title: Guanylate cyclase-C receptor activation: unexpected biology.
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.
authors.affiliation: Nerve-Gut Research Laboratory, Discipline of Medicine, The University of Adelaide, Adelaide, South Australia, 5000 Australia. stuart.brierley@adelaide.edu.au
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Brierley
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004573:Electrolytes / Q000378:metabolism; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression; D006801:Humans; D007419:Intestinal Secretions / Q000378:metabolism; D009154:Mutation; D010455:Peptides / Q000494:pharmacology; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D004573:Electrolytes; D010455:Peptides; D018000:Receptors, Peptide; C000613654:GUCY2C protein, human; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; C523483:linaclotide