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The Small IntestineSecretions, Digestion and Motility
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Guanylin is a gastrointestinal polypeptide that binds to guanylyl cyclase. It is secreted by cells of the intestinal mucosa. It increases cGMP and this increases Cl− secretion into the intestinal lumen and may lead to diarrhoea.
Cyclic Nucleotides
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
An increase in cGMP concentrations is one of the earliest events following binding of some peptide hormones and growth factors to their target cells. The recent identification and characterization of transmembrane receptors with intrinsinc guanylyl cyclase activity has shown that cGMP is a second messenger for natriuretic peptides.160,161 Receptor guanylyl cyclases constitute an important family of proteins involved in the transmission of signals across the cell membrane. An endogenous peptide isolated from the intestine, guanylin, may be recognized by guanylyl cyclase C, a cell surface receptor for bacterially derived peptides known as heat-stable enterotoxins involved in acute secretory diarrheas.162 The guanylin gene is expressed in various mammalian tissues in addition to intestine, suggesting an important role for the guanylin/guanylyl cyclase C receptor system in epithelial function.
Intestinal Chloride Secretion: Cyclic Amp and Ca2+ Interactions
Published in T. S. Gaginella, Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Vincenzo Calderaro, Francesco Rossi
The second major group, which associated with the particulate fraction of cell homogenates, contains a subgroup of cell surface receptor guanylyl cyclase, sea urchin spermatozoa, GC-A, GC-B, and GC-C.316,325 GC-A and CG- B are atrial natriuretic factor (ANF) receptors largely represented in the intestinal tract.326 Although ANF stimulates guanylyl cyclase in rat intestinal mucosa,327 it is still unclear whether the ANF-stimulated Cl− secretion in the rectal gland of Squalus acanthias is really mediated by cGMP.328 CG-C receptor, widely distributed in the intestine329 with a predominant localization on the luminal membrane of the enterocytes, is activated by a variety of acidic peptides, heat-stable enterotoxins (STa), produced by pathogenic strains of Escherichia coli and other bacteria. It was suggested that the function of GC- C in the intestine is to regulate fluid secretion, since upon binding of the receptor to STa, cyclic GMP increases and an acute secretory diarrhea ensues.330 This was confirmed by the finding that the incubation of colonic cells with STa promoted a cGMP-mediated ISC increase, mainly due to electrogenic Cl− secretion.331-333 However, the presence of a receptor for STa focuses on the existence of an endogenous GC-C receptor ligand, which is presumably represented by guanylin, an endogenous peptide with a high degree of homology with STa that increases cellular cGMP concentrations and displaces the binding of STa from the T84 cell line.334 To bind to its receptor, guanylin must be converted to the active form from its inactive precursor, preproguanylin, which has been recently cloned.335 Mucosal, but not serosal, addition of 1 μM synthetic rat guanylin caused a rapid and sustained in increase in ISC as well as in cGMP tissue levels.336 It therefore appears that guanylin is a physiological activator of intestinal guanylyl cyclase through the same receptor binding region as STa.334
Emerging drug targets for colon cancer: A preclinical assessment
Published in Expert Opinion on Therapeutic Targets, 2022
Madison M. Crutcher, Trevor R. Baybutt, Jessica S. Kopenhaver, Adam E. Snook, Scott A. Waldman
Guanylyl cyclase C (GUCY2C) is a transmembrane receptor expressed by normal intestinal cells from the duodenum to the rectum. GUCY2C is activated by endogenous peptides guanylin (GUCA2A), produced in the colorectum, and uroguanylin (GUCA2B), produced in the small intestine, as well as exogenous ligands like heat-stable enterotoxins (STs) produced by diarrhea-producing enterotoxigenic E. coli (ETEC). In normal cells, binding of the extracellular domain of GUCY2C by its ligands activates the cytoplasmic domain catalyzing the conversion of GTP into cGMP [49]. As discussed earlier, cGMP has anticancer effects through a variety of mechanisms. In CRC, the expression of those endogenous ligands is universally lost leading to silencing of GUCY2C, decreasing cGMP, increasing proliferation, and reducing DNA repair mechanisms. Restoration of signaling by this hormone-receptor axis may have anti-tumorigenic effects. This hormone hypothesis suggests that colorectal cancer can be prevented by oral administration of exogenous GUCY2C ligands, which replace the lost ligands. Linaclotide (an ST analog) and plecanatide (a uroguanylin analog) are being investigated as chemopreventives in cancer [50]. Beyond chemoprevention, GUCY2C also is overexpressed on the surface of most CRC cells making it a potential diagnostic marker and therapeutic target, discussed further in the following section.
Plasma levels of guanylins are reduced in patients with Crohn’s disease
Published in Scandinavian Journal of Gastroenterology, 2020
Hilde L. von Volkmann, Ingeborg Brønstad, Rune R. Tronstad, Vernesa Dizdar, Kim Nylund, Kurt Hanevik, Trygve Hausken, Odd Helge Gilja, Torunn Fiskerstrand
Active inflammation in colonic mucosa seems to lead to reduced GC-C signaling in this tissue, as gene expression and cellular protein content of both GC-C and guanylins are reduced compared to levels in HC and to non-inflamed colonic tissue in IBD patients (normal levels) [3,5,21]. Such reduction in guanylin formation could be reflected in a lower secretion of guanylins to the bloodstream, but this was not measured in the studies referred to above. Interestingly, our data show that CD patients with little inflammation (low HBI) compared to those with higher levels of inflammation (high HBI) had reduced plasma guanylin levels compared to HC. This may reflect additional unknown mechanisms for reduced signaling of guanylins in CD patients.
Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome
Published in Expert Opinion on Pharmacotherapy, 2018
The potential for exploitation of the physiology of uroguanylin is enormous. Efficient and symptom free digestion is extraordinarily complex involving appetite, appropriate taste and smell sensations, control of motility, regulating a changing luminal osmolarity to allow proximal dilution of chyme and to regulate stool viscosity, luminal pH, an adaptive immune response permitting tolerance of benign immune stimulation and activating immunologic protection against harmful immune stimulates, downregulation of the sensation of the normal digestive process while retaining the protective pain activation pathways, limiting environmental damage to the mucosa that may lead to neoplasia, and many, many more. The law of biologic conservation of function suggests that an effective biologic pathway will be used for many different functions. Uroguanylin and guanylin influence several of these examples with evidence of effects on appetite, olfactory function, sophisticated fluid control in the small intestine, decrease intestinal inflammation, regulation of intestinal permeability, regulation of visceral sensation, modulation of immunologic function, and protecting against mitotic change [11,24]. In addition to the effect of uroguanylin on the GC-C receptor, there is evidence that uroguanylin modulates mRNA on a transcriptional level [25]. Plecanatide represents the successful development of the first uroguanylin analog that activates intestinal secretion in a precise fashion with the sophisticated control of function tied into intestinal pH level. It is clear to me we stand on the threshold of greater understanding of the physiology of the guanylin peptides and new horizons in pharmacophysiology.