Luminary Learning Gastrointestinal Disorder- Issue 1

Pharmacological and Clinical Treatment of Irritable Bowel Syndrome •  17 Activation of GC-C leads to the increase of the intracellular level of cGMP, what causes acti- vation of the cGMP-dependent protein kinase II (PKG II). PKG II by phosphorylation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel induces secretion of chloride and HCO 3 -into the intestinal lumen. Moreover, cGMP reduces absorption of Na + ions by Na + /H + exchanger [11]. All these events lead to the accumulation of osmotically active molecules in the intestines what causes massive influx of water and increased excretion [12]. The pro-excretory properties of GC-C activators have been exploited in the development of synthetic GC-C agonists that are used in the treatment of functional GI disorders manifested by chronic constipation, such as IBS-C [8, 13, 14]. Cystic Fibrosis Transmembrane Conductance Regulator in the Gastrointestinal Tract Cystic fibrosis transmembrane conductance regulator is a cyclic AMP (cAMP)-regulated ion channel that transfers chloride and thiocyanate ions through the membrane of various types of epithelial cells. It consists of two transmembrane domains linked by the R domain whose phos- phorylation by the protein kinase A (PKA) leads to the opening of the gate for the ions [15]. The expression of CFTR alters throughout the GI tract. The lowest level is observed in the mucosal epithelium of the stomach. In the ileum the expression is relatively high and exhibits decreasing gradient along the crypt axis [16]. Furthermore, a small subpopulation of the cells of yet unre- vealed function has been shown to express CFTR in the duodenum and jejunum [16]. In the colon the expression of CFTR is the highest in the base of the crypts and resembles the pattern occur- ring in the small intestine [16]. In the physiological conditions CFTR is responsible for the proper production of the mucus, secretion of fluids into the intestinal lumen and has a strong impact on GI motility and excretion. Knock out of CFTR gene impairs the intestinal transit and lowers the volume of fluids in the gut [17]. On the other hand, CFTR upregulates some of the genes associ- ated with the GI inflammation and stimulates accumulation of mast cells in the intestinal smooth muscle tissue [18]. In line, cystic fibrosis patients (possessing mutation on the CFTR gene) reveal prolonged intestinal transit compared to healthy controls [18]. Cystic fibrosis transmembrane conductance regulator is one of the most important factors involved in the proper formation of the intestinal mucus, which constitutes a niche for the growth of intestinal microbiota. Thus, perhaps not surprisingly, loss of CFTR is associated with significant decreases in GI bacterial community richness, evenness and diversity as well as reduced abun- dance of protective species, including a multitude of Lactobacillales members [19]. The properties and functions of CFTR made it an attractive target for the treatment of disor- ders accompanied with deregulated motility and abdominal pain. Endogenous Opioid System in the Gastrointestinal Tract Endogenous opioid system (EOS) consists of three main types of opioid receptors, namely µ, κ and Δ (MOR, KOR and DOR respectively). Their respective endogenous ligands, endor- phins, dynorphins and enkephalins as well as enzymatic machinery dedicated to their degra- dation, including various proteases [e.g. aminopeptidase N (APN) and dipeptidyl peptidase IV