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| Entity | Colorectal cancer |
| Note | The endogenous GUCY2C ligands, guanylin and uroguanylin, are lost early in the neoplastic process, resulting in inactivation of downstream tumor suppressive GUCY2C signaling. Targeted deletion of GUCY2C in mice results in a phenotype of intestinal cancer susceptibility in the context of predisposing genetic mutations (apcmin) or exposure to carcinogen (azoxymethane). GUCY2C has a wide range of homeostatic functions in preventing tumorigenesis, including regulation of crypt proliferation, DNA damage repair and oncogenic signaling such as PI3K/Akt (Li et al., 2007a; Li et al., 2007b; Lin et al., 2010). |
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| Entity | Obesity |
| Note | GUCY2C is expressed in the hypothalamus, and targeted deletion in mice results in an obese phenotype which has been attributed to increased food consumption and dysregulated satiety. Importantly, the GUCY2C hormone ligand uroguanylin has been shown to mediate this effect. The uroguanylin peptide is released into the circulation postprandially and travels to the brain where it induces satiety in the hypothalamus, thus comprising a gut-brain neuroendocrine axis which regulates feeding (Valentino et al., 2011). |
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| Entity | Irritable bowel syndrome with constipation (IBS-C), and associated abdominal pain |
| Note | GUCY2C is a known mediator of intestinal fluid secretion. Work in mice and humans has demonstrated that the bacterial heat stable enterotoxin (ST) causes GI fluid secretion, motility and diarrhea via GUCY2C activation in the intestine. Recently, an oral GUCY2C ligand linaclotide (Linzess Ironwood Pharmaceuticals) was approved by the FDA for treatment of constipation-predominant irritable bowel syndrome (IBS). Further work has revealed a role for linaclotide in preventing GI pain associated with IBS. The mechanism for this effect is believed to be release of cGMP by enterocytes from their basolateral membrane following ligand activation. This cGMP then inhibits nociception in adjacent visceral neurons, relieving pain (Chey et al., 2012; Castro et al., 2013). |
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| Entity | Inflammatory bowel disease (IBD) / colitis |
| Note | Work in mice has identified a possible role for GUCY2C in preventing colitis. Targeted deletion of GUCY2C results in more severe disease in a chemical model of colitis. Additionally, oral administration of GUCY2C ligand improved colitis in wild-type mice in the same model. These findings suggest a role for GUCY2C in regulating intestinal inflammation and associated disorders (Lin et al., 2012). |
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| Entity | Attention deficit hyperactivity disorder (ADHD) |
| Note | Work in mice has demonstrated the presence of GUCY2C in midbrain neurons, and targeted deletion of GUCY2C resulted in a phenotype of hyperactivity, which was reversible by treating with either ADHD therapeutics or an activator of downstream GUCY2C signaling (PKG activator) (Gong et al., 2011). |
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| Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. |
| Castro J, Harrington AM, Hughes PA, Martin CM, Ge P, Shea CM, Jin H, Jacobson S, Hannig G, Mann E, Cohen MB, MacDougall JE, Lavins BJ, Kurtz CB, Silos-Santiago I, Johnston JM, Currie MG, Blackshaw LA, Brierley SM. |
| Gastroenterology. 2013 Dec;145(6):1334-46.e1-11. doi: 10.1053/j.gastro.2013.08.017. Epub 2013 Aug 16. |
| PMID 23958540 |
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| Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. |
| Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, MacDougall JE, Jia XD, Shao JZ, Fitch DA, Baird MJ, Schneier HA, Johnston JM. |
| Am J Gastroenterol. 2012 Nov;107(11):1702-12. |
| PMID 22986437 |
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| Familial diarrhea syndrome caused by an activating GUCY2C mutation. |
| Fiskerstrand T, Arshad N, Haukanes BI, Tronstad RR, Pham KD, Johansson S, Havik B, Tonder SL, Levy SE, Brackman D, Boman H, Biswas KH, Apold J, Hovdenak N, Visweswariah SS, Knappskog PM. |
| N Engl J Med. 2012 Apr 26;366(17):1586-95. doi: 10.1056/NEJMoa1110132. Epub 2012 Mar 21. |
| PMID 22436048 |
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| Role for the membrane receptor guanylyl cyclase-C in attention deficiency and hyperactive behavior. |
| Gong R, Ding C, Hu J, Lu Y, Liu F, Mann E, Xu F, Cohen MB, Luo M. |
| Science. 2011 Sep 16;333(6049):1642-6. doi: 10.1126/science.1207675. Epub 2011 Aug 11. |
| PMID 21835979 |
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| Homeostatic control of the crypt-villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine. |
| Li P, Lin JE, Chervoneva I, Schulz S, Waldman SA, Pitari GM. |
| Am J Pathol. 2007a Dec;171(6):1847-58. Epub 2007 Nov 1. |
| PMID 17974601 |
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| Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. |
| Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, Baran AA, Siracusa LD, Pitari GM, Waldman SA. |
| Gastroenterology. 2007b Aug;133(2):599-607. Epub 2007 Jun 2. |
| PMID 17681179 |
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| The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. |
| Lin JE, Li P, Snook AE, Schulz S, Dasgupta A, Hyslop TM, Gibbons AV, Marszlowicz G, Pitari GM, Waldman SA. |
| Gastroenterology. 2010 Jan;138(1):241-54. doi: 10.1053/j.gastro.2009.08.064. Epub 2009 Sep 6. |
| PMID 19737566 |
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| GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. |
| Lin JE, Snook AE, Li P, Stoecker BA, Kim GW, Magee MS, Garcia AV, Valentino MA, Hyslop T, Schulz S, Waldman SA. |
| PLoS One. 2012;7(2):e31686. doi: 10.1371/journal.pone.0031686. Epub 2012 Feb 22. |
| PMID 22384056 |
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| Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. |
| Romi H, Cohen I, Landau D, Alkrinawi S, Yerushalmi B, Hershkovitz R, Newman-Heiman N, Cutting GR, Ofir R, Sivan S, Birk OS. |
| Am J Hum Genet. 2012 May 4;90(5):893-9. doi: 10.1016/j.ajhg.2012.03.022. Epub 2012 Apr 19. |
| PMID 22521417 |
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| A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. |
| Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA. |
| J Clin Invest. 2011 Sep;121(9):3578-88. doi: 10.1172/JCI57925. Epub 2011 Aug 25. |
| PMID 21865642 |
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