Secretin helps regulate thepH of the duodenum by inhibiting the secretion ofgastric acid from theparietal cells of the stomach and stimulating the production ofbicarbonate from theductal cells of the pancreas.[7][8] It also stimulates the secretion of bicarbonate and water bycholangiocytes in the bile duct, protecting it frombile acids by controlling the pH and promoting the flow in the duct.[9] Meanwhile, in concert with secretin's actions, the other main hormone simultaneously issued by the duodenum,cholecystokinin (CCK), stimulates thegallbladder 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 bygastric acid. This indirectly results in the neutralisation of duodenal pH, thus ensuring no damage is done to the small intestine by the aforementioned acid.[10]
In 1902,William Bayliss andErnest Starling were studying how the nervous system controls the process of digestion.[13] It was known that thepancreas secreted digestive juices in response to the passage of food (chyme) through thepyloric 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 secretionsecretin. This type of 'chemical messenger' substance is now called ahormone, a term coined by Starling in 1905.[14]
Secretin is frequently erroneously stated to have been the first hormone identified.[15] However, British researchersGeorge Oliver andEdward 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, makingadrenaline the first discovered hormone.[16][17]
Secretin is initially synthesized as a 120 amino acid precursor protein known asprosecretin. This precursor contains anN-terminal signal peptide, spacer, secretin itself (residues 28–54), and a 72-amino acidC-terminal peptide.[6]
The mature secretin peptide is a linearpeptide hormone, which is composed of 27amino acids and has amolecular 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 ofglucagon,vasoactive intestinal peptide (VIP), andgastric 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.[18]
Secretin is synthesized in cytoplasmic secretory granules of S-cells, which are found mainly in themucosa of theduodenum, and in smaller numbers in thejejunum of thesmall intestine.[20]
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 tohydrochloric acid in thechyme that enters the duodenum from the stomach via thepyloric sphincter.[21] Also, the secretion of secretin is increased by the products of protein digestion bathing the mucosa of the upper small intestine.[22]
Secretin release is inhibited byH2 antagonists, which reduce gastric acid secretion. As a result, if the pH in the duodenum increases above 4.5, secretin cannot be released.[23]
Secretin targets thepancreas; pancreatic centroacinar cells havesecretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and convertsATP tocyclic AMP.[25] Cyclic AMP acts as second messenger in intracellular signal transduction and causes the organ to secrete abicarbonate-rich fluid that flows into theintestine. Bicarbonate is a base that neutralizes the acid, thus establishing a pH favorable to the action of other digestive enzymes in the small intestine.[26]
Secretin also increases water and bicarbonate secretion from duodenalBrunner's glands to buffer the incomingprotons of the acidic chyme,[24] and also reduces acid secretion byparietal cells of thestomach.[27] It does this through at least three mechanisms: 1) By stimulating release ofsomatostatin, 2) By inhibiting release ofgastrin in thepyloric antrum, and 3) By directdownregulation of the parietal cell acid secretory mechanics.[28][21]
It counteractsblood glucose concentration spikes by triggering increasedinsulin release from pancreas, following oralglucose intake.[29]
Secretin is found in the magnocellular neurons of the paraventricular and supraoptic nuclei of thehypothalamus and along the neurohypophysial tract toneurohypophysis. During increased osmolality, it is released from theposterior pituitary. In the hypothalamus, it activatesvasopressin release.[12] 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.[34]
It has been suggested that abnormalities in such secretin release could explain the abnormalities underlying type Dsyndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).[12] In these individuals, vasopressin release and response are normal, although abnormal renal expression, translocation ofaquaporin 2, or both are found.[12] 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."[12]
Secretin and its receptor are found in discrete nuclei of the hypothalamus, including theparaventricular nucleus and thearcuate 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 thecentral melanocortin system.[35]
Secretin is used in diagnostic tests for pancreatic function; secretin is injected and the pancreatic output can then be imaged withmagnetic 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.[36][37][38]
A recombinant human secretin has been available since 2004 for these diagnostic purposes.[39] There were problems with the availability of this agent from 2012 to 2015.[40]
A wave of enthusiasm for secretin as a possible treatment forautism 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.[41][42][43]
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.[44]
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^Chow BK, Cheung KH, Tsang EM, Leung MC, Lee SM, Wong PY (June 2004). "Secretin controls anion secretion in the rat epididymis in an autocrine/paracrine fashion".Biology of Reproduction.70 (6):1594–1599.doi:10.1095/biolreprod.103.024257.PMID14749298.S2CID1189550.
^Domínguez Muñoz JE (June 2010). "Diagnosis of chronic pancreatitis: Functional testing".Best Practice & Research. Clinical Gastroenterology.24 (3):233–241.doi:10.1016/j.bpg.2010.03.008.PMID20510825.
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