Article

Transmembrane guanylate cyclase in intestinal pathophysiology

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Current opinion in gastroenterology (Impact Factor: 3.66). 03/2011; 27(2):139-45. DOI: 10.1097/MOG.0b013e328341ead5
Source: PubMed

ABSTRACT Production of cyclic guanosine monophosphate (cGMP) by guanylate cyclase is of critical importance to gastrointestinal physiology. Tight regulation of cGMP concentration is necessary for proper intestinal secretion and intestinal epithelial cell proliferative and apoptotic homeostasis. This review focuses on recent work detailing the role of a subset of transmembrane guanylate cyclases in the pathophysiology of intestinal secretory and motility disorders and intestinal epithelial cell transformation. Also considered is the potential for therapeutic manipulation of intestinal guanylate cyclase/cGMP signaling for the correction of chronic constipation and gastrointestinal cancer.
Recent work in mice and humans suggests a role for transmembrane guanylate cyclases in intestinal fluid secretion as well as hormonal enteric-renal signaling which mediates postprandial natriuresis. Transmembrane guanylate cyclases are also important in gastrointestinal transit rate and motility. Ongoing clinical trials have found that guanylate cyclase activating peptides are safe and effective in the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. In addition, accumulating evidence indicates that membrane-associated guanylate cyclase receptors regulate intestinal epithelial cell homeostatic proliferation and apoptosis as well as gastrointestinal malignancy. The anticancer activity of cGMP signaling in animal studies suggests additional therapeutic applications for guanylate cyclase agonists.
Progress toward understanding gastrointestinal transmembrane guanylate cyclase/cGMP physiology has recently accelerated due to definitive in-vitro studies and work using gene-targeted animal models and has facilitated the development of safe and effective drugs designed to regulate cGMP production in the intestine. Current work should be directed toward a detailed understanding of cGMP effector pathways and the manner in which subcellular concentrations of cGMP regulate them to influence intestinal health and disease.

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    • "Ligand binding to transmembrane guanylate cyclase (GC) receptors initiates cyclic guanosine monophosphate (cGMP) production and activates a variety of cell-type specific signaling cascades [1], [2]. The primary transmembrane GC on epithelial cells of the intestine is guanylate cyclase C (GC-C) which binds peptide ligands present in the lumen of the gut. "
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    ABSTRACT: Guanylate Cyclase C (GC-C; Gucy2c) is a transmembrane receptor expressed in intestinal epithelial cells. Activation of GC-C by its secreted ligand guanylin stimulates intestinal fluid secretion. Familial mutations in GC-C cause chronic diarrheal disease or constipation and are associated with intestinal inflammation and infection. Here, we investigated the impact of GC-C activity on mucosal immune responses. We utilized intraperitoneal injection of lipopolysaccharide to elicit a systemic cytokine challenge and then measured pro-inflammatory gene expression in colonic mucosa. GC-C(+/+) and GC-C(-/-) mice were bred with interleukin (IL)-10 deficient animals and colonic inflammation were assessed. Immune cell influx and cytokine/chemokine expression was measured in the colon of wildtype, IL-10(-/-), GC-C(+/+)IL-10(-/-) and GC-C(-/-)IL-10(-/-) mice. GC-C and guanylin production were examined in the colon of these animals and in a cytokine-treated colon epithelial cell line. Relative to GC-C(+/+) animals, intraperitoneal lipopolysaccharide injection into GC-C(-/-) mice increased proinflammatory gene expression in both whole colon tissue and in partially purified colonocyte isolations. Spontaneous colitis in GC-C(-/-)IL-10(-/-) animals was significantly more severe relative to GC-C(+/+)IL-10(-/-) mice. Unlike GC-C(+/+)IL-10(-/-) controls, colon pathology in GC-C(-/-)IL-10(-/-) animals was apparent at an early age and was characterized by severely altered mucosal architecture, crypt abscesses, and hyperplastic subepithelial lesions. F4/80 and myeloperoxidase positive cells as well as proinflammatory gene expression were elevated in GC-C(-/-)IL-10(-/-) mucosa relative to control animals. Guanylin was diminished early in colitis in vivo and tumor necrosis factor α suppressed guanylin mRNA and protein in intestinal goblet cell-like HT29-18-N2 cells. The GC-C signaling pathway blunts colonic mucosal inflammation that is initiated by systemic cytokine burst or loss of mucosal immune cell immunosuppression. These data as well as the apparent intestinal inflammation in human GC-C mutant kindred underscore the importance of GC-C in regulating the response to injury and inflammation within the gut.
    PLoS ONE 11/2013; 8(11):e79180. DOI:10.1371/journal.pone.0079180 · 3.23 Impact Factor
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    • "It has long been speculated that this GC-C-conferred susceptibility to some forms of enteric infection is offset by a critical role for this receptor in intestinal homeostasis. We and others have suggested that GC-C is important for epithelial ion transport, cell proliferation, and barrier function and that GC-C modulates intestinal disorders ranging from cystic fibrosis to gastrointestinal cancer to intestinal injury and inflammation via these effects [14,16-18,45]. Here, we extend the role of GC-C in the intestine by demonstrating that, although it is exploited by ST-producing ETEC, this pathway is highly protective during enteric infection by attaching/effacing bacterial pathogens which do not produce ST toxin. "
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    ABSTRACT: Guanylate Cyclase C (GC-C) is an apically-oriented transmembrane receptor that is expressed on epithelial cells of the intestine. Activation of GC-C by the endogenous ligands guanylin or uroguanylin elevates intracellular cGMP and is implicated in intestinal ion secretion, cell proliferation, apoptosis, intestinal barrier function, as well as the susceptibility of the intestine to inflammation. Our aim was to determine if GC-C is required for host defense during infection by the murine enteric pathogen Citrobacter rodentium of the family Enterobacteriacea. GC-C+/+ control mice or those having GC-C genetically ablated (GC-C-/-) were administered C. rodentium by orogastric gavage and analyzed at multiple time points up to post-infection day 20. Commensal bacteria were characterized in uninfected GC-C+/+ and GC-C-/- mice using 16S rRNA PCR analysis. GC-C-/- mice had an increase in C. rodentium bacterial load in stool relative to GC-C+/+. C. rodentium infection strongly decreased guanylin expression in GC-C+/+ mice and, to an even greater degree, in GC-C-/- animals. Fluorescent tracer studies indicated that mice lacking GC-C, unlike GC-C+/+ animals, had a substantial loss of intestinal barrier function early in the course of infection. Epithelial cell apoptosis was significantly increased in GC-C-/- mice following 10 days of infection and this was associated with increased frequency and numbers of C. rodentium translocation out of the intestine. Infection led to significant liver histopathology in GC-C-/- mice as well as lymphocyte infiltration and elevated cytokine and chemokine expression. Relative to naive GC-C+/+ mice, the commensal microflora load in uninfected GC-C-/- mice was decreased and bacterial composition was imbalanced and included outgrowth of the Enterobacteriacea family. This work demonstrates the novel finding that GC-C signaling is an essential component of host defense during murine enteric infection by reducing bacterial load and preventing systemic dissemination of attaching/effacing-lesion forming bacterial pathogens such as C. rodentium.
    BMC Gastroenterology 09/2013; 13(1):135. DOI:10.1186/1471-230X-13-135 · 2.11 Impact Factor
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    ABSTRACT: In Crohn’s Disease (CD) and ulcerative colitis (UC), the major manifestations of inflammatory bowel disease (IBD), genetically predisposed individuals develop chronic intestinal inflammation in response to environmental stimuli, which are mainly derived from luminal flora. Intestinal responses to luminal flora breaching the intestinal barrier require cytokine-regulated activation of elements of innate and acquired immunity, leading to a targeted and contained inflammatory response. Recent population-based genetic analyses have identified polymorphisms in specific genes relevant to pathways critical for inflammatory signalling and cellular response to stress as carrying increased risk for the development of either CD or UC. Specifically, key mediators of apoptosis and autophagy are implicated in the genetic vulnerability to IBD. Patients with IBD have a compromise of their intestinal barrier integrity, as do their first-degree relatives even in the absence of clinical disease, underscoring the critical nature of barrier integrity in the prevention of aberrant immune responses to intestinal flora. Here we explore the relationships between two of the key proinflammatory cytokines mediating intestinal inflammation in IBD, TNF-α and IFNγ, and the mechanisms by which they regulate epithelial apoptosis and intestinal barrier. Specifically we review factors regulating the balance between pro- and antiapoptotic stimuli resulting from the activation of NF-κB and Aktdependent signalling by proinflammatory cytokines, as well as the influence of oxygen tension and nutritional factors on these pathways.
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