Luminary Learning Gastrointestinal Disorder- Issue 1

16  • LUMINARY LEARNING: GASTROINTESTINAL DISORDERS depending on the receptor type. Serotonin secreted by the EC cells mediates various GI func- tions including those involved in the pathophysiology of IBS such as peristalsis, electrolyte secre- tion and absorption, vasodilatation, as well as perception of pain (for comprehensive review, see Mawe et al. [2]). Moreover, it has been shown that the plasma 5-HT concentration correlates with colonic motility under both fasting and fed conditions [1]. Hence, perhaps not surprisingly, serotonin system has been recognized as one of the most promising targets for anti-IBS drugs and stimulation of serotonin receptors has been clinically validated for the treatment of disorders manifested by disturbed intestinal motility and pain. Chloride Ion Channel 2 in the Gastrointestinal Tract Chloride ion channels (ClC) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. To date several types of ClC have been identified, including ClC-0, ClC-1, ClC-2, ClC-4 and ClC-5 [5]. CICs are involved in the regulation of the excitability of neurones, smooth muscle cells, cell volume control and transepithelial salt transport. Chloride ion channel-2 is a member of the ClC family that is ubiquitously expressed in mam- malian tissues and has been found in both small and large intestinal epithelial cells as well as on GI parietal cells [6]. In the physiological membrane conditions the channel is closed; however, it may be activated by hyperpolarisation, cell swelling as well as acidic extracellular pH [5]. Chloride secretion is responsible for maintenance of mucosal hydration throughout the GI tract, and chlo- ride transport is also pivotal in the regulation of fluid secretion into the intestinal lumen [6]. Activation of ClC-2 enables translocation of chloride ions across the membrane followed by the release of sodium and water into the gut lumen. The influx of fluid into the intestine promotes GI motility and increases the colonic transit together with the number of spontaneous bowel move- ments. The surplus of water is absorbed by the colonic epithelial tissue what limits the emergence of diarrhea [6]. Taken together, ClC-2 has been validated as a target for the treatment of chronic idiopathic constipation as well as constipation-predominant IBS (IBS-C) [7]. Guanylate Cyclase-C in the Gastrointestinal Tract Guanylate cyclase-C is a transmembrane enzyme, belonging to the protein family synthesizing one of the most common and important secondary messengers—cyclic guanosine monophos- phate (cGMP) [8]. There are seven members of the GC family (GC-A–G); however, only GC-C has been validated as a pharmacological target for the treatment of GI pathologies. The endogenous activators of GC-C include peptides, guanylin and uroguanylin which play important function in the maintenance of gut homeostasis. Moreover, GC-C is known as a target protein for heat- stable enterotoxins produced by numerous enteric pathogens that colonize intestines, including Escherichia coli, Citrobacter freundii, Vibrio cholerae and Yersinia enterocolitica [8, 9]. GC-C is expressed on the brush border of intestinal cells along the small and large intestine. Its expression is regulated by intestine-specific transcription factor Cdx2 and is higher in the crypt of the colonic mucosa compared to the crypt of the small intestine [10, 11].