Gastrin

Digestive system, Gastrin, Somatostatin, Stomach

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).
- ^{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. S2CID 32216320.}

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:

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. Aromatic amino acids are particularly powerful stimuli for gastrin release.
- ^{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}
hypercalcemia (via calcium-sensing receptors)
- ^{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. Bibcode:2010PNAS..10717791F. doi:10.1073/pnas.1009078107. PMC 2955134. PMID 20876097.}

Gastrin release is inhibited by:

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.
- ^{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.}
- ^{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.}

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.

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^{[failed verification]} 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.
- ^{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.}

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.
- ^{Tortora, G. J., & Grabowski, S. R. (1996). Principles of anatomy and physiology. New York, NY: HarperCollins College. 14th Ed. Pg 906}
Plays a role in the relaxation of the ileocecal valve.
- ^{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. S2CID 31858033}
Induces pancreatic secretions and gallbladder emptying.
- ^{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}
May impact lower esophageal sphincter (LES) tone, causing it to contract,
- ^{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.}
– although pentagastrin, rather than endogenous gastrin, may be the cause.
- ^{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}
Gastrin contributes to the gastrocolic reflex.

Factors influencing secretion

Factors influencing secretion of gastrin can be divided into 2 categories:
- ^{Indu Khurana (2006). Textbook medical physiology. New Delhi: Reed Elsevier India. p. 605. ISBN 978-8181478504. OCLC 968478170.}

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

Stimulatory factors: Beta-adrenergic agents, cholinergic agents, gastrin-releasing peptide (GRP)
Inhibitory factor: Enterogastric reflex

Circulation

Stimulatory factor: gastrin
Inhibitory factors:gastric inhibitory peptide (GIP), secretin, somatostatin, glucagon, calcitonin

Pathophysiologic

Paraneoplastic

Gastrinoma paraneoplastic oversecretion (see Role in disease)

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.
- ^{Baron, J. H. (1978). Clinical Tests of Gastric Secretion. doi:10.1007/978-1-349-03188-7. ISBN 978-1-349-03190-0.}
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.
- ^{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. Bibcode:1998PNAS…95.1207S. doi:10.1073/pnas.95.3.1207. PMC 18720. PMID 9448310}
Additionally, elevated gastrin levels may be present in chronic gastritis resulting from H pylori infection.
- ^{“Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause”. www.medscape.com.}

History

Its existence was first suggested in 1905 by the British physiologist John Sydney Edkins,
- ^{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.}
- ^{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. S2CID 28243696}
- John Sydney Edkins
  - Progastrin
    - In 1905, John Sydney Edkins demonstrated the existence of a hormone responsible for the secretion of gastric acid.
      - ^{Modlin, Irvin M.; Kidd, Mark; Marks, I. N.; Tang, Laura H. (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. ISSN 0364-2313. PMID 8995084. S2CID 28243696.}
    - This hormone was named gastric secretin or gastrin. But it was not until 1979 and later in 1987 and 1988 that progastrin was identified as the precursor to gastrin.
      - ^{Noyes, B. E.; Mevarech, M.; Stein, R.; Agarwal, K. L. (1979-04-01). “Detection and partial sequence analysis of gastrin mRNA by using an oligodeoxynucleotide probe”. Proceedings of the National Academy of Sciences. 76 (4): 1770–4. Bibcode:1979PNAS…76.1770N. doi:10.1073/pnas.76.4.1770. ISSN 0027-8424. PMC 383472. PMID 88048.}
      - ^{Desmond, H.; Pauwels, S.; Varro, A.; Gregory, H. (1987-01-05). “Isolation and characterization of the intact gastrin precursor from a gastrinoma”. FEBS Letters. 210 (2): 185–8. doi:10.1016/0014-5793(87)81334-0. PMID 3792562. S2CID 20561440.}
      - ^{“Announcements”. Regulatory Peptides. 34 (1): 71–72. 1991. doi:10.1016/0167-0115(91)90226-7. ISSN 0167-0115. S2CID 208789664.}
    - His protein sequence and mRNA were revealed.
    - Not to be confused with progastrin, Pro-Gastrin-Releasing-Peptide is the precursor of Gastrin-releasing peptide (GRP), a neuropeptide which belongs to the bombesin/neuromedin B family and whose expression is important in the intestine and brain. GRP is involved in many physiological and pathophysiological processes.
      - ^{You, Benoit; Mercier, Frédéric; Assenat, Eric; Langlois-Jacques, Carole; Glehen, Olivier; Soulé, Julien; Payen, Léa; Kepenekian, Vahan; Dupuy, Marie; Belouin, Fanny; Morency, Eric (January 2020). “The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients”. EBioMedicine. 51: 102574. doi:10.1016/j.ebiom.2019.11.035. PMC 6938867. PMID 31877416.}
    - Gastrin-Releasing Peptide stimulates the release of gastrin and other gastrointestinal hormones. It helps regulate food intake. There are also two types of progastrin, the intracellular progastrin discussed in this article and the extracellular progastrin, mainly called hPG80.
      - ^{Benoit You, Frédéric Mercier, Eric Assenat; Alexandre Prieur; Léa Payen, Vahan Kepenekian, Marie Dupuy; Fanny Belouin, Eric Morency (January 2020). “The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients”. EBioMedicine. 51: 102574. doi:10.1016/j.ebiom.2019.11.035. PMC 6938867. PMID 31877416.}

and gastrins were isolated in 1964 by Hilda Tracy and Roderic Alfred Gregory at the University of Liverpool.
- ^{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. PMC1552180. PMID14159395}
- Hilda Tracy and Roderic Alfred Gregory
  - Author or co-author of over 32 scientific publications. They included:
    - R.A. Gregory and Tracy, H.J., French, J.M. and Sircus, W. Extraction of a gastrin-like substance from a pancreatic tumour in a case of Zollinger-Ellison syndrome. Lancet, 1, 1045 – 1048 (1960)
    - Grossman, M.I., Tracy, H.J., and Gregory R.A. Zollinger-Ellison syndrome in a Bantu woman, with isolation of a gastrin-like substance from primary and secondary tumors. 2. Extraction of gastrin-like activity from tumors. Gastroenterology 41 87- (1961)
    - R.A. Gregory and Hilda J. Tracy. Preparation and properties of gastrin. J Physiology (London) 156 523 – 543 (1961)
    - Stanley R. Friesen, Tracy, Hilda J., and Gregory, R. A. Mechanism of the gastric hypersection in the Zollinger-Ellison Syndrome: successful extraction of gastrin-like activity from metastases and primary pancreatico-duodenal islet cell carcinoma. Annals of Surgery, 155(2): 167–174. (1962)
    - Hilda J. Tracy and Gregory, R. A. The antral Hormone Gastrin: Physiological Properties of a Series of Synthetic Peptides structurally related to Gastrin I. Nature, 204, 935 – 938 (1964)
    - R.A. Gregory and Hilda J. Tracy. 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, 103 – 107 (1964)
    - R.A. Gregory and Hilda J. Tracy. The constitution and properties of two gastrins extracted from hog antral mucosa. Part II The properties of two gastrins isolated from hog antral mucosa. Gut 5, 107 – 117 (1964)
    - R.A. Gregory and Hilda J, Tracy, Note on nature of gastrin-like stimulant present in Zollinger-Ellison tumours. Gut 5 115 – (1964)
    - J.S. Morley, Tracy, Hilda J., and Gregory, R. A. Structure–Function Relationships in the Active C-Terminal Tetrapeptide Sequence of Gastrin. Nature, 207, 1356 – 1359 (1965).
    - R.A. Gregory, Tracy, Hilda J., and Grossman, Morton I. Human Gastrin: Isolation, Structure and Synthesis. Nature, 209, 583 (5 February 1966)
    - R.A. Gregory and Hilda J. Tracy. Isolation of 2 big-gastrins from Zollinger-Ellison tumor tissue. Lancet 2 (7781) 797 – 799 (1972)
    - G.J. Dockray and Hilda J. Tracy. Atropine does not abolish cephalic vagal stimulation of gastrin release in dogs. J. Physiol., 306, 473–480 (1980)
    - G.J. Dockray, Gregory, R.A., Tracy, H.J. and Wen-Yu Zhu. Transport of cholecystokinin-octapeptide-like immunoreactivity toward the gut in afferent vagal fibers in cat and dog. J Physiology (London) 314 501 – 511 (1981)

In 1964 the structure of gastrin was determined.
- ^{Gregory H, Hardy PM, Jones DS, Kenner GW, Sheppard RC (December 1964). “The antral hormone gastrin. Structure of gastrin”. Nature. 204 (4962): 931–3. Bibcode:1964Natur.204..931G. doi:10.1038/204931a0. PMID 14248711. S2CID 4262131.}

External links

Overview at colostate.edu
Nosek, Thomas M. “Section 6/6ch4/s6ch4_14”. Essentials of Human Physiology. Archived from the original on 2016-03-24.

Physiology of the gastrointestinal system

Hormones

Peptides: neuropeptides

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From Wikipedia where the main page was last updated April 8, 2022

Gastrin