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  • Given the role that activation of GC C has


    Given the role that activation of GC-C has in stimulating fluid secretion in the intestine, attempts have been made to exploit this pathway to relieve symptoms of chronic constipation. Currently, an orally administered synthetic ST mimic, linaclotide [29], has been successfully shown to alleviate constipation [30], and this drug is currently awaiting FDA approval. The mechanism of ST-induced diarrhea is unique in that it is the only example where the primary target of a diarrheal disease-causing agent is a receptor directly controlling intestinal fluid-ion homeostasis. GC-C is well conserved from Pisces to Mammalia and given its function and exploitation by microbes to cause a disease, it was anticipated that the receptor was conserved because of its importance in intestinal physiology [16]. Two independent groups generated knock-out mice for GUCY2C, the gene encoding GC-C. Surprisingly, the GC-C knock-out mouse showed no abnormalities in the gut that pha web could be associated with luminal dehydration, but were found to be resistant to ST-induced diarrhea [31], [32]. This appeared to be paradoxical for a receptor so well conserved evolutionarily, suggesting that the critical role(s) of GC-C would become apparent when animals were subjected to stresses not normally encountered in the restricted environment in which these knock-out mice were bred. It is worth mentioning at this stage that extra-intestinal roles for GC-C, specifically in the nervous system, emerged on studies with the knock-out mouse, and warrant a brief summary. Hyperphagia, obesity and metabolic syndrome were observed in GC-C knock-out mice, and these functions appeared to be controlled by circulating levels of uroguanylin, and neuronally-expressed GC-C [33]. This finding was the first report of specific extra-intestinal roles for both GC-C and uroguanylin, highlighting the endocrine function of uroguanylin, which is primarily synthesized in the intestine and acts on intestinal GC-C in a paracrine manner [34]. A second example for the role of GC-C in the nervous system was reported by Gong et al. [35]. Midbrain dopamine neurons express GC-C, and on activation enhance excitatory responses mediated by glutamate and pha web in a cGMP and PKG-dependent manner. GC-C knock-out mice demonstrated attention deficiency and hyperactive behavior, which was reversed on administration of a PKG activator. GC-C, guanylin and uroguanylin are expressed in reproductive tissues of the rat [36], though no role for this signaling pathway has been described in these tissues. Perhaps subtle roles for this signaling axis, in controlling fertility and reproduction may become evident in the future through studies on the GC-C knock-out mouse.
    Role of GC-C and cGMP in colon cancer cell cytostasis The intestinal epithelium undergoes homeostatic cycles of proliferation, migration, differentiation and apoptosis, driven by multipotent stem cells. An imbalance between cell proliferation and apoptosis can therefore lead to the formation of tumours within the gastrointestinal tract. Some years ago, it was noted that there appeared to be an inverse correlation between the incidence of colorectal cancer and secretory diarrhea caused by ETEC [37], leading to the hypothesis that activated GC-C could act as an anti-proliferative agent in the intestine. Studies on both colorectal cell lines [38] as well as GC-C knock-out mice [39] indicated that GC-C exerts a cytostatic effect on epithelial cells following ligand-mediated activation. This induction of colon cell cytostasis was mediated by the regulation of calcium ion influx via a cyclic nucleotide gated channel, and was mimicked by analogs of cGMP [27], [40], [41]. Additional signaling pathways in the intestinal cell also appear to be modulated by GC-C activity. Thus, in GC-C knock-out mice, an increased activity of Akt (protein kinase B) was observed, resulting in accelerated cell proliferation, which could be reversed by the administration of cGMP [39]. In human colonic cell lines, activation of GC-C resulted in changes in the expression of genes that are involved in the Akt signaling pathway, suggesting that GC-C could prevent intestinal tumour formation by inhibiting Akt signaling [39]. It is not readily apparent at this time whether calcium influx and/or lower Akt activity are principally responsible for mediating the cytostatic effects of activated GC-C. It is equally likely that the main driving force for inducing colon cell cytostasis may involve other signaling molecules that are operative under a particular intestinal milieu, and such studies are awaited.