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Curr Opin Pharmacol. 2012 Dec;12(6):632-40. doi: 10.1016/j.coph.2012.10.005. Epub 2012 Nov 3.

Guanylate cyclase-C receptor activation: unexpected biology.

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1
Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, 5000 Australia. stuart.brierley@adelaide.edu.au

Abstract

Guanylate cyclase-C (GC-C) is a transmembrane receptor activated by bacterial heat-stable enterotoxins and by the endogenous hormones guanylin and uroguanylin. GC-C plays key roles in the regulation of intestinal fluid and electrolyte homeostasis. This is highlighted by several recently identified human mutations in GUCY2C, the gene encoding GC-C, which leads to the respective gain or loss of function of GC-C, resulting in profound effects on gastrointestinal function. However, a wealth of recent studies indicates GC-C signalling extends to a multitude of diverse additional functions. Recent pre-clinical and clinical studies demonstrate a novel first-in-class GC-C activating peptide, Linaclotide, provides effective relief from constipation and abdominal pain in patients with chronic constipation and constipation-predominant Irritable Bowel Syndrome. Accumulating evidence also suggests GC-C plays protective roles in mucosal barrier function, tissue injury and inflammation, whilst GC-C signalling is a key regulator of intestinal cell proliferation and apoptosis. Finally, recently identified extra-intestinal GC-C signalling pathways make novel contributions to the regulation of food intake and symptoms associated with Attention Deficit Hyperactivity Disorder. Consequently, these findings provide GC-C expression and its associated mutations as potential diagnostic markers for disease. They also provide current and future therapeutic potential for GC-C signalling within and outside the gastrointestinal tract.

PMID:
23131468
DOI:
10.1016/j.coph.2012.10.005
[Indexed for MEDLINE]
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