Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heat-stable enterotoxin, produced by Escherichia coli, binds to particulate guanylate cyclase to increase cyclic GMP in intestinal cells. This in turn stimulates the cyclic-GMP- or cyclic-AMP-dependent protein kinase, activating the same chloride channel that is defective in cystic fibrosis. It is possible that the relatively high prevalence of cystic fibrosis in humans results from its protective effect against diarrhea.
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PMID:Gates of Janus: cystic fibrosis and diarrhea. 751 20

Infection with enterotoxigenic Escherichia coli is a leading cause of traveler's diarrhea. Many enterotoxigenic E. coli strains produce heat-stable enterotoxin (ST), a peptide that binds to the intestinal receptor guanylyl cyclase C known as STaR. The toxin-receptor interaction elevates intracellular cGMP, which then activates apical chloride secretion, resulting in secretory diarrhea. In this report, we examine how the intracellular domains of STaR participate in the propagation and regulation of signaling. We show that STaR exists as an oligomer in both the presence and the absence of toxin. We also demonstrate that deletion of the intracellular kinase-homology domain produces a constitutively active mutant, suggesting that this domain subserves an autoinhibitory function. Finally, we constructed a point mutant within a highly conserved region of the cyclase domain that completely inactivates the catalytic activity of guanylyl cyclase. Cotransfection of this point mutant with wild-type receptor causes a dominant-negative effect on receptor activation. This suggests that interaction of receptor subunits is required for toxin-induced activation and that the cyclase domain is involved in this essential interaction. We propose that the binding of ST to STaR promotes a conformational change across the cell membrane. This removes the inhibitory effects of the kinase-homology domain and promotes an interaction between cyclase domains that leads to receptor activation. The data suggest a paradigm of signal transduction that may also be relevant to other members of the guanylyl cyclase receptor family.
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PMID:Regulation of cell signaling by the cytoplasmic domains of the heat-stable enterotoxin receptor: identification of autoinhibitory and activating motifs. 753 43

Regulation of intestinal salt and water transport is critical to the maintenance of fluid volume. Control of this life-sustaining activity is mediated by the concerted actions of hormones, neurotransmitters, and locally acting factors. The intestinal peptide guanylin is ideally suited to play a pivotal role in this regulation. Guanylin is produced by the epithelium and appears to be secreted mucosally to act locally on an apical receptor. The guanylin receptor is a member of the guanylate cyclase (GC-C) family of proteins. Elevation of intracellular cyclic GMP by guanylin mediates the stimulation of Cl- secretion, which results in the increased intestinal fluid secretion. Proguanylin is found in the circulation and GC-C occurs in other epithelia, suggesting that guanylin plays an endocrine role by regulating the function of tissues such as the kidney and liver. Uroguanylin is a structurally related peptide that is abundant in urine, has biological activity similar to guanylin, and appears to be made by the intestine. This peptide may link the intestine and kidney in an endocrine pathway for control of renal salt excretion. Overproduction of guanylin/uroguanylin would be expected to elicit secretory diarrhea similar to that caused by the bacteria that produce peptide analogs of these endogenous peptide hormones. This unique molecular mimicry has provided clues leading to the discovery of guanylin and insight into the mechanism of action of these intestinal peptides. The discoveries of guanylin and uroguanylin have provided exciting opportunities for further enhancing our understanding of epithelial transport and function.
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PMID:Guanylin: a peptide regulator of epithelial transport. 776 56

The heat-stabile enterotoxin produced by Escherichia coli (ST) induces diarrhea by binding to receptors on intestinal cells, activating guanylyl cyclase, and increasing cyclic GMP. High- and low-affinity receptors for this toxin have been identified previously. ST induces intestinal secretion in suckling mice in picomole doses, suggesting a role for high-affinity receptors in this process. The present studies examine the relative roles of high- and low-affinity receptors in this process. The time course of changes in free ST concentrations in suckling mouse intestine was determined after intragastric inoculation. Also, binding characteristics of high- and low-affinity receptors and their coupling to guanylyl cyclase were defined in intestinal membranes from suckling mice. Intestinal concentrations of toxin and receptor binding characteristics empirically determined were used in a dynamic model correlating fractional occupancy of high- and low-affinity receptors with intestinal secretion to estimate their relative contributions to ST-induced diarrhea.
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PMID:Intestinal kinetics and dynamics of Escherichia coli heat-stabile enterotoxin in suckling mice. 799 90

The heat stable enterotoxins (ST) of enterotoxigenic Escherichia coli (ETEC) cause diarrhoea by binding specific intestinal receptors. Precise histochemical localization of ST receptors could provide more information about the pathophysiology of secretory diarrhoea and the role of ST receptors in normal biology. To accomplish this, we quantitatively coupled biotin to the N-terminus of ST1b using biotin-X-X-N-hydroxysuccinimide ester. The derivatized toxin (BST) has an apparent Kd of 11.7 +/- 10 nM for rat brush border receptors. We used BST in an affinity panning cell-capture system, to validate its ability to discriminate between receptor-positive and receptor-negative cells. Cell lines expressing ST receptors (human colon carcinoma T84, and COS cells transfected with guanylyl cyclase-C (GC-C) ST receptor cDNA) were captured to streptavidin and anti-biotin-coated plates with high efficiency and specificity. This system provides a novel approach to screening cells for the presence of unique ST-binding proteins. BST was then used with streptavidin-gold to demonstrate the cellular topography of ST receptors at the light microscopic level. Villus enterocytes were intensely stained, but only a faint signal was observed in upper crypts of rat small intestine. Thus, a gradient of increasing receptor density was seen as upper crypt cells matured into villus enterocytes. Higher magnification revealed that ST receptors are concentrated at the apical aspect of villus enterocytes. Recently, guanylin, a putative endogenous ligand for ST receptors, has been localized to Paneth cells, at the base of intestinal crypts. Thus, ST receptors are concentrated in villus enterocytes, while guanylin appears to be produced at the base of the crypts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ligand-based histochemical localization and capture of cells expressing heat-stable enterotoxin receptors. 810 72

The mechanism by which bacterial heat-stable enterotoxins (ST I STA) cause diarrhea in humans and animals has been linked to the activation of an intestinal membrane-bound guanylate cyclase. Guanylin, a recently discovered rat intestinal peptide, is homologous in structure to ST I and can activate guanylate cyclase present on the human colonic carcinoma cell line T84. To directly test the mechanistic association of guanylate cyclase activation with diarrhea, we synthesized guanylin and a guanylin analog termed N9P10 guanylin and compared their biological activities with those of a synthetic ST I analog, termed ST Ib(6-18). We report that guanylin is able to inhibit the binding of a radiolabeled ST I analog to rat intestinal cells but causes diarrhea in infant mice only at doses at least 4 orders of magnitude higher than that of ST Ib(6-18). In contrast, N9P10 guanylin was enterotoxic in mice at much lower doses than guanylin but proved to be a weaker inhibitor of radiolabeled ST I than guanylin in the receptor binding assay. The pattern of guanylate cyclase activation observed for ST Ib(6-18) and the two guanylin analogs parallels the results observed in the receptor binding assay rather than those observed in the diarrheal assay. Treatment of guanylin with chymotrypsin or lumenal fluid derived from newborn mouse intestines resulted in a rapid loss of binding activity. Together, these results suggest that ST I enterotoxins may represent a class of long-lived superagonists of guanylin.
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PMID:The Escherichia coli heat-stable enterotoxin is a long-lived superagonist of guanylin. 810

From diarrheal diseases come profound lessons about health and population growth, microbial pathogenesis, and the molecular pharmacology of signal transduction. Epidemics such as cholera, hemorrhagic colitis, salmonellosis, and cryptosporidiosis remind us of how interdependent we are, sharing enteric microbial flora on a global scale. Diarrhea morbidity and mortality teach us that disease and poverty do not control but are associated with population overgrowth. Great advances are being made in understanding new bacterial, viral, and parasitic causes and treatment of diarrhea, especially persistent diarrhea. In addition, microbial toxins provide unique pharmacologic tools to probe cell signaling pathways. The mechanism of action of cholera toxin, once thought so clear, now appears to involve additional pathways such as platelet-activating factor and prostaglandin synthesis. Escherichia coli ST has opened a whole family of activators of guanylate cyclase, including new mammalian products that regulate sodium transport. Clostridium difficile toxin A provides a novel tool to dissect mediators involved in inflammatory diarrhea. These lessons have both basic implications for science and practical applications for medicine and society.
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PMID:Lessons from diarrheal diseases: demography to molecular pharmacology. 819 98

The heat-stable enterotoxins (ST) elaborated by enterotoxigenic Escherichia coli are a family of small cysteine-rich peptides that bind to specific epithelial receptors in the mammalian intestine, causing a secretory diarrhea. The expression of ST receptors is tightly regulated; they are found primarily in intestine, and their expression is developmentally modulated. One receptor for ST has been cloned, and its cDNA encodes a approximately 120-kDa particulate guanylyl cyclase (guanylyl cyclase-C). Recent studies suggest that there are additional ST receptors that are not homologous to guanylyl cyclase-C. We used an expression cloning strategy to identify intestinal mRNAs that lead to expression of ST receptor activity in transfected cells. Using an ST-specific affinity panning system, we identified a novel 1891-base pair cDNA that does not encode a receptor protein, but instead, consists primarily of untranslated sequence. This cDNA induced receptor activity in both COS and 293 embryonic kidney cells. Northern analysis of the T84 human intestinal cell line, from which this cDNA was cloned, suggests that it is part of a 7.8-kilobase mRNA transcript. This transcript was also identified in human small intestine and colon, as well as in several extra-intestinal tissues. Functional analysis of subcloned fragments reveals that ST binding activity is induced by a 457-base pair human Alu repetitive sequence within the cDNA and that the phenotype is independent of orientation. These findings suggest that a human Alu element induces expression of a unique ST receptor by a transacting mechanism. An unrelated Alu-rich genomic clone did not confer ST binding, suggesting that there may be structural and functional specificity within individual Alu sequences.
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PMID:Induction of heat-stable enterotoxin receptor activity by a human Alu repeat. 820 79

Nitric Oxide (NO) is synthesized in the intestinal tract and may serve as a physiological regulator of intestinal ion transport and/or a pathophysiologic mediator of secretory diarrhea associated with inflammatory mucosal diseases. Indirect approaches, employing inhibitors of nitric oxide synthase or compounds capable of donating NO in solution, have been used to demonstrate the effects on gastrointestinal muscle and the mucosa. To determine directly whether nitric oxide itself is capable of stimulating electrolyte secretion we mounted muscle-stripped rat distal colon in Ussing chambers and monitored short-circuit current (Isc), as an indicator of effects on mucosal ion transport. Comparisons were made to sodium nitroprusside (SNP). NO and SNP stimulated concentration-dependent (0.1 microM to 100 microM) increases in Isc, with NO being more potent than SNP. The EC50 for NO was approximately 8 microM compared to a value < 20 microM for SNP. The response to NO was immediate. In contrast, SNP required a mean lag-time of 41 +/- 4 seconds, and a significantly longer time was required for SNP to reach its maximum effect. The response to both of these agonists was blocked by bumetanide, indicating that they were stimulating a chloride ion secretory response. The cyclooxygenase inhibitor piroxicam, the neurotoxin tetrodotoxin and the inhibitor of guanylate cyclase, methylene blue, all inhibited the response to both agonists. These studies demonstrate that NO itself can stimulate chloride secretion by the rat colonic mucosa through a prostaglandin-dependent, and partially neural mechanism that may involve guanylate cyclase.
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PMID:Direct evidence for nitric oxide stimulation of electrolyte secretion in the rat colon. 829 47

Enterotoxigenic Escherichia coli elaborate a heat-stable enterotoxin that causes diarrhea in humans and animals. The primary event in the diarrheal cascade is the binding of this enterotoxin to specific receptors on enterocytes and activation of guanylyl cyclase. Two intestinal cell lines, Caco-2 and IEC-6, were tested for the presence of these receptors. Although both cell lines exhibited specific binding, only the Caco-2 cell line responded to heat-stable enterotoxin with increased guanylyl cyclase activity. Cloning and expression studies confirmed that the receptor present in Caco-2 cells is a homologue of guanylyl cyclase C, a known transmembrane heat-stable enterotoxin receptor. Expression of the receptor in differentiating Caco-2 cells increases with cell maturation, indicating that these cells are a suitable model for future studies. However, Northern and polymerase chain reaction analyses demonstrated that guanylyl cyclase C is not expressed in IEC-6 cells, strongly suggesting the presence of a novel heat-stable enterotoxin receptor that is not coupled to guanylyl cyclase activity.
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PMID:Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells. 838 96


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