Why is secretin released

Basal and stimulated concentrations are low normally in the pM range. Secretin also acts to potentiate CCK action on acinar cells, to inhibit gastric acid secretion and to inhibit gastric emptying. Secretin also has actions in the brain. At the cellular level the action of secretin is primarily mediated by cAMP which is increased in response to activation of secretin receptors. Secretin has the distinction of being the first peptide hormone identified. Bayliss and Starling in showed that an acid extract of the proximal small intestine mucosa, when injected intravenously into dogs, brought about pancreatic secretion similar to that induced by acid perfusion of the duodenum 4.

Thus was born the field of Endocrinology. For a personal view of more recent secretin research from a leading investigator see After multiple attempts and improvements, secretin was isolated in purified form through the work of Jorpes and Mutt 50 and later its amino acid sequence was determined 11, It is a linear peptide of 27 amino acids and is structurally similar to glucagon and VIP Its cDNA 56 and gene sequences 57, have been determined and the gene consists of four exons with the mature peptide in a single exon.

A precursor for secretin was isolated from porcine and rat intestine which has additional N-terminal and C- terminal peptides that are cleaved to result in the mature peptide which is then amidated at the C-terminal 36, The domain structure of the precursor and the amino acid sequence of secretin is shown in Fig. At present there are no known functions for the N or C-terminal peptides. The entire 27 amino acid sequence is required for maximal potency but the amino acid C-terminal fragment has partial activity Secretin producing cells have been identified as a specific type of enteroendocrine cell by immunohistochemistry and are located in the duodenal and jejunal mucosa 18,63,83, Chey et al also reported the presence of secretin containing cells in the gastric antral mucosa but this has not been confirmed These cells are of the open type with apical surface exposed to the intestinal luminal contents.

Ultrastructurally, they possess small dense granules of diameter nm located in the basal pole of the cell which have been identified as containing secretin by immunogold staining , Their differentiation as part of the secretory lineage and the importance of the transcription factors NeuroD in the endocrine lineage has been reviewed These studies have shown decreasing concentration of secretin from the duodenum to ileum 76, One early report identified immunoreactive secretin mRNA in the brain 82 and this has subsequently been confirmed and studied in detail by quantitative PCR and in-situ hybridization.

Both secretin and its receptor have been found in the cerebellum, amygdala, hippocampus and other areas 66, Thus secretin clearly belongs to the general family of brain — gut peptides.

Figure 1. The domain structure and amino acid sequence of secretin. Individual amino acids serving to localize processing sites are shown in the domain structure.

The primary physiological stimulus for release of secretin is acidification of the duodenal lumen which brings about an increase in plasma secretion and thereby pancreatic bicarbonate secretion 7,32, In dogs, both a normal meal and infusion of acid into the duodenum brings about secretion with a duodenal pH threshold of about 4.

Increased gastric acid secretion or experimental infusion of acid brings about more secretin release both by being a stronger stimulus to individual S-cells and by extending acidification further down the small intestine thereby stimulating more S-cells Inhibition of acid secretion as brought about by H2 blocker cimetidine inhibits the plasma secretin increase. The plasma half life is about minutes In humans, either feeding a normal meal or infusing acid into the duodenum increased plasma secretin with a similar pH threshold of 4.

No significant changes occurred after intraduodenal infusion of glucose, amino acids, fat emulsion or ethanol The secretin response was also reported similar in normal subjects, patients with duodenal ulcers and after vagotomy The half life of secretin in human plasma was reported to be 4 minutes Studies in other species include the showing that luminal acid stimulates secretin release in anesthetized pigs 88 , in the perfused pig intestine 44 and in fasting rats The mechanism by which acid brings about secretin release is not fully understood but probably involves acid sensing ion channels of the Trp family present in the brush border of S-cells.

An alternative mechanism presented by Chey and colleagues based on studies in rats was for the existence of a intestinal derived secretin releasing peptide, analogous to the CCK releasing peptide concept, that was released in response to acid A secretin releasing peptide was also reported in dog pancreatic juice The existence of such a mechanism has not been further confirmed. What is currently needed is the development of a mechanism to sort and study S-cells similar to methods being used for CCK release from I-cells.

For more detailed coverage of the older literature on secretin secretion see Walsh In addition to acid, there is a considerable amount of evidence that fatty acids can stimulate secretin release in dogs 31,79, , humans 92 and rats 95 although the plasma secretin levels are usually lower than the response to acid. Oleic acid is the most common form of fat used and some studies show no response although this could be due to limits on the RIAs used. One report indicated that intraduodenal oligopeptides could also increase plasma secretin and stimulate pancreatic bicarbonate output in rats Multiple studies have shown the lack of neural involvement in secretin release using both atropine administration and vagotomy in dogs, humans and rats 19,42,95, Both basal and stimulated levels of plasma secretin are low 1 to 10 pM and there are issues with preparing samples as well as the need for sensitivity that make it hard to perform in small animals.

Description and validation of secretin RIAs used in studies reviewed here have been presented 10,12, Antibodies have usually been raised against the C- terminal of the secretin molecule. Studies have indicated that the kidney is the major organ metabolizing secretin All known actions of secretin are mediated by the secretin receptor, a G-protein coupled, 7 transmembrane domain protein whose primary signal transduction mechanism is to activate adenylate cyclase and stimulate formation of cAMP The receptor is structurally similar to receptors for VIP, glucagon, parathyroid hormone and other Class II G-protein linked receptors.

Secretin receptors have been identified by ligand binding and recognition of its mRNA in pancreas, biliary system, stomach, brain and kidney 47,48,58, For more information see the Secretin receptor Molecule Page.

The principle action of secretin is to stimulate bicarbonate secretion to neutralize gastric acid in the duodenum 37,62, Actions on the pancreas to stimulate duct cells to secrete bicarbonate is considered in the next section. Secretin also stimulates bicarbonate secretion by cholangiocytes, the cells lining the bile ducts with most studies having been carried out in dogs, humans and rats 39,43, The cellular mechanism appears identical to pancreatic secretion by pancreatic duct cells although the final concentration in bile is not as high.

Secretin does not appear to affect canalicular bile formation where the driving force is secretion of bile salts 8. In addition to stimulating bicarbonate secretion from the pancreas and liver, secretin also stimulates Brunners glands in the duodenal submucosa to secrete bicarbonate rich fluid 53, In a second protective action against duodenal acid, secretin acts as an enterogastrone and both reduces acid secretion and inhibits gastric emptying thereby reducing entry of acid into the duodenum 23,54,, Secretin is also of some historical interest, as it was the first hormone to be discovered.

Secretin is synthesized as a preprohormone, then proteolytically processed to yield a single amino acid peptide by removal of the signal peptide plus amino and carboxy-terminal extensions. The sequence of the mature peptide is related to that of glucagon, vasoactive intestinal peptide and gastric inhibitory peptide.

The secretin receptor has seven membrane-spanning domains and characteristics typical of a G protein-coupled receptor. Secretin is secreted in response to one known stimulus: acidification of the duodenum, which occurs most commonly when liquified ingesta from the stomach are released into the small intestine. The principal target for secretin is the pancreas, which responds by secreting a bicarbonate-rich fluid, which flows into the first part of the intestine through the pancreatic duct.

Bicarbonate ion is a base and serves to neutralize the acid, thus preventing acid burns and establishing a pH conducive to the action of other digestive enzymes. A similar, but quantitatively less important response to secretin is elicited by bile duct cells , resulting in additional bicarbonate being dumped into the small gut.

As acid is neutralized by bicarbonate, the intestinal pH rises toward neutrality, and secretion of secretin is turned off. Secretin is sometimes used to treat peptic ulcers and for diagnosis of exocrine pancreatic disorders. Diseases associated with excessive or deficient secretion of secretin are not recognized.