Uroguanylin

Our proprietary gastrointestinal (GI) platform is based on uroguanylin, a naturally occurring human GI peptide that plays an important role in supporting normal bowel function.1,2

Guanylate cyclase-C (GC-C) receptors are located throughout the GI tract and can be activated to increase intracellular concentrations of cyclic guanosine monophosphate (GMP).1,3

Genetic alterations of the GC-C receptor have been shown to cause constipation or diarrhea.4,5

Elevated intracellular cyclic GMP activates cyclic GMP- and cyclic AMP-dependent protein kinases that leads to6:

  • Activation of cystic fibrosis transmembrane conductance regulator (CFTR), which results in the secretion of chloride and bicarbonate into the intestinal lumen7,8
  • Inhibition of sodium-hydrogen exchange that results in reduced reabsorption of sodium7,8 

The net result of this cascade is water flux into the lumen of the GI tract to increase stool function.6 In addition, GC-C-receptor activation may lead to decreased inflammation and pain sensation in the GI tract.9

Uroguanylin binding to GC-C receptors is pH-dependent and more potent at slightly acidic pH levels.10 Therefore, its activity is primarily targeted to the proximal small bowel in a regulated manner.11 

Uroguanylin physiologically regulates bowel function, fluid balance, and stool consistency.2

Dysregulation of fluid balance in the GI tract may contribute to the etiology of chronic idiopathic constipation and chronic irritable bowel syndrome.

Uroguanylin and GI Fluid Balance

See how uroguanylin helps play a key role in the GI process.

References

  1. Hamra FK, Forte LR, Eber SL, et al. Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase. Proc Natl Acad Sci USA. 1993;90:10464–10468.
  2. Gonzalez-Martinez MA, Ortiz-Olvera NX, Mendez-Navarro J. Novel pharmacological therapies for management of chronic constipation. J Clin Gastroenterol. 2014;48(1):21–28.
  3. Krause WJ, Cullingford GL, Freeman RH, et al. Distribution of heat-stable enterotoxin/guanylin receptors in the intestinal tract of man and other mammals. J Anat. 1994;184:407–417.
  4. Romi H, Cohen I, Landau D, et al. Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. Am J Hum Genet. 2012;90:893–899.
  5. Fiskerstrand T, Arshad N, Haukanes BI, et al. Familial diarrhea syndrome caused by an activated GUCY2C mutation. N Engl J Med. 2012;366(17):1586–1595.
  6. Arshad N, Visweswariah SS. The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis. FEBS Lett. 2012;586:2835–2840.
  7. Sindic A. Current understanding of guanylin peptides actions. ISRN Nephrol. 2013;2013:1–17.
  8. Lee MG, Wigley WC, Zeng W, et al. Regulation of Cl3/HCO3 exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells. J Biol Chem. 1999;274(6):3414–3421.
  9. Silos-Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain. 2013;154:1820–1830.
  10. Hamra FK, Eber SL, Chin DT, Currie MG, Forte LR. Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity. Proc Natl Acad Sci USA. 1997;94:2705–2710.
  11. Bown RL, Gibson JA, Sladen GE, Hicks B, Dawson AM. Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device. Gut. 1974;15:999–1004.