Diarrhea, GC-C and guanylin

During my fellowship, I participated in research studying the effects of guanylin and its interaction with the receptor, guanylate cyclase C (GC-C).  So whenever clinical articles demonstrate clinical significance, I am interested.  This month there is evidence that some cases of familial diarrhea are due to mutations which activate the GC-C receptor (NEJM 2012; 366: 1586-95).

The authors describe a novel dominant disease in 32 members of a Norwegian family due  to a mutation in the sequence of GUCYC which encodes GC-C.  Exposure of this mutant receptor to its ligands results in increased cyclic guanosine monophosphate (cGMP).  This in turn likely causes hyperactivation of the cystic fibrosis transmembrance regulator (CFTR)  resulting in diarrhea.  Individuals with this mutation tended to have mild chronic diarrhea with an early onset as well as a susceptibility to inflammatory bowel disease and small bowel obstruction.

While this mutation is rare, there is a larger role for GC-C.  Heat-stable enterotoxins form E. coli bind to this receptor starting a cascade which results in diarrhea.  Since there had to be a role for GC-C other than facilitating development of diarrhea after exposure to pathogens (Why would our body create a receptor for a pathogen?), researchers discovered an endogenous ligand for GC-C, guanylin.   Guanylin acts as an agonist of  GC-C and regulates electrolyte and water transport in intestinal and renal epithelia.  In addition, guanylin and GC-C serve as a model for intestinal gene regulation.  Also, GC-C has been investigated as a predictive marker for colorectal cancer and for a role in renal electrolyte transport in humans; in animals, GC-C and its ligands have been shown to have effects on behavior and satiety.  

Additional references:

  • -Steinbrecher KA, Cohen MB. Transmembrane guanylate cylase in intestinal pathophysiology. Curr Opin Gastroenterol 2011; 27: 139-45.
  • -Gastroenterology 2010; 138: 886.  Linaclotide -a guanylin analog –use for constipation.
  • -Hochman JA, Sciaky D, Whittaker T, Hawkins JA, Witte DP, Cohen MB. “HNF-1 Regulates the Transcriptional Activation of Guanylin” Am. J.  Physiol. 273 (Gastrointest. Liver Physiol. 36): G833-G841, 1997.
  • It’s often elemental  Previous post discusses protracted diarrhea of infancy

2 thoughts on “Diarrhea, GC-C and guanylin

  1. Pingback: Linaclotide –not for kids | gutsandgrowth

  2. Pingback: FDA Approves Plecanatide (Trulance) for Adults with Idiopathic Constipation | gutsandgrowth

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