Guanylin peptides: cyclic GMP signaling mechanisms

Abstract

Guanylate cyclases (GC) serve in two different signaling pathways involving cytosolic and membrane enzymes. Membrane GCs are receptors for guanylin and atriopeptin peptides, two families of cGMPregulating peptides. Three subclasses of guanylin peptides contain one intramolecular disulfide (lymphoguanylin), two disulfides (guanylin and uroguanylin) and three disulfides (E. coli stable toxin, ST). The peptides activate membrane receptor-GCs and regulate intestinal Cl -and HCO 3 -secretion via cGMP in target enterocytes. Uroguanylin and ST also elicit diuretic and natriuretic responses in the kidney. GC-C is an intestinal receptor-GC for guanylin and uroguanylin, but GC-C may not be involved in renal cGMP pathways. A novel receptor-GC expressed in the opossum kidney (OK-GC) has been identified by molecular cloning. OK-GC cDNAs encode receptor-GCs in renal tubules that are activated by guanylins. Lymphoguanylin is highly expressed in the kidney and heart where it may influence cGMP pathways. Guanylin and uroguanylin are highly expressed in intestinal mucosa to regulate intestinal salt and water transport via paracrine actions on GC-C. Uroguanylin and guanylin are also secreted from intestinal mucosa into plasma where uroguanylin serves as an intestinal natriuretic hormone to influence body Na + homeostasis by endocrine mechanisms. Thus, guanylin peptides control salt and water transport in the kidney and intestine mediated by cGMP via membrane receptors with intrinsic guanylate cyclase activity.

The effect of water deprivation on signalling molecules that utilise cGMP in the spinifex hopping mouse Notomys alexis.

“…Increasing the secretion of these ions neutralizes hydrochloric acid in the small intestine, and organic acids produced by enteric bacteria in the colon (Joo et al 1998). Guanylin peptides can also inhibit the absorption of salt and water throughout the gastrointestinal tract (Forte et al 1999). Uroguanylin is released into the blood stream after salt is ingested and it is also released locally from the cells lining the renal tubules (Fan et al 1997;Forte and Hamra 1996).…”

Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain

“…Guanylin (GN) and uroguanylin (UGN) are two closely related endogenous peptides released by enterocytes within the GI tract that promote electrolyte and water secretion into the lumen 11–14 . The discovery of these peptides was associated with studies concerning the pathogenesis of bacterial diarrhoea, which is caused by heat‐stable (STa) enterotoxins.…”

Innovative techniques and applications in histochemistry and cell biology

“…Here, endogenous ligands, cystein-rich peptides that comprise guanylin, lymphoguanylin, and uroguanylin, bind to membrane receptor guanylate cyclase C, leading to intracellular production of cGMP, which in turn activates the cystic fibrosis transmembrane conductance regulator (CFTR), inducing an increased transepithelial chloride, sodium, and bicarbonate secretion that is accompanied by the excretion of water (see, for example, Forte et al 1999). Maake et al (2003) have investigated the occurrence and localization of uroguanylin in the aging human prostate.…”