955134. PMID 20876097.
  8. 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. doi:10.1159/000200882. PMID 1354190.
  9. Johnson LR (March 1984). "Effects of somatostatin and acid on inhibition of gastrin release in newborn rats". Endocrinology. 114 (3): 743–6. doi:10.1210/endo-114-3-743. PMID 6141932. Archived from the original on 2008-09-05. Retrieved 2011-05-17.
  10. Lindström, E.; Chen, D.; Norlén, P.; Andersson, K.; Håkanson, R. (2001). "Control of gastric acid secretion:the gastrin-ECL cell-parietal cell axis". Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology. 128 (3): 505–514. doi:10.1016/s1095-6433(00)00331-7. ISSN 1095-6433. PMID 11246041.
  11. Tortora, G. J., & Grabowski, S. R. (1996). Principles of anatomy and physiology. New York, NY: HarperCollins College. 14th Ed. Pg 906
  12. 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. doi:10.1046/j.1365-2982.1997.d01-59.x. PMID 9430795.
  13. 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. doi:10.1016/S0016-5085(76)80445-3. PMID 950091.
  14. Castell DO (February 1978). "Gastrin and lower esophageal sphincter tone". Archives of Internal Medicine. 138 (2): 196. doi:10.1001/archinte.138.2.196. PMID 626547.
  15. 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. doi:10.1136/gut.19.2.99. PMC 1411818. PMID 631634.
  16. Indu Khurana (2006). Textbook medical physiology. New Delhi: Reed Elsevier India. p. 605. ISBN 978-8181478504. OCLC 968478170.
  17. Baron, J. H. (1978). Clinical Tests of Gastric Secretion. doi:10.1007/978-1-349-03188-7. ISBN 978-1-349-03190-0.
  18. 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. doi:10.1073/pnas.95.3.1207. PMC 18720. PMID 9448310.
  19. "Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause". www.medscape.com.
  20. Edkins JS (March 1906). "The chemical mechanism of gastric secretion". The Journal of Physiology. 34 (1–2): 133–44. doi:10.1113/jphysiol.1906.sp001146. PMC 1465807. PMID 16992839.
  21. 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. doi:10.1007/s002689900221. PMID 8995084.
  22. 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. PMC 1552180. PMID 14159395.
  23. Gregory H, Hardy PM, Jones DS, Kenner GW, Sheppard RC (December 1964). "The antral hormone gastrin. Structure of gastrin". Nature. 204 (4962): 931–3. doi:10.1038/204931a0. PMID 14248711.

Further reading
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