Biology:Secretin

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Short description: Hormone involved in stomach, pancreas and liver secretions

Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands.[1] In humans, the secretin peptide is encoded by the SCT gene.[2] Secretin helps regulate the pH of the duodenum by inhibiting the secretion of gastric acid from the parietal cells of the stomach and stimulating the production of bicarbonate from the ductal cells of the pancreas.[3][4] It also stimulates the secretion of bicarbonate and water by cholangiocytes in the bile duct, protecting it from bile acids by controlling the pH and promoting the flow in the duct.[5] Meanwhile, in concert with secretin's actions, the other main hormone simultaneously issued by the duodenum, cholecystokinin (CCK), stimulates the gallbladder to contract, delivering its stored bile.

Prosecretin is a precursor to secretin, which is present in digestion. Secretin is stored in this unusable form, and is activated by gastric acid. This indirectly results in the neutralisation of duodenal pH, thus ensuring no damage is done to the small intestine by the aforementioned acid.[6]

In 2007, secretin was discovered to play a role in osmoregulation by acting on the hypothalamus, pituitary gland, and kidney.[7][8]

History

In 1902, William Bayliss and Ernest Starling were studying how the nervous system controls the process of digestion.[9] It was known that the pancreas secreted digestive juices in response to the passage of food (chyme) through the pyloric sphincter into the duodenum. They discovered (by cutting all the nerves to the pancreas in their experimental animals) that this process was not, in fact, governed by the nervous system. They determined that a substance secreted by the intestinal lining stimulates the pancreas after being transported via the bloodstream. They named this intestinal secretion secretin. This type of 'chemical messenger' substance is now called a hormone, a term coined by Starling in 1905.[10]

Secretin is frequently erroneously stated to have been the first hormone identified.[11] However, British researchers George Oliver and Edward Albert Schäfer had already published their findings of an adrenal extract increasing blood pressure and heart rate in brief reports in 1894 and a full publication in 1895, making adrenaline the first discovered hormone.[12][13]

Structure

Secretin is initially synthesized as a 120 amino acid precursor protein known as prosecretin. This precursor contains an N-terminal signal peptide, spacer, secretin itself (residues 28–54), and a 72-amino acid C-terminal peptide.[2]

The mature secretin peptide is a linear peptide hormone, which is composed of 27 amino acids and has a molecular weight of 3055. A helix is formed in the amino acids between positions 5 and 13. The amino acids sequences of secretin have some similarities to that of glucagon, vasoactive intestinal peptide (VIP), and gastric inhibitory peptide (GIP). Fourteen of 27 amino acids of secretin reside in the same positions as in glucagon, 7 the same as in VIP, and 10 the same as in GIP.[14]

Secretin also has an amidated carboxyl-terminal amino acid which is valine.[15] The sequence of amino acids in secretin is H–His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Glu-Leu-Ser-Arg-Leu-Arg-Asp-Ser-Ala-Arg-Leu-Gln-Arg-Leu-Leu-Gln-Gly-Leu-Val–NH2.[15]

Physiology

Production and secretion

Secretin is synthesized in cytoplasmic secretory granules of S-cells, which are found mainly in the mucosa of the duodenum, and in smaller numbers in the jejunum of the small intestine.[16]

Secretin is released into circulation and/or intestinal lumen in response to low duodenal pH that ranges between 2 and 4.5 depending on species; the acidity is due to hydrochloric acid in the chyme that enters the duodenum from the stomach via the pyloric sphincter.[17] Also, the secretion of secretin is increased by the products of protein digestion bathing the mucosa of the upper small intestine.[18]

Secretin release is inhibited by H2 antagonists, which reduce gastric acid secretion. As a result, if the pH in the duodenum increases above 4.5, secretin cannot be released.[19]

Function

pH regulation

Secretin primarily functions to neutralize the pH in the duodenum, allowing digestive enzymes from the pancreas (e.g., pancreatic amylase and pancreatic lipase) to function optimally.[20]

Secretin targets the pancreas; pancreatic centroacinar cells have secretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and converts ATP to cyclic AMP.[21] Cyclic AMP acts as second messenger in intracellular signal transduction and causes the organ to secrete a bicarbonate-rich fluid that flows into the intestine. Bicarbonate is a base that neutralizes the acid, thus establishing a pH favorable to the action of other digestive enzymes in the small intestine.[22]

Secretin also increases water and bicarbonate secretion from duodenal Brunner's glands to buffer the incoming protons of the acidic chyme,[20] and also reduces acid secretion by parietal cells of the stomach.[23] It does this through at least three mechanisms: 1) By stimulating release of somatostatin, 2) By inhibiting release of gastrin in the pyloric antrum, and 3) By direct downregulation of the parietal cell acid secretory mechanics.[24][17]

It counteracts blood glucose concentration spikes by triggering increased insulin release from pancreas, following oral glucose intake.[25]

Osmoregulation

Secretin modulates water and electrolyte transport in pancreatic duct cells,[26] liver cholangiocytes,[27] and epididymis epithelial cells.[28] It is found[29] to play a role in the vasopressin-independent regulation of renal water reabsorption.[7]

Secretin is found in the magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and along the neurohypophysial tract to neurohypophysis. During increased osmolality, it is released from the posterior pituitary. In the hypothalamus, it activates vasopressin release.[8] It is also needed to carry out the central effects of angiotensin II. In the absence of secretin or its receptor in the gene knockout animals, central injection of angiotensin II was unable to stimulate water intake and vasopressin release.[30]

It has been suggested that abnormalities in such secretin release could explain the abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).[8] In these individuals, vasopressin release and response are normal, although abnormal renal expression, translocation of aquaporin 2, or both are found.[8] It has been suggested that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades."[8]

Food intake

Secretin and its receptor are found in discrete nuclei of the hypothalamus, including the paraventricular nucleus and the arcuate nucleus, which are the primary brain sites for regulating body energy homeostasis. It was found that both central and peripheral injection of Sct reduce food intake in mouse, indicating an anorectic role of the peptide. This function of the peptide is mediated by the central melanocortin system.[31]

Uses

Secretin is used in a diagnostic tests for pancreatic function; secretin is injected and the pancreatic output can then be imaged with magnetic resonance imaging, a noninvasive procedure, or secretions generated as a result can gathered either through an endoscope or through tubes inserted through the mouth, down into the duodenum.[32][33][34]

A recombinant human secretin has been available since 2004 for these diagnostic purposes.[35] There were problems with the availability of this agent from 2012 to 2015.[36]

Research

A wave of enthusiasm for secretin as a possible treatment for autism arose in the 1990s based on a hypothetical gut-brain connection; as a result the NIH ran a series of clinical trials that showed that secretin was not effective, which brought an end to popular interest.[37][38][39]

A high-affinity and optimized secretin receptor antagonist (Y10,c[E16,K20],I17,Cha22,R25)sec(6-27) has been designed and developed which has allowed the structural characterization of secreting inactive conformation.[40]

See also

References

  1. ↑ "Secretin". Clinics in Gastroenterology 9 (3): 609–632. September 1980. doi:10.1016/S0300-5089(21)00474-0. PMID 7000396. 
  2. ↑ 2.0 2.1 "Secretin: structure of the precursor and tissue distribution of the mRNA". Proceedings of the National Academy of Sciences of the United States of America 87 (6): 2299–2303. March 1990. doi:10.1073/pnas.87.6.2299. PMID 2315322. Bibcode: 1990PNAS...87.2299K. 
  3. ↑ "Human secretin (SCT): gene structure, chromosome location, and distribution of mRNA". Cytogenetics and Cell Genetics 90 (1–2): 47–52. 2000. doi:10.1159/000015658. PMID 11060443. 
  4. ↑ Costanzo, Linda S. (2006). Physiology (3rd ed.). Philadelphia, PA: Saunders Elsevier. ISBN 9781416023203. OCLC 62326921. 
  5. ↑ "Cholangiocyte pathobiology". Nature Reviews. Gastroenterology & Hepatology 16 (5): 269–281. May 2019. doi:10.1038/s41575-019-0125-y. PMID 30850822. 
  6. ↑ "Processing of prosecretin: isolation of a secretin precursor from porcine intestine". Proceedings of the National Academy of Sciences of the United States of America 87 (17): 6781–6785. September 1990. doi:10.1073/pnas.87.17.6781. PMID 2395872. Bibcode: 1990PNAS...87.6781G. 
  7. ↑ 7.0 7.1 "Phenotypes developed in secretin receptor-null mice indicated a role for secretin in regulating renal water reabsorption". Molecular and Cellular Biology 27 (7): 2499–2511. April 2007. doi:10.1128/MCB.01088-06. PMID 17283064. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Secretin as a neurohypophysial factor regulating body water homeostasis". Proceedings of the National Academy of Sciences of the United States of America 106 (37): 15961–15966. September 2009. doi:10.1073/pnas.0903695106. PMID 19805236. Bibcode: 2009PNAS..10615961C. 
  9. ↑ "The mechanism of pancreatic secretion". The Journal of Physiology 28 (5): 325–353. September 1902. doi:10.1113/jphysiol.1902.sp000920. PMID 16992627. 
  10. ↑ "Secretin and the exposition of hormonal control". The Journal of Physiology 560 (Pt 2): 339. October 2004. doi:10.1113/jphysiol.2004.073056. PMID 15308687. 
  11. ↑ "[Secretin--the first hormone]" (in da). Ugeskrift for Laeger 164 (3): 320–325. January 2002. INIST:13419424. PMID 11816326. 
  12. ↑ "The Physiological Effects of Extracts of the Suprarenal Capsules". The Journal of Physiology 18 (3): 230–276. July 1895. doi:10.1113/jphysiol.1895.sp000564. PMID 16992252. 
  13. ↑ "The Physiological Effects of Extracts of the Suprarenal Capsules". The Journal of Physiology 18 (3): 230–276. July 1895. doi:10.1113/jphysiol.1895.sp000564. PMID 16992252. 
  14. ↑ Textbook of Endocrinology. Philadelphia: Saunders. 1981. p. 697. ISBN 978-0-7216-9398-9. https://archive.org/details/textbookofendocre6will/page/697. 
  15. ↑ 15.0 15.1 Endocrinology. Philadelphia: Saunders. 1989. pp. 2748. ISBN 978-0-7216-2888-2. https://archive.org/details/endocrinology0002unse/page/2748. 
  16. ↑ "Immunofluorescent localization of secretin and enteroglucagon in human intestinal mucosa". Scandinavian Journal of Gastroenterology 6 (8): 739–744. 1971. doi:10.3109/00365527109179946. PMID 4945081. 
  17. ↑ 17.0 17.1 "Gastrointestinal Hormones and Carcinoid Syndrome". Endocrinology & metabolism. New York: McGraw-Hill, Medical Pub. Div. 2001. pp. 1675–701. ISBN 978-0-07-022001-0. 
  18. ↑ "Regulation of Gastrointestinal Function". Review of Medical Physiology (21st ed.). New York: McGraw-Hill, Medical Pub. Div. 2003. ISBN 978-0-07-140236-1. [page needed]
  19. ↑ "Plasma secretin concentrations and gastric pH in healthy subjects and patients with digestive diseases". Digestive Diseases and Sciences 26 (7): 591–597. July 1981. doi:10.1007/BF01367670. PMID 7249893. 
  20. ↑ 20.0 20.1 Textbook of medical physiology. St. Louis, Mo: Elsevier Saunders. 2006. pp. 800–1. ISBN 978-0-7216-0240-0. 
  21. ↑ "Receptors and gastrointestinal hormones". Gastrointestinal Disease (2nd ed.). Philadelphia: WB Saunders Company. 1978. pp. 179–95. 
  22. ↑ "Exocrine pancreatic secretion and immunoreactive secretin (IRS) release after intraduodenal instillation of bile in man". Gut 19 (3): 180–184. March 1978. doi:10.1136/gut.19.3.180. PMID 631638. 
  23. ↑ "Alimentary track and pancreatic disease". Davidson's Principles and Practice of Medicine (20th ed.). Edinburgh: Churchill Livingstone. 2010. p. 844. ISBN 978-0-7020-3085-7. 
  24. ↑ "Acid secretion". Medical Physiology (2nd ed.). Philadelphia: Saunders. 2012. p. 1352. ISBN 978-1-4377-1753-2. 
  25. ↑ "The gastrointestinal stimulus to insulin release. II. A dual action of secretin". The Journal of Clinical Investigation 49 (3): 524–529. March 1970. doi:10.1172/JCI106262. PMID 5415678. 
  26. ↑ "Secretin causes H+/HCO3- secretion from pig pancreatic ductules by vacuolar-type H(+)-adenosine triphosphatase". Gastroenterology 108 (3): 850–859. March 1995. doi:10.1016/0016-5085(95)90460-3. PMID 7875488. 
  27. ↑ "Secretin promotes osmotic water transport in rat cholangiocytes by increasing aquaporin-1 water channels in plasma membrane. Evidence for a secretin-induced vesicular translocation of aquaporin-1". The Journal of Biological Chemistry 272 (20): 12984–12988. May 1997. doi:10.1074/jbc.272.20.12984. PMID 9148905. 
  28. ↑ "Secretin controls anion secretion in the rat epididymis in an autocrine/paracrine fashion". Biology of Reproduction 70 (6): 1594–1599. June 2004. doi:10.1095/biolreprod.103.024257. PMID 14749298. 
  29. ↑ "Vasopressin-independent mechanisms in controlling water homeostasis". Journal of Molecular Endocrinology 43 (3): 81–92. September 2009. doi:10.1677/JME-08-0123. PMID 19318428. 
  30. ↑ "An indispensable role of secretin in mediating the osmoregulatory functions of angiotensin II". FASEB Journal 24 (12): 5024–5032. December 2010. doi:10.1096/fj.10-165399. PMID 20739612. 
  31. ↑ "Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system". Neuropsychopharmacology 36 (2): 459–471. January 2011. doi:10.1038/npp.2010.178. PMID 20927047. 
  32. ↑ "Pancreatic function testing: here to stay for the 21st century". World Journal of Gastroenterology 14 (20): 3149–3158. May 2008. doi:10.3748/WJG.14.3149. PMID 18506918. 
  33. ↑ "Diagnosis of chronic pancreatitis: Functional testing". Best Practice & Research. Clinical Gastroenterology 24 (3): 233–241. June 2010. doi:10.1016/j.bpg.2010.03.008. PMID 20510825. 
  34. ↑ "Secretin stimulation test". MedlinePlus Medical Encyclopedia. United States National Library of Medicine. https://www.nlm.nih.gov/medlineplus/ency/article/003892.htm#Definition. Retrieved 2008-11-01. 
  35. ↑ "Human Secretin". Patient Information Sheets. United States Food and Drug Administration. 2004-07-13. https://www.fda.gov/cder/consumerinfo/druginfo/Human_Secretin.HTM. 
  36. ↑ American Society of Health-System Pharmacists (5 August 2015). "Secretin Injection". Current Drug Shortage Bulletin. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=913. Retrieved 9 November 2016. 
  37. ↑ "News this Week: Stalled Trial for Autism Highlights Dilemma of Alternative Treatments" (in en). Science: pp. 324. 18 July 2008. http://science.sciencemag.org/content/321/5887/news-summaries. 
  38. ↑ "The Use of Secretin to Treat Autism". NIH News Alert. United States National Institutes of Health. 1998-10-16. http://www.nichd.nih.gov/news/releases/secretin.cfm. 
  39. ↑ "Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder". The New England Journal of Medicine 341 (24): 1801–1806. December 1999. doi:10.1056/NEJM199912093412404. PMID 10588965. 
  40. ↑ "Rational development of a high-affinity secretin receptor antagonist". Biochemical Pharmacology 177: 113929. July 2020. doi:10.1016/j.bcp.2020.113929. PMID 32217097. 

Further reading

External links



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