Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Secretin Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101788

Synonyms

 SCTR

Historical Background

Secretin and the secretin receptor hold special places in history, with the discovery of the biological activity of this peptide hormone by Bayliss and Starling in 1902 representing the first humoral mediator identified and launching the field of endocrinology and with the description of this receptor by Ishihara et al. in 1991 representing the first class B G protein-coupled receptor (GPCR) identified. Both of these events marked the beginning of exciting and important chapters in biomedical history. The class B GPCRs comprise a small family within this superfamily, including receptors for only a small number of moderate length peptides (also including receptors for vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating peptide, glucagon, glucagon-like peptides 1 and 2, glucose-dependent insulinotropic polypeptide, calcitonin, calcitonin gene-related peptide, amylin, adrenomedullin, parathyroid hormone, parathyroid hormone-related peptide, corticotropin-releasing factor, and growth hormone-releasing hormone), but all of these are physiologically quite important, with almost all of these receptors also representing potentially very important drug targets. Secretin and its receptor are prototypic of this entire family, and the themes developed below are applicable to all of these drug targets (Miller et al. 2012; Miller and Dong 2013).

The classical action of secretin is to stimulate bicarbonate-rich fluid secretion from the pancreatic and biliary ductular tree, yet, over time, additional actions have become clear, such as effects on gastric secretion and gastric emptying, appetite, glucose tolerance, and renal and cardiovascular function. The impact of this hormone continues to grow and the potential to target this hormone-receptor system is considerable.

Tissue Distribution and Physiological Actions of Secretin Receptors

The location for secretin receptors responsible for its classically described effect is on duct cells in the pancreas and biliary tree, where it mediates the secretion of bicarbonate-rich fluid. Secretin receptors are also prominent on pancreatic acinar cells and are present in lower concentration within pancreatic islets and vascular structures. In the liver, these receptors are present exclusively on duct cells. In stomach, they are present on circular and longitudinal smooth muscle, various mucosal cells, and on vagal afferent neurons. Of note, secretin receptors are also present in the central nervous system, with highest levels in the cerebellum, and intermediate levels in the cortex, thalamus, hypothalamus, hippocampus, and striatum, and with low levels in the midbrain, pons, and medulla. Secretin receptors are found on smooth muscle at other levels of the gastrointestinal tract and in the epididymis, kidney, heart, and lung. This broad distribution of secretin receptors throughout the body could support a wide spectrum of biological actions.

Consistent with its early history, the best studied physiological action of secretin is stimulation of the secretion of bicarbonate-rich fluid from pancreatic and biliary ducts into the duodenum where it can neutralize, or at least offset, some of the gastric acid being emptied into the intestine. This helps to optimize the milieu for micelle formation and for digestive events necessary for nutrient absorption. Secretin has also been shown to inhibit gastrin-stimulated gastric acid secretion to contribute to the same result. It also stimulates pepsinogen and mucous secretion in the stomach, and it stimulates alkaline secretion from Brunner’s glands in the duodenum. Consistent with optimizing the milieu in the duodenum, secretin also slows gastric emptying, so contents do not overwhelm the digestive and absorptive mechanisms.

This theme of regulation of fluid and electrolyte secretion has been substantially extended over time, with new insights coming from observations of the phenotype of secretin-null and secretin receptor–null mice (Chu et al. 2011). Secretin plays a modulatory role in renal water reabsorption, and it is important in regulating drinking behavior in response to hyperosmolality. These effects seem to be interdependent with vasopressin and with angiotensin. One report suggests that this may be mediated by direct interactions between the secretin receptor and receptors for these hormones (Lee et al. 2014). Another location for secretin to influence fluid and electrolyte secretion is in the epididymis, where this again seems to optimize the milieu for a physiologically important process.

Other effects that may be physiologic include reduction of appetite, with this probably mediated through secretin action on vagal afferent neurons, and possibly being contributed to by its effect on delaying gastric emptying. It has also been described as an insulinotropic factor, enhancing the insulin response to glucose administered orally or enterally relative to that when the same glucose load is administered directly into the circulation.

Effects of exogenously administered secretin may also be pharmacological, dependent on dose provided. Exogenous secretin has been reported to have a variable effect on growth of different cells, likely reflecting both direct effects on end organs and indirect effects that could be mediated by endocrine interactions. This is likely not physiologic and would need to be carefully evaluated for any secretin-like agonist and dose regimen to be utilized clinically in the future. In model systems, secretin has been shown to stimulate insulin, glucagon, somatostatin, pancreatic polypeptide, and even parathyroid hormone and calcitonin secretion; however, which of these events may have physiologic significance is also currently unclear. Secretin has also been described to stimulate cardiac contractility and to increase coronary and renal blood flow, while maintaining normal blood pressure, all potentially beneficial in heart failure. Only scattered preclinical and small early clinical trials have pursued this possible application.

Secretin is commonly administered parenterally as a diagnostic test to stimulate biliary and pancreatic secretions and fluid flow. This maneuver can be used to stress the sphincter of Oddi, examining possible functional obstruction at that level, monitored radiographically. This is also utilized for biochemical analysis of pancreatic exocrine secretion to explore possible pancreatic insufficiency. As described below, secretin can also be administered as a provocative test for gastrinoma, based on the abnormal level of receptor expression and amplified biological response in some islet cell tumors.

Based on an early report of secretin administered during a diagnostic test in autistic children with prominent gastrointestinal symptoms who subsequently had apparent improvement in their autism, there was transient excitement that this hormone may have a potential role in therapy of this disorder. However, subsequent studies have not confirmed any clinical usefulness of secretin in autism.

Structure of Secretin Receptors and Molecular Basis of Ligand Binding

The secretin receptor is a prototypic class B GPCR (Fig. 1). Like all members of this superfamily, it has seven hydrophobic transmembrane segments that associate with each other to form a helical bundle within the plasma membrane. The class B GPCRs possess a characteristic moderate length amino-terminal tail, ranging from 100 to approximately 150 residues, that includes six conserved cysteine residues that form three disulfide bonds (Bortolato et al. 2014). This has been described as a Sushi motif, defined by these conserved disulfide bonds, as well as two sets of antiparallel beta sheets with connecting loop regions, and an amino-terminal alpha helical segment. This domain is highly conserved in this family and provides a cleft with a hydrophobic base to accommodate the carboxyl-terminal portion of the natural ligands of these receptors in a helical conformation.
Secretin Receptor, Fig. 1

Shown is a schematic diagram of the primary structure of the secretin receptor, highlighting the characteristic Sushi motif in the extracellular amino terminus that includes a cleft to dock the carboxyl-terminal portion of the secretin ligand in a helical conformation. This directs the biologically active amino terminus of secretin toward its site of docking high in the open seven-transmembrane-segment helical bundle intramembranous domain. Characteristic signature sequences are present within the transmembrane segments and in architecturally important portions of the amino terminus of the receptor

We now also have crystal structures for the helical bundle portion of two members of this receptor family, the glucagon and CRF1 receptors, in inactive conformations occupied by antagonists (Hollenstein et al. 2014). These structures have been quite informative, showing the characteristic helical bundle pattern of this superfamily but having major structural differences from the class A GPCRs. This is not surprising, since the signature sequences defining class A and class B receptors are quite distinct. For the class B GPCRs, the top of the bundle was found to be wide open, without clear small molecule-docking clefts. This is believed to include the site of action of the natural agonist pharmacophore, but the absence of distinct docking sites is likely responsible for the great difficulty there has been in identifying small molecule agonists for these receptors. Instead, the agonist pharmacophore that resides within the amino-terminal end of the natural peptide ligands seems to be directed into this locus as a second step after the carboxyl-terminal region of these ligands occupies the receptor amino-terminal cleft (Hollenstein et al. 2014). The current understanding of this two-step process has come about as a result of receptor mutagenesis, ligand structure-activity variations, dynamic fluorescence studies, and photoaffinity labeling. Many of the insights for this family have come from detailed spatial approximation studies of the secretin-occupied secretin receptor (Dong et al. 2011). Up to the present time, there have been no structures solved for intact receptors in this family or those occupied by an agonist peptide ligand. While the two major structural domains of these receptors have been solved, the relative orientation between them is still unclear.

Much is also known about higher order complexes involving the secretin receptor. Here, too, the themes have been representative of the whole family. The secretin receptor has a tendency to form symmetrical homo-dimeric structures along the lipid face of its fourth transmembrane segment (Gao et al. 2009). These complexes form independent of ligand occupation, and agonist occupation does not disrupt the homo-dimers but leads to their internalization. This complex is believed to be responsible for the high affinity, high potency action of natural agonist ligands and also to be responsible for the negative cooperativity observed. The latter is explained by occupation of only one of the two receptor protomers resulting in the association of a single heterotrimeric G protein with the dimeric receptor structure. The members of the class B GPCR family also tend to form heterodimeric complexes, but the nature of these is currently less well understood.

Signaling at the Secretin Receptor

Like all members of the class B family of GPCRs, secretin stimulates its receptor to associate with Gs, resulting in stimulation of adenylate cyclase and production of cAMP (Siu et al. 2006). High concentrations of agonist also result in association with Gq, with the typical stimulation of phospholipase C and effects to increase diacyl glycerol, phosphatidyl inositol, and intracellular calcium. The secretin receptor also associates with arrestin-like molecules in an agonist-dependent manner. Downstream of these proximal events are a large number of signaling events, with cross regulation and different biological impact in different receptor-bearing cells.

To date, only the natural secretin full agonist has been utilized clinically. No partial agonists or biased agonists for this receptor have been described. Structure-activity studies with this peptide have supported the family-wide general theme of the presence of a pharmacophore throughout the 27-residue secretin peptide, with determinants for binding affinity spread along the entire peptide, but with the agonist activity determinants at the amino-terminal end of the peptide. Alanine scanning mutagenesis has been performed and truncation studies suggest that amino-terminally truncated analogues lose their biological activity and become antagonists. Unfortunately with such truncation of secretin, the analogues also lose considerable binding affinity. Currently, the most widely accepted antagonist is a secretin analogue possessing a pseudopeptide bond in the 4–5 position; however, this continues to possess some partial agonist activity, and it also binds with only very low affinity.

Biochemical and Cellular Regulation of the Secretin Receptor

Like most members of this superfamily, the secretin receptor is regulated by both biochemical and cellular mechanisms. Most prominent and most rapid is the agonist-stimulated phosphorylation of this receptor. This occurs on serine and threonine residues exposed to the cytosol as sites of action of signaling kinases, such as protein kinase A and possibly protein kinase C, as well as by G protein-coupled receptor kinases. This event is believed to uncouple the receptor from its G protein. Agonists also stimulate the internalization of this receptor as another mechanism for desensitization of this signaling system. This occurs predominantly through clathrin-coated pits and classical receptor-mediated endocytosis. There are no data yet to explore possible signaling events from the secretin receptor located within intracellular compartments, as has recently been described for other members of this superfamily. Because the natural peptide agonist ligand for the secretin receptor is a hydrophilic peptide, it can only recognize and bind to cell surface receptors, thereby having internalization interfere with access for agonist binding, and thereby result in desensitization.

Clinical Relevance of the Secretin Receptor

At this time, the major clinical relevance for secretin has been as a diagnostic reagent. As noted above, secretin administration is currently utilized in magnetic resonance cholangiopancreatography to aid in the diagnosis of sphincter of Oddi dysfunction, and it is used as a diagnostic test for exocrine pancreatic insufficiency. It is also utilized as a provocative test for the diagnosis of gastrinoma, based on the large increase in serum gastrin in response to secretin administration in such patients. This relates to an excessive number of gastrinoma cell secretin receptors and their occupation by secretin agonist resulting in gastrin secretion. In contrast, in patients having hypergastrinemia on the basis of hypochlorhydria, the provocative secretin test results in reduction in the level of serum gastrin.

To date, no small molecule ligands have been described for the secretin receptor. This likely reflects lack of urgency for drug discovery, due to the absence of recognition of a clinical or pathological setting in which modulation of secretin activity might be critically necessary and in which chronic administration of such an agonist might be useful. While this hormone possesses clear physiological importance and it has proven to possess diagnostic importance, the latter need has been met fully by acute parenteral administration of the natural peptide.

There are multiple examples of overexpression of hormone receptors on various malignancies, as well as the use of those to target antitumor therapies. Based on the large number of secretin receptors on pancreatic duct cells, pancreatic ductal carcinomas have been studied to determine relative expression of secretin receptors; however, these receptors were found to be downregulated in these malignant tumors. This might reflect receptor mRNA misprocessing, but this needs to be further examined.

Summary

The secretin receptor is a class B GPCR that is physiologically quite important for the maintenance of a milieu in the proximal duodenum that is optimal for nutritional homeostasis. This includes neutralization of gastric acid, reduction in secretion of that acid, and slowing of delivery of gastric contents to the major sites of digestion and absorption within the intestine. It also has potential roles in appetite and glycemic control, as well as possible therapeutic uses in heart failure and in abnormalities of fluid and electrolyte status. Currently, secretin is used predominantly in diagnostic studies, but the potential also exists for new therapeutic applications for this hormone and secretin-like agonists in the future.

References

  1. Bortolato A, Dore AS, Hollenstein K, Tehan BG, Mason JS, Marshall FH. Structure of Class B GPCRs: new horizons for drug discovery. Br J Pharmacol. 2014;171:3132–45. doi: 10.1111/bph.12689.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Chu JY, Cheng CY, Lee VH, Chan YS, Chow BK. Secretin and body fluid homeostasis. Kidney Int. 2011;79:280–7. doi: 10.1038/ki.2010.397.PubMedCrossRefGoogle Scholar
  3. Dong M, Lam PC, Pinon DI, Hosohata K, Orry A, Sexton PM, et al. Molecular basis of secretin docking to its intact receptor using multiple photolabile probes distributed throughout the pharmacophore. J Biol Chem. 2011;286:23888–99. doi: 10.1074/jbc.M111.245969.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Gao F, Harikumar KG, Dong M, Lam PC, Sexton PM, Christopoulos A, et al. Functional importance of a structurally distinct homodimeric complex of the family B G protein-coupled secretin receptor. Mol Pharmacol. 2009;76:264–74. doi: 10.1124/mol.109.055756.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC. Insights into the structure of class B GPCRs. Trends Pharmacol Sci. 2014;35:12–22. doi: 10.1016/j.tips.2013.11.001.PubMedCrossRefGoogle Scholar
  6. Lee LT, Ng SY, Chu JY, Sekar R, Harikumar KG, Miller LJ, et al. Transmembrane peptides as unique tools to demonstrate the in vivo action of a cross-class GPCR heterocomplex. FASEB J. 2014;28:2632–44. doi: 10.1096/fj.13-246868.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Miller LJ, Dong M. The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor. Biochem Soc Trans. 2013;41:154–8. doi: 10.1042/BST20120204.PubMedCrossRefGoogle Scholar
  8. Miller LJ, Dong M, Harikumar KG. Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor. Br J Pharmacol. 2012;166:18–26. doi: 10.1111/j.1476-5381.2011.01463.x.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Siu FK, Lam IP, Chu JY, Chow BK. Signaling mechanisms of secretin receptor. Regul Pept. 2006;137:95–104. doi: 10.1016/j.regpep.2006.02.011.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Experimental Therapeutics and Department of Internal Medicine, Division of GastroenterologyMayo ClinicScottsdaleUSA