Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:013878 (secretin receptor)
 226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The secretin receptor is prototypic of the class II family of G protein-coupled receptors, with a long extracellular amino-terminal domain containing six highly conserved Cys residues and one Cys residue (Cys(11)) that is present only in the most closely related family members. This domain is critical for function, with some component Cys residues believed to be involved in key disulfide bonds, although these have never been directly demonstrated. Here, we examine the functional importance of each of these residues and determine their involvement in disulfide bonds. Secretin binding was markedly diminished after treating cells with cell-impermeant reducing reagents, supporting the presence of important extracellular disulfide bonds. To determine whether the amino-terminal domain was covalently attached to the receptor body by disulfide linkage, a strategy was implemented that involved introduction of an acid-labile Asp-Pro sequence to enable specific cleavage at the boundary of these domains. Under nonreducing conditions, the amino terminus was released from the receptor body, supporting the absence of covalent association between these domains. Quantitative [(14)C]iodoacetamide incorporation into the isolated amino-terminal domain of the receptor in the absence and presence of chemical reduction established the ratio of free to total Cys residues as 1:7, consistent with three disulfide bonds. Mutagenesis of each of the amino-terminal Cys residues to Ala was tolerated only for Cys(11), suggesting that these bonds linked the conserved Cys residues. This was further supported by treatment of intact cells expressing wild-type or C11A mutant secretin receptor with a cell-impermeant sulfhydryl-reactive reagent. Thus, the functionally important amino terminus of the secretin receptor represents a structurally independent, highly folded, and disulfide-bonded domain, with a pattern that is likely critical and conserved throughout this receptor family.
 ...
PMID:Structural insights into the amino-terminus of the secretin receptor: I. Status of cysteine and cystine residues. 1104 37

Only one secretin receptor has been cloned and its properties characterized in native and transfected cells. To test the hypothesis that stimulatory and inhibitory effects of secretin are mediated by different secretin receptor subtypes, pancreatic and gastric secretory responses to secretin and secretin-Gly were determined in rats. Pancreatic fluid secretion was increased equipotently by secretin and secretin-Gly, but secretin was markedly more potent for inhibition of basal and gastrin-induced acid secretion. In Chinese hamster ovary cells stably transfected with the rat secretin receptor, secretin and secretin-Gly equipotently displaced (125)I-labeled secretin (IC(50) values 5.3 +/- 0.5 and 6.4 +/- 0.6 nM, respectively). Secretin, but not secretin-Gly, caused release of somatostatin from rat gastric mucosal D cells. Thus the equipotent actions of secretin and secretin-Gly on pancreatic secretion appear to result from equal binding and activation of the pancreatic secretin receptor. Conversely, secretin more potently inhibited gastric acid secretion in vivo, and only secretin released somatostatin from D cells in vitro. These results support the existence of a secretin receptor subtype mediating inhibition of gastric acid secretion that is distinct from the previously characterized pancreatic secretin receptor.
 ...
PMID:Different actions of secretin and Gly-extended secretin predict secretin receptor subtypes. 1112 1

Secretin not only increases ductular bile secretion in vivo in rats after bile duct ligation (BDL) [1], but also increases cAMP levels and stimulates exocytosis in isolated cholangiocytes [2]. Although we have previously reported that secretin receptor mRNA was upregulated in cholangiocytes after BDL [3], the cholangiocyte secretin receptor has not been functionally characterized or quantified after BDL. In this work, we used a novel, photolabile and biologically active analogue of secretin to quantify and characterize secretin receptors on cholangiocytes isolated from normal and BDL rats. The cholangiocyte secretin receptor bound radioligand with high affinity and in a rapid, reversible, and temperature-dependent manner. While receptors on cholangiocytes from normal and BDL rats were functionally and biochemically identical, receptor density on cholangiocytes was increased 5-fold following BDL. The combination of increased cell number with increased functional secretin receptors per cell is due to the fact that cholangiocyte hyperplasia represents a reactive response to a cholestatic condition and this effort on the part of the organism to maintain bile secretion, explains the increased hormone-responsive choleresis observed after BDL and may reflect an adaptive response of the organism to cholestasis.
 ...
PMID:Upregulation of secretin receptors on cholangiocytes after bile duct ligation. 1116

Secretin was discovered by Starling & Bayliss in 1902. Three years later the hormone concept and hormonal regulation were described and early regulatory physiology took a major step forward. After several years of unsuccessful investigations, secretin was isolated with new chromatographic techniques and subsequently synthesised in the 1960s. Radioimmunoassays in the 1970s confirmed the final endocrine role of secretin. Cloning and molecular hybridisation in the 1990s have identified the size of production, precursor, genetic structure, and evolutionary relation to other gastrointestinal peptides. In addition, the secretin receptor has been described. In recent years, synthetic secretin has been applied in the functional and structural diagnostics of pancreatic function and in experimental therapy. Although it was the first bioactive substance to be identified as a hormone, our knowledge of secretin today, 100 years on, is still incomplete.
 ...
PMID:[Secretin--the first hormone]. 1181 26

Secretin receptors that are key for regulation of healthy pancreatic ductal epithelial cells have been reported to be functionally absent on ductal pancreatic adenocarcinomas. Here, we examine the possible presence and function of molecular forms of the secretin receptor in pancreatic cancer cell lines and in primary tumors. Surprisingly, reverse transcription-PCR and sequencing demonstrated wild-type secretin receptor mRNA in each of four cell lines and three primary tumors. Lack of biological response to nanomolar concentrations of secretin was best explained by the demonstrated coexpression of a second and predominant transcript in each of the cell lines and tumors. This represented a variant of the secretin receptor in which the third exon was spliced out to eliminate residues 44-79 from the NH(2)-terminal tail. This spliceoform has only recently been recognized in a rare gastrinoma, where it was incapable of binding secretin or signaling, and possessed dominant-negative activity to suppress hormone action at the wild-type secretin receptor (1). Overexpression of wild-type secretin receptor in Panc-1 cells driven by transfection of fully processed cDNA resulted in normal responsiveness to low concentrations of secretin, establishing the ability of these cells to produce a receptor capable of normal biosynthesis, trafficking, and signaling. Bioluminescence resonance energy transfer demonstrated that the variant receptor could form a heterodimer with wild-type receptor, providing a molecular mechanism for its dominant-negative activity. This suggests that missplicing is responsible for expression of a secretin receptor variant having the ability to suppress the function of wild-type receptor by a direct interaction. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in receptor-bearing Chinese hamster ovary cells, the secretin receptor was shown to have growth-inhibitory effects. Suppression of this activity in pancreatic carcinoma might, therefore, facilitate tumor growth and progression of this aggressive neoplasm.
 ...
PMID:Silencing of secretin receptor function by dimerization with a misspliced variant secretin receptor in ductal pancreatic adenocarcinoma. 1223 88

Photoaffinity labeling of receptors by bound agonists can provide important spatial constraints for molecular modeling of activated receptor complexes. Secretin is a 27-residue peptide hormone with a diffuse pharmacophoric domain that binds to the secretin receptor, a prototypic member of the Class B family of G protein-coupled receptors. In this work, we have developed, characterized, and applied two new photolabile probes for this receptor, with sites for covalent attachment in peptide positions 12 and 14, surrounding the previously most informative site of affinity labeling of this receptor. The [Tyr10,(BzBz)Lys12]rat secretin-27 probe covalently labeled receptor residue Val6, whereas the [Tyr10,(BzBz)Lys14]rat secretin-27 probe labeled receptor residue Pro38. When combined with previous photoaffinity labeling data, there are now seven independent sets of constraints distributed throughout the peptide and receptor amino-terminal domain that can be used together to generate a new molecular model of the ligand-occupied secretin receptor. The amino-terminal domain of this receptor presented a stable platform for peptide ligand interaction, with the amino terminus of the peptide hormone extended toward the transmembrane helix domain of the receptor. This provides clear insights into the molecular basis of natural ligand binding and supplies testable hypotheses regarding the molecular basis of activation of this receptor.
 ...
PMID:Spatial approximation between two residues in the mid-region of secretin and the amino terminus of its receptor. Incorporation of seven sets of such constraints into a three-dimensional model of the agonist-bound secretin receptor. 1450 Jul 9

I.v. injection of secretin activates neurons in brain areas controlling autonomic function and emotion. Peripheral administration of secretin inhibits gastric functions through a central mechanism that is mediated by vagal dependent pathways. We investigated whether the vagus nerve is involved in i.p. injection of secretin-induced brain neuronal activation in conscious rats as monitored by Fos immunohistochemistry. Secretin (40 or 100 microg/kg, i.p., 90 min) induced a dose-related increase in the number of Fos positive neurons in the central nucleus of the amygdala (CeA), and a plateau Fos response in the area postrema (AP), nucleus tractus solitarii (NTS), locus coeruleus (LC), Barrington's nucleus (Bar), external lateral subnucleus of parabrachial nucleus (PBel) and arcuate nucleus, and at 100 microg/kg, in the dorsal motor nucleus of the vagus (DMV) compared with i.p. injection of vehicle. Double immunohistochemistry showed that secretin (40 microg/kg, i.p.) activates tyrosine hydroxylase neurons in the NTS. Subdiaphragmatic vagotomy (7 days) abolished Fos expression-induced by i.p. secretin (40 microg/kg) in the NTS, DMV, LC, Bar, PBel and CeA, while a significant rise in the AP was maintained. In contrast, s.c. capsaicin (10 days) did not influence the Fos induction in the above nuclei. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR showed that secretin receptor mRNA is expressed in the nodose ganglia and levels were higher in the right compared with the left ganglion. These results indicate that peripheral secretin activates catecholaminergic NTS neurons as well as neurons in medullary, pontine and limbic nuclei regulating autonomic functions and emotion through vagal-dependent capsaicin-resistant pathways. Secretin injected i.p. may signal to the brain by interacting with secretin receptors on vagal afferent as well as on AP neurons outside the blood-brain barrier.
 ...
PMID:Peripheral secretin-induced Fos expression in the rat brain is largely vagal dependent. 1545 Mar 60

The expression and spatial distribution of secretin and its receptor in human cerebellum were investigated by in situ hybridization and immunohistochemical techniques. Secretin mRNAs are found in Purkinje cells whereas secretin receptor transcripts are present in Purkinje cells and basket cells in the molecular cell layer. In addition, secretin-immunoreactivities are localized in both the soma and dendrites of Purkinje cells. These data are the first demonstration of the spatial distribution of secretin and its receptor in distinct neurons within the human cerebellum. The cellular localizations of this ligand-receptor pair are consistent with the proposed actions of secretin in the cerebellum of rodents and hence suggest that secretin also serves specific neural functions in the human cerebellum.
 ...
PMID:Expression and spatial distribution of secretin and secretin receptor in human cerebellum. 1570 23

Receptors for gut hormones, which are often overexpressed in cancer, are clinically relevant for receptor-targeted tumor imaging and therapy. Because the receptors for the gut hormone secretin are poorly characterized, we assessed secretin receptor expression in the main secretin target, the human pancreas. We investigated 58 non-neoplastic pancreases and 55 pancreatic tumors for receptor localization and density by in vitro receptor autoradiography using [(125)I]Tyr(10) rat secretin and for secretin receptor mRNA by reverse transcriptase-polymerase chain reaction. Secretin receptors were highly expressed in non-neoplastic ducts and lobuli and also in lower amounts in ductal neoplasias, including ductal adenocarcinoma, intraductal papillary mucinous tumors, and pancreatic intraepithelial neoplasia. Reverse transcriptase-polymerase chain reaction revealed wild-type receptor mRNA in the non-neoplastic pancreas and both wild-type and spliced variant receptor transcripts in ductal adenocarcinomas. Serous cystic tumors were highly positive for secretin receptors, whereas mucinous cystic tumors were negative. This study is the first to describe the precise secretin receptor distribution in human non-neoplastic pancreas and various pancreatic tumors. High secretin receptor expression in the non-neoplastic ducts reflects the major role of secretin in bicarbonate secretion. Reduced secretin binding in pancreatic ductal tumors may relate to (alternatively spliced) secretin receptor isoforms. Thus, secretin receptors in pancreatic tumors may represent potential clinical targets.
 ...
PMID:Secretin receptors in normal and diseased human pancreas: marked reduction of receptor binding in ductal neoplasia. 1619 32

Secretin is a classical gastrointestinal peptide while its neuroactive functions in the central nervous system have recently been consolidated. In the past, there was little information regarding the expression of secretin receptor in prenatal development. In this article, using mouse embryos and by in situ hybridization, secretin receptor transcripts were detected in several developing brain regions including the cerebellar primordium and choroid plexus. In the developing intestine, secretin receptor is present in the epithelial lining of the villi and the inner circular muscle. Interestingly, the transcripts for secretin receptor were also detected in the epicardium and myocardium of the developing heart as well as the glomerulus and collecting duct in the developing kidney. Taken together, our data suggest a potential pleiotrophic role of secretin during embryonic development.
 ...
PMID:The prenatal expression of secretin receptor. 1688 25


<< Previous 1 2 3 4 5 6 Next >>