Guanylate Cyclase-C Receptor and Ligand Expression in Colonic Mucosa in Chronic Constipation

Videlock, Elizabeth J.; Mahurkar-Joshi, Swapna; Hoffman, Jill M.; Shih, Wendy; Alberto, Melissa; Chang, Lin

doi:10.14309/00000434-201410002-01826

Cited by 3 publications

(2 citation statements)

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“…However, there was significant negative correlation between levels of expression of guanylin protein (endogenous ligand of guanylate cyclase C receptor resulting in chloride and water secretion) and current overall GI symptom severity in patients with chronic constipation (r = À0.701, P = 0.024). 28 These differential mucosal expressions represent potential biomarkers of mechanisms resulting in the common symptom phenotype, such as increased expression of uroguanylin presumed from the increased mRNA expression of GUCA2B in IBS-D, and reduced protein levels of guanylin protein in patients with chronic constipation. Further validation of these biomarkers may provide targets for individualised therapy in patients with IBS-C or IBS-D, such as guanylate cyclase C agonists or chloride channel activators for IBS-C with reduced guanylin protein levels, or tenapanor, a minimally absorbed small molecule inhibitor of NHE3 which is a transporter of sodium in patients with IBS-C that bypasses the chloride secretory pathway in the enterocyte (reviewed in ref.…”

Section: Single or Combination Biomarkers For Diagnosis Of Ibs?mentioning

confidence: 99%

“…In a study of mRNA expression in colonic mucosa in 12 patients with chronic constipation and 12 healthy controls (all female), there were no significant group differences in expression of the GC‐C receptor or endogenous GC‐C receptor agonists (guanylin and uroguanylin), or expression of the cGMP transporter proteins. However, there was significant negative correlation between levels of expression of guanylin protein (endogenous ligand of guanylate cyclase C receptor resulting in chloride and water secretion) and current overall GI symptom severity in patients with chronic constipation ( r = −0.701, P = 0.024) …”

Section: Introductionmentioning

confidence: 99%

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Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders

Camilleri

2015

Aliment Pharmacol Ther

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SUMMARY Background Treatment of IBS and lower functional gastrointestinal disorders is still based predominantly on symptoms; biomarkers that reflect the mechanism or pathophysiology have been identified. Given the diverse mechanisms that result in the same clinical phenotype of IBS, it is hypothesized that identification of biomarkers may lead to individualization of medical therapy. Aim To review the biomarkers that have been appraised in IBS. Methods A single author reviewed the published literature on biomarkers appraised in IBS. Results The current literature suggests that these biomarkers are insufficiently sensitive or specific to differentiate IBS from health or from other diseases causing similar symptoms, such as celiac disease or inflammatory bowel disease. Most of the proposed biomarkers are not actionable, that is, they do not lead to an efficacious therapy based on the biological inference of the biomarker itself. However, among proposed biomarkers in IBS, some are actionable, as they specifically reflect a quantitative difference in a mediator of dysfunction or result in a quantifiable disturbance of function that can be specifically treated. Such biomarkers may potentially identify relevant subgroups that respond to specific therapy. The most promising actionable biomarkers are measurement of colonic transit (leading to treatments that reverse the abnormal transit) and measurements of bile acid diarrhea to identify responders to bile acid sequestrants. Conclusions Therefore, although biomarkers are not ready for prime time as diagnostic tests in IBS, some biomarkers could identify subgroups of patients with IBS for inclusion in clinical trials that target specific dysfunctions. Such an approach may enhance treatment efficacy, and may ultimately help reduce costs in drug development and in the management of patients in clinical practice.

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Section: Single or Combination Biomarkers For Diagnosis Of Ibs?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders

Camilleri

2015

Aliment Pharmacol Ther

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Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders

Waldman

Camilleri

2018

Gut

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Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome–constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs.

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Catalytic region mimetics in Na+/H+ exchanger regulatory factor 4 suppress Guanylate Cyclase 2C activity to regulate enterotoxin triggered diarrhea

Ramananda,

Liyanage,

Huang

et al. 2024

Preprint

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Guanylate cyclase 2C (GCC), a receptor for bacterial heat-stable enterotoxin ST on the apical intestinal epithelium, generates cGMP and causes excessive intestinal secretion leading to diarrhea upon activation. This study reports that the C-terminal PSD95, Dlg1, ZO-1 (PDZ) domain interacting motif in GCC interacts with scaffolding proteins sodium-hydrogen exchanger regulatory factor (NHERF)1–4. NHERF4 binding inhibits GCC catalytic activity, unlike NHERF1, 2, and 3. The inhibition of GCC activity was mimicked by two synergistically acting NHERF4 peptides (N4-110 [NH2-LERPRFCLL-COOH] and N4-195 [NH2-RHAHDVARAQLG-COOH]), peptides with high sequence homology to the GCC catalytic domain. In native NHERF4, these peptides are in close spatial proximity to each other within the PDZ domain. Based on 3-D guanylate cyclase domain modeling, the binding sites for N4-110 and N4-195 were both mapped to the GCC dimer interface. FRET analysis confirmed that NHERF4 PDZ1 domain binding interferes with GCC oligomerization. Studies in murine and human enteroid models showed that NHERF4 binding and inhibition of GCC activity are enhanced by excessive GCC activation following ST stimulation. This suggests NHERF4 inhibits unregulated GCC activity in diarrhea. Overall, our findings reveal a novel regulatory mechanism of GCC, offering insights for developing new therapies for enterotoxin-triggered diarrheas.

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Guanylate Cyclase-C Receptor and Ligand Expression in Colonic Mucosa in Chronic Constipation

Cited by 3 publications

References 0 publications

Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders

Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders

Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders

Catalytic region mimetics in Na+/H+ exchanger regulatory factor 4 suppress Guanylate Cyclase 2C activity to regulate enterotoxin triggered diarrhea

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