Distribution of &lt;i&gt;Escherichia coli&lt;/i&gt; Heat-Stable Enterotoxin/Guanylin/Uroguanylin Receptors in the Avian Intestinal Tract

Krause, William J.; Freeman, Ronald H.; Eber, Sammy L.; Hamra, F. K.; Fok, Kam F.; Currie, Mark G.; Forte, Leonard R.

doi:10.1159/000147735

Cited by 71 publications

(79 citation statements)

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“…This hypothesis was tested using competitive radioligand-binding assays in cultured T84 cells with 125 I-ST-(1-19) as the radioligand (2,15). Uroguanylin, guanylin, and ST-(5-17) fully inhibited the binding of 125 I-ST- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) to apical receptors on T84 cells when tested at medium pH values of 5.0 and 8.0. Examination of the radioligand-binding data using computer-assisted fitting of curves to a two-site model (15) confirms that T84 cells have both high-and low-affinity binding sites for each ligand.…”

Section: Resultsmentioning

confidence: 99%

“…8 and 9). Membrane receptor-guanylate cyclases are found on the luminal surface of enterocytes throughout the small and large intestine and in other epithelia (10)(11)(12)(13). Binding of peptide agonists to an extracellular domain of the receptor activates the intracellular catalytic domain producing the second messenger cGMP within target enterocytes (1)(2)(3)(4)(5)(6).…”

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confidence: 99%

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Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity

Hamra¹,

Eber²,

Chin³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

104

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Guanylin and uroguanylin are intestinal peptides that stimulate chloride secretion by activating a common set of receptor-guanylate cyclase signaling molecules located on the mucosal surface of enterocytes. High mucosal acidity, similar to the pH occurring within the f luid microclimate domain at the mucosal surface of the intestine, markedly enhances the cGMP accumulation responses of T84 human intestinal cells to uroguanylin. In contrast, a mucosal acidity of pH 5.0 renders guanylin essentially inactive. T84 cells were used as a model epithelium to further explore the concept that mucosal acidity imposes agonist selectivity for activation of the intestinal receptors for uroguanylin and guanylin, thus providing a rationale for the evolution of these related peptides. At an acidic mucosal pH of 5.0, uroguanylin is 100-fold more potent than guanylin, but at an alkaline pH of 8.0 guanylin is more potent than uroguanylin in stimulating intracellular cGMP accumulation and transepithelial chloride secretion. The relative affinities of uroguanylin and guanylin for binding to receptors on the mucosal surface of T84 cells is inf luenced dramatically by mucosal acidity, which explains the strong pH dependency of the cGMP and chloride secretion responses to these peptides. The guanylin-binding affinities for peptide-receptor interaction were reduced by 100-fold at pH 5 versus pH 8, whereas the affinities of uroguanylin for these receptors were increased 10-fold by acidic pH conditions. Deletion of the N-terminal acidic amino acids in uroguanylin demonstrated that these residues are responsible for the increase in binding affinities that are observed for uroguanylin at acidic pH. We conclude that guanylin and uroguanylin evolved distinctly different structures, which enables both peptides to regulate, in a pHdependent fashion, the activity of receptors that control intestinal salt and water transport via cGMP.Guanylin and uroguanylin are structurally related peptides that were isolated from intestinal mucosa and urine (1-5). A receptor for guanylin and uroguanylin that has been identified at the molecular level is a transmembrane form of guanylate cyclase, termed GC-C (6). This membrane protein was originally discovered as an intestinal receptor for the heat-stable toxin (ST) peptides, which are secreted intraluminally by enteric bacteria that cause traveler's diarrhea (7). Bacterial ST peptides are related in primary structure to uroguanylin and guanylin, thus acting as molecular mimics of the enteric peptide hormones (reviewed in refs. 8 and 9). Membrane receptor-guanylate cyclases are found on the luminal surface of enterocytes throughout the small and large intestine and in other epithelia (10-13). Binding of peptide agonists to an extracellular domain of the receptor activates the intracellular catalytic domain producing the second messenger cGMP within target enterocytes (1-6). Intracellular cGMP stimulates transepithelial chloride secretion by regulating the phosphorylation state and chloride channel activit...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity

Hamra¹,

Eber²,

Chin³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Mutations were identified in the GUCY2C gene, which encodes guanylyl cyclase 2C, a regulator of ion and fluid balance that is predominantly localized at the apical brush border membrane of the intestinal epithelium. 3,4 Binding of ligands to GUCY2C catalyzes the synthesis of cyclic GMP, which in turn causes activation of PKGII that leads to phosphorylation and subsequent opening of the cystic fibrosis transmembrane receptor. 5 The first family was found to have a homozygous missense mutation (p.Asp367Gly) in the GUCY2C gene, in a highly conserved area in the extracellular ligand binding domain.…”

Section: Introductionmentioning

confidence: 99%

Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene

et al. 2014

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Meconium ileus is most often associated with mutations in the CFTR gene; however recently, mutations in GUCY2C in the Bedouin population have also been shown to result in this phenotype. This gene codes for an intestinal transmembrane receptor that generates cyclic GMP, which activates cystic fibrosis transmembrane receptor. We report a third family that supports the association of variants in the GUCY2C gene with meconium ileus (MI). A Lebanese kindred was studied and individuals affected with MI had either homozygous or compound heterozygous variants in GUCY2C. The earliest manifestation of the affected individuals was the presence of second trimester fetal echogenic bowel, thus resulting in the expansion of the differential diagnosis of this ultrasound finding.

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“…10 In both human and mouse intestine, GC-C is expressed in villus and crypt enterocytes of the small intestine as well as the surface epithelium and crypts of the colon. 11,12 The endogenous ligands for GC-C are expressed in an overlapping gradient, with uroguanylin expression highest in the proximal intestine and guanylin levels highest in the distal intestine. 13 By both biochemical and molecular methods, expression of GC-C has been widely observed in human primary and metastatic colorectal adenocarcinomas.…”

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confidence: 99%

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Mann

Steinbrecher

Stroup

et al. 2005

Intl Journal of Cancer

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Guanylyl cyclase C (GC-C), a transmembrane receptor for bacterial heat-stable enterotoxin and the mammalian peptides guanylin and uroguanylin, mediates intestinal ion secretion and affects intestinal cell growth via cyclic GMP signaling. In intestinal tumors, GC-C expression is maintained while guanylin and uroguanylin expression is lost, suggesting a role for GC-C activation in tumor formation or growth. We show by in situ hybridization that GC-C expression is retained in adenomas from multiple intestinal neoplasia (Apc Min/+ ) mice. In order to determine the in vivo role of GC-C in intestinal tumorigenesis, we generated Apc Min/+ mice homozygous for a targeted deletion of the gene encoding GC-C and hypothesized that these mice would have increased tumor multiplicity and size compared to wild-type Apc Min/+ mice on the same genetic background. In contrast, the absence of GC-C resulted in a reduction of median polyp number by 55%. There was no change in the median diameter of polyps, suggesting no effect on tumor growth. Somatic loss of the wild-type Apc allele, an initiating event in intestinal tumorigenesis, also occurred in polyps from GC-C-deficient Apc Min/+ mice. We have found increased levels of apoptosis as well as increased caspase-3 and caspase-7 gene expression in the intestines of GC-C-deficient Apc Min/+ mice compared with Apc Min/+ mice. We propose that these alterations are a possible compensatory mechanism by which loss of GC-C signaling also affects tumorigenesis. Published 2005 Wiley-Liss, Inc.

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Distribution of <i>Escherichia coli</i> Heat-Stable Enterotoxin/Guanylin/Uroguanylin Receptors in the Avian Intestinal Tract

Cited by 71 publications

References 1 publication

Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity

Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity

Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

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