- Rodger A Liddle, MD
Rodger A Liddle, MD
- Professor of Medicine
- Duke University Medical School
The field of endocrinology and the study of "hormones" began at the turn of the 20th century when Bayliss and Starling described a chemical substance in intestinal extracts that, when injected intravenously, stimulated pancreatic secretion . They named this substance secretin because it caused the pancreas to secrete fluid when acid was present in the gut. This discovery led to a search for other chemical substances that when released from one tissue could excite or stimulate organ function in a different location. The Greek word "hormone," meaning "arise to activity," was used to designate these chemical messengers. It is now known that secretin stimulates pancreatic fluid and bicarbonate secretion leading to neutralization of acidic chyme in the intestine. Secretin also inhibits gastric acid release and intestinal motility.
Despite knowledge of physiological activity, it took more than 50 years for the chemical nature of the hormone secretin to be identified. The amino acid sequence was not determined until the 1960s . Human secretin is a 27 amino-acid peptide, with a molecular weight of 3055 D. Its sequence is conserved across many mammalian species (figure 1).
Similar to other gastrointestinal peptides, secretin is amidated at the C-terminus. It is the founding member of the secretin/glucagon/vasoactive intestinal polypeptide family of gastrointestinal hormones. The gene structure of preprosecretin contains an N-terminal signal peptide, a short peptide sequence, secretin, and a C-terminal extension peptide . The gene encoding secretin is selectively expressed in specialized enteroendocrine cells of the small intestine, called S cells. The details of secretin gene transcriptional control have been studied in secretin-producing islet cells .
Immunocytochemistry has demonstrated that secretin-producing cells are found along the small intestine (figure 2) . Other sites shown to produce secretin mRNA include the hypothalamus, cortex, cerebellum, and brainstem [3,6].
The secretin receptor is a member of the family of G protein-coupled receptors (GPCRs), within which the secretin/glucagon family is structurally unique. This group consists of receptors for secretin, glucagon, calcitonin, parathyroid hormone, pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal polypeptide, and others. These receptors lack structural signature sequences present in the rhodopsin/beta-adrenergic receptor family (such as a DRY motif — Asp-Arg-Tyr — at the end of the third transmembrane spanning domain), which appear to be important in receptor coupling to G proteins. Secretin binds to its specific heptahelical membrane receptor and activates the heterotrimeric G protein, Gs, leading to elevation of cellular cAMP levels. This second messenger begins the signaling cascade that initiates appropriate cell physiological responses. (See "Peptide hormone signal transduction and regulation".)
- Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902; 28:325.
- Mutt V, Jorpes JE, Magnusson S. Structure of porcine secretin. The amino acid sequence. Eur J Biochem 1970; 15:513.
- Kopin AS, Wheeler MB, Leiter AB. Secretin: structure of the precursor and tissue distribution of the mRNA. Proc Natl Acad Sci U S A 1990; 87:2299.
- Nishitani J, Rindi G, Lopez MJ, et al. Transcriptional regulation of secretin gene expression. J Clin Gastroenterol 1995; 21 Suppl 1:S50.
- Leiter AB, Chey WY, Kopin AS. Secretin, 1st ed, Raven Press, New York 1994.
- Lee SM, Yung WH, Chen L, Chow BK. Expression and spatial distribution of secretin and secretin receptor in human cerebellum. Neuroreport 2005; 16:219.
- Ozcelebi F, Holtmann MH, Rentsch RU, et al. Agonist-stimulated phosphorylation of the carboxyl-terminal tail of the secretin receptor. Mol Pharmacol 1995; 48:818.
- Shetzline MA, Premont RT, Walker JK, et al. A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor. J Biol Chem 1998; 273:6756.
- Walker JK, Premont RT, Barak LS, et al. Properties of secretin receptor internalization differ from those of the beta(2)-adrenergic receptor. J Biol Chem 1999; 274:31515.
- Li Y. Sensory signal transduction in the vagal primary afferent neurons. Curr Med Chem 2007; 14:2554.
- Körner M, Miller LJ. Alternative splicing of pre-mRNA in cancer: focus on G protein-coupled peptide hormone receptors. Am J Pathol 2009; 175:461.
- Schaffalitzky de Muckadell OB, Fahrenkrug J. Secretion pattern of secretin in man: regulation by gastric acid. Gut 1978; 19:812.
- Li P, Lee KY, Chang TM, Chey WY. Mechanism of acid-induced release of secretin in rats. Presence of a secretin-releasing peptide. J Clin Invest 1990; 86:1474.
- You CH, Rominger JM, Chey WY. Effects of atropine on the action and release of secretin in humans. Am J Physiol 1982; 242:G608.
- You CH, Chey WY. Secretin is an enterogastrone in humans. Dig Dis Sci 1987; 32:466.
- Boyer JL, Bloomer JR. Canalicular bile secretion in man. Studies utilizing the biliary clearance of (14C)mannitol. J Clin Invest 1974; 54:773.
- Dinoso VP Jr, Meshkinpour H, Lorber SH, et al. Motor responses of the sigmoid colon and rectum to exogenous cholecystokinin and secretin. Gastroenterology 1973; 65:438.
- Cohen S, Lipshutz W. Hormonal regulation of human lower esophageal sphincter competence: interaction of gastrin and secretin. J Clin Invest 1971; 50:449.
- Afroze S, Meng F, Jensen K, et al. The physiological roles of secretin and its receptor. Ann Transl Med 2013; 1:29.
- Solomon TE, Vanier M, Morisset J. Cell site and time course of DNA synthesis in pancreas after caerulein and secretin. Am J Physiol 1983; 245:G99.
- Talamini G. Duodenal acidity may increase the risk of pancreatic cancer in the course of chronic pancreatitis: an etiopathogenetic hypothesis. JOP 2005; 6:122.
- Rindi G, Ratineau C, Ronco A, et al. Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine. Development 1999; 126:4149.
- Cheng CY, Chu JY, Chow BK. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 2011; 36:459.
- Chu JY, Cheng CY, Sekar R, Chow BK. Vagal afferent mediates the anorectic effect of peripheral secretin. PLoS One 2013; 8:e64859.
- Nishijima I, Yamagata T, Spencer CM, et al. Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior. Hum Mol Genet 2006; 15:3241.
- Lossi L, Bottarelli L, Candusso ME, et al. Transient expression of secretin in serotoninergic neurons of mouse brain during development. Eur J Neurosci 2004; 20:3259.
- McGuigan JE, Wolfe MM. Secretin injection test in the diagnosis of gastrinoma. Gastroenterology 1980; 79:1324.
- Brady CE 3rd. Secretin provocation test in the diagnosis of Zollinger-Ellison syndrome. Am J Gastroenterol 1991; 86:129.
- Catalano MF, Lahoti S, Geenen JE, Hogan WJ. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest Endosc 1998; 48:11.
- Raimondo M, Imoto M, DiMagno EP. Rapid endoscopic secretin stimulation test and discrimination of chronic pancreatitis and pancreatic cancer from disease controls. Clin Gastroenterol Hepatol 2003; 1:397.
- Khalid A, Peterson M, Slivka A. Secretin-stimulated magnetic resonance pancreaticogram to assess pancreatic duct outflow obstruction in evaluation of idiopathic acute recurrent pancreatitis: a pilot study. Dig Dis Sci 2003; 48:1475.
- Monill J, Pernas J, Clavero J, et al. Pancreatic duct after pancreatoduodenectomy: morphologic and functional evaluation with secretin-stimulated MR pancreatography. AJR Am J Roentgenol 2004; 183:1267.
- Akisik MF, Sandrasegaran K, Aisen AA, et al. Dynamic secretin-enhanced MR cholangiopancreatography. Radiographics 2006; 26:665.
- Balci NC, Alkaade S, Magas L, et al. Suspected chronic pancreatitis with normal MRCP: findings on MRI in correlation with secretin MRCP. J Magn Reson Imaging 2008; 27:125.
- Bali MA, Metens T, Denolin V, et al. Pancreatic perfusion: noninvasive quantitative assessment with dynamic contrast-enhanced MR imaging without and with secretin stimulation in healthy volunteers--initial results. Radiology 2008; 247:115.
- Williams K, Wray JA, Wheeler DM. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2012; :CD003495.