Secretins、分泌素

Definition

Secretin is a peptide hormone composed of 27 amino acids, which is released from S cells of the duodenum in response to the presence of acidic contents in the stomach. Secretin increases the volume and bicarbonate content of secretions from pancreatic acinar cells 1.

Related Peptides

Secretin is synthesized as a preprohormone, which is  proteolytically processed to yield a single 27-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 .

Discovery

In 1902, William Bayliss and Ernest Starling determined that a substance secreted by the intestinal lining stimulates the pancreas after being transported via the bloodstream. They named this intestinal secretion secretin 2.

Structural Characteristics

Three COOH-terminally extended forms of secretin have been isolated from porcine intestinal extracts using an in vivo bioassay. These three COOH-terminally extended peptides correspond to sequential steps in the post-translational processing of preprosecretin that ultimately produce the COOH-terminal amidated form. Cleavage of the signal peptide and an NH2-terminal flanking peptide from preprosecretin produces an intermediate form consisting of secretin extended by an amidation region (Gly-Lys-Arg-) and the COOH-terminal flanking peptide; this 71-amino acid form has been purified from porcine intestine and shown to be bioactive. The next step in processing probably involves a trypsin-like peptidase, specific for pairs of basic residues that cleaves at the COOH side of the amidation region and yields secretin-Gly-Lys-Arg. A carboxypeptidase then removes the arginine and lysine residues to give secretin-Gly. Both of these extended forms have also been purified from porcine intestine, and the former is reported to be bioactive. In a final step, peptide amide monoamine oxygenase then would produce secretin with a COOH-terminal valine-amide, the molecular form that was first isolated and sequenced. These processing events are similar to those seen for other amidated peptides and are likely to be the steps for processing all mammalian secretins.

In addition, an alternative pathway for secretin processing may exist; isolation of an NH2-terminally extended, amidated form of secretin suggests that the steps described above may occur before cleavage of the NH2-terminal flanking region 3.

Mode of Action

Secretin's actions are mediated via interaction with the human secretin receptor (hSCTR), a cell surface, GS-coupled receptor, for which it exhibits nanomolar affinity. The hSCTR is a member of the class II G protein–coupled receptor family, which includes vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase–activating polypeptide (PACAP). Receptors of this family are structurally related, show sequence homology, and are all physiologically activated by peptide ligands. Primarily, hSCTR stimulation leads to elevations in cAMP, although independent activation of alternative Ca2+ signaling pathways in the pancreatic epithelium. Physiologically, agonist binding to the hSCTR results in potent stimulation of electrolyte (Cl–, HCO3–, K+, and Na+) and water movement, and enzymatic secretion in the pancreatic and bile duct epithelium 4.

Functions

Secretin stimulates:

a.The pancreas to emit digestive fluids that are rich in bicarbonate which neutralizes the acidity of the intestines,

b.The stomach to produce pepsin (an enzyme that aids digestion of protein), and

c.The liver to produce bile.

The physiological role of the duodenal peptide secretin is as a potent stimulant of electrolyte and water movement in pancreatic and biliary epithelium.

Secretin receptors are present in human lung and activation of these receptors with human secretin potently stimulates concentration-dependent Cl– efflux from bronchial epithelial cells and bronchorelaxation 4. In the rat cerebellum, secretin functions as a retrograde messenger to facilitate GABA transmission, indicating that it can modulate motor and other functions. Recent data support strongly the neuropeptide role of secretin. Secretin is derived from the duodenum of pigs, and the purified porcine secretin (Ferring Laboratories, Suffern, N.Y.) was approved by the Food and Drug Administration (FDA) in 1981 for single-dose use in the diagnosis of gastrointestinal disorders. Pure human secretin was synthesized and manufactured in 1998 by ChiRhoClin (Silver Spring, Md.). The human and porcine forms of secretin have equivalent kinetics and pharmacologic effects on the exocrine pancreas in humans 1.

References

1.Sandler AD, Sutton KA, DeWeese J, Girardi MA, Sheppard V, Bodfish JW (1999). Lack of Benefit of a Single Dose of Synthetic Human Secretin in the Treatment of Autism and Pervasive Developmental Disorder. NEJM., 341:1801-1806.

2.Bayliss W, Starling EH (1902). "The mechanism of pancreatic secretion". J. Physiol, 28: 325–353.

3.Solomon TE, Walsh JH, Bussjaeger L, Zong Y, Hamilton JW, Ho FJ, Lee TD, Reeve JR Jr (1999). COOH-terminally extended secretins are potent stimulants of pancreatic secretion. Am J Physiol., 276:808-816

4.Davis RJ, Page KJ, Dos Santos Cruz GJ, Harmer DW, Munday PW, Williams SJ, Picot J, Evans TJ, Sheldrick RL, Coleman RA, Clark KL (2004). Expression and Functions of the Duodenal Peptide Secretin and its Receptor in Human Lung. Am J Respir Cell Mol Biol., 31(3):302-308.