Cyclic nucleotide signaling in intestinal epithelia: getting to the gut of the matter

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.

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

“…‡Universal primer (Clontech SMARTer RACE cDNA Amplification Kit) consists of both a long and short sequence. 3 Ϫ secretion on the isolated intestinal tissues, Ussing chambers were set up in tandem with a pH-stat titration system (TIM 854 or 856 Titration Managers; Radiometer), as outlined previously (24). A pH electrode (model PHC4000.8; Radiometer) and a microburette tip (from which acid was delivered) was submersed in the luminal half-chamber to allow for pH readings and pH-stat titrations.…”

“…The pH values and rate of acid titrant (0.005 mol/l HCl) additions were recorded onto personal computers using the Titramaster software (v. 5.1.0). Epithelial HCO 3 Ϫ secretion rates were calculated from the rate of titrant addition and its concentration, as described in Grosell and Genz (24).…”

“…Guanylin (GN) and uroguanylin (UGN) are upstream regulators of apical CFTR and modulate intestinal Na ϩ , Cl Ϫ , fluid, and HCO 3 Ϫ fluxes in mammals (3,50,61). GN and UGN bind to guanylyl cyclase-C (GC-C), a transmembrane receptor on the apical membrane of intestinal tissues (50,52,53), causing an intracellular transduction cascade that increases the formation of cyclic guanosine monophosphate (cGMP).…”

“…GN and UGN bind to guanylyl cyclase-C (GC-C), a transmembrane receptor on the apical membrane of intestinal tissues (50,52,53), causing an intracellular transduction cascade that increases the formation of cyclic guanosine monophosphate (cGMP). cGMP can either stimulate cGMP-dependent protein kinase (PKG) or lead to increases in cyclic adenosine monophosphate (cAMP) levels that stimulate cAMP-dependent protein kinase (PKA); both PKG and PKA activate CFTR (3,4,9,13,34,42). In mammals, this leads to Cl Ϫ , fluid, and HCO 3 Ϫ secretion into the intestinal lumen to help neutralize the effects of acidic chyme (2,5,30,54).…”

“…In mammals, this leads to Cl Ϫ , fluid, and HCO 3 Ϫ secretion into the intestinal lumen to help neutralize the effects of acidic chyme (2,5,30,54). This process is especially important after the ingestion of food, where GN and UGN are secreted into the intestine, bind GC-C, and elevate the levels of intracellular cGMP in enterocytes (3).…”