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WIREs Syst Biol Med
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Cyclic nucleotide signaling in intestinal epithelia: getting to the gut of the matter

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Abstract The intestine is the primary site of nutrient absorption, fluid‐ion secretion, and home to trillions of symbiotic microbiota. The high turnover of the intestinal epithelia also renders it susceptible to neoplastic growth. These diverse processes are carefully regulated by an intricate signaling network. Among the myriad molecules involved in intestinal epithelial cell homeostasis are the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP). These cyclic nucleotides are synthesized by nucleotidyl cyclases whose activities are regulated by extrinsic and intrinsic cues. Downstream effectors of cAMP and cGMP include protein kinases, cyclic nucleotide gated ion channels, and transcription factors, which modulate key processes such as ion‐balance, immune response, and cell proliferation. The web of interaction involving the major signaling pathways of cAMP and cGMP in the intestinal epithelial cell, and possible cross‐talk among the pathways, are highlighted in this review. Deregulation of these pathways occurs during infection by pathogens, intestinal inflammation, and cancer. Thus, an appreciation of the importance of cyclic nucleotide signaling in the intestine furthers our understanding of bowel disease, thereby aiding in the development of therapeutic approaches. WIREs Syst Biol Med 2013, 5:409–424. doi: 10.1002/wsbm.1223 This article is categorized under: Biological Mechanisms > Cell Signaling Physiology > Mammalian Physiology in Health and Disease

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Diagrammatic representation of the intestinal epithelia. A transverse section of the small intestine shows the lamina propria, which forms villi (singular: villus) which project into the lumen, with crypts between them. The villi are supplied with blood vessels. The lamina propria supports various epithelial cells. At the base of the crypt are the immune‐related Paneth cells (dark purple). The stem cells (pink) give rise to the transit amplifying cells (green), which start to differentiate as they move to the tip of the villus. Absorptive enterocytes (light purple) are the major population, and other specialized cells such as the mucus‐secreting goblet cells (blue), the enteroendocrine cells, the immune cells such as the microfold or M‐cells (orange), and dendritic cells (brown) are also present.

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Downstream effectors cAMP and cGMP signaling: ion secretion (purple)—cAMP and cGMP signaling stimulate the activity of cyclic nucleotide gated (CNG) ion channels and inhibit the activity of the sodium‐hydrogen exchanger (NHE3). cGMP regulated protein kinase‐II (PKG‐II) is activated by cGMP and it phosphorylates cystic fibrosis transmembrane conductance regulator (CFTR) leading to ion secretion. cAMP‐dependent protein kinase (PKA) and exchange protein activated by cAMP (Epac) are both activated by cAMP and phosphorylate CFTR, elevating chloride secretion. Epac also activates an as yet unidentified chloride ion channel. Epac also activates an as yet unidentified chloride ion channel. Regulation of metabolic genes (green)—PKA and Epac upregulate the transcription of the proglucagon gene, which encodes Glucagon‐like peptide‐1. PKA upregulates the expression of glucose‐6‐phosphatase, via the action of the cAMP response element binding (CREB) protein. Regulation of immune response (red)—PKA also promotes IL6 expression in intestinal epithelial cells via CREB. In dendritic cells, PKA negatively regulates the expression of IL10/8, and this is inhibited by the action of Epac. PKA upregulates the expression of the inducible cAMP early repressor (ICER) which also inhibits cytokine release in T cells. PKA activity also inhibits the activation of T‐cell receptors (TCR). Regulation of cell proliferation (blue)—cAMP, by unknown intermediates, upregulates the expression of the CDKN1A and CDKN1B genes, which encode p21 and p27, respectively. Paradoxically, cAMP can also inhibit apoptosis. Activation of CNG by cAMP or cGMP inhibits cell proliferation. cGMP can upregulate the expression of p27, and also activate PTEN, which inhibits AKT activity. Other mechanisms by which cGMP induces cell cytostasis are currently unknown.

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Synthesis and degradation of cyclic nucleotides in the intestinal cell. The ligands vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and epinephrine bind to their respective receptors namely VIP receptor (VIPR), prostaglandin receptor 2 or 4 (EP2/4) and β‐2 adrenergic receptor (β‐2‐AR). These are coupled to the heterotrimeric G‐proteins containing the Gαs subunit that stimulates the production of cAMP via transmembrane adenylyl cyclases (tmAC). The somatostatin receptor (STTR) and the EP3 receptor for PGE2 are both GPCRs associated with the Gαi subunit, which inhibits the production of cAMP by tmAC. Ligands for the soluble guanylyl cyclase (sGC) include nitric oxide (NO) and carbon monoxide (CO) which elevate cGMP production. NO and the Bacteriodis fragilis toxin (BFT) also activates Cox‐2, elevating PGE2 levels. Cox‐2 is inhibited by nonsteroidal, anti‐inflammatory drugs or NSAIDs (1). Guanylyl cyclase C (GC‐C) is a membrane‐associated receptor and its endogenous ligands are uroguanylin and guanylin, and exogenous ligands are the heat‐stable enterotoxin (ST) and linaclotide. Activation of sGC and GC‐C elevates cGMP levels in the intestinal epithelia. Phosphodiesterases (PDEs) present in the intestine lower the levels of cyclic nucleotides. PDE4 and PDE8 specifically degrade cAMP, and PDE4 is inhibited by the small molecule inhibitor Rolipram (2). PDE11 and PDE2 exhibit dual specificity and are activated by cGMP. PDE3 is cAMP specific, and is inhibited by cGMP and by the small molecule inhibitor cilostazol (3). PDE5 is a cGMP‐specific PDE which is activated by cGMP and inhibited by the small molecule inhibitor sildenafil citrate (4).

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Biological Mechanisms > Cell Signaling
Physiology > Mammalian Physiology in Health and Disease

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