Guanylin peptides: cyclic GMP signaling mechanisms

Guanylate cyclases (GC) serve in two different signaling pathways involving cytosolic and membrane enzymes. Membrane GCs are receptors for guanylin an d atriopeptin peptides, two families of cGMP-regulating peptides, Three sub classes of guanylin peptides contain one intramolecular disulfide (lymphogu anylin), two disulfides (guanylin and uroguanylin) and three disulfides (E. coli stable toxin, ST). The peptides activate membrane receptor-GCs and re gulate intestinal Cl- and HCO3- secretion via cGMP in target enterocytes. U roguanylin and ST also elicit diuretic and natriuretic responses in the kid ney. 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 expresse d in the opossum kidney (OK-GC) has been identified by molecular cloning. O K-GC cDNAs encode receptor-GCs in renal tubules that are activated by guany lins. Lymphoguanylin is highly expressed in the kidney and heart where it m ay influence cGMP pathways. Guanylin and uroguanylin are highly expressed i n intestinal mucosa to regulate intestinal salt and water transport via par acrine actions on GC-C. Uroguanylin and guanylin are also secreted from int estinal mucosa into plasma where uroguanylin serves as an intestinal natriu retic hormone to influence body Na+ homeostasis by endocrine mechanisms. Th us, guanylin peptides control salt and water transport in the kidney and in testine mediated by cGMP via membrane receptors with intrinsic guanylate cy clase activity.