Guanylin peptides: renal actions mediated by cyclic GMP

The guanylin family of cGMP-regulating peptides has three subclasses of pep tides containing either three intramolecular disulfides found in bacterial heat-stable enterotoxins (ST)I or two disulfides observed in guanylin and u roguanylin, or a single disulfide exemplified by lymphoganylin. These small , heat-stable peptides bind to and activate cell-surface receptors that hav e intrinsic guanylate cyclase (GC) activity. Two receptor GC signaling mole cules have been identified that are highly expressed in the intestine (GC-C ) and/or the kidney (OK-GC) and are selectively activated by the guanylin p eptides. Stimulation of cGMP production in renal target cells by guanylin p eptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis. Activation of GC-C receptors in target cells of intestinal muco sa markedly stimulates the transepithelial secretion of Cl- and HCO,, causi ng enhanced secretion of fluid and electrolytes into the intestinal lumen. Bacterial ST peptides act as mimics of guanylin and uroguanylin in the inte stine, which provide a cellular mechanism underlying the diarrhea caused by ST-secreting strains of Escherichia coli. Uroguanylin and guanylin may par ticipate in a novel endocrine axis linking the digestive system and kidney as a physiological mechanism that influences Na+ homeostasis. Guanylin, uro guanylin, and/or lymphoguanylin may also serve within intrarenal signaling pathways controlling cGMP production in renal target cells. Thus we propose that guanylin regulatory peptides participate in a complex multifactorial biological process that evolved to regulate the urinary excretion of NaCl w hen dietary salt levels exceed the body's physiological requirements. This highly integrated and redundant mechanism allows the organism to maintain s odium balance by eliminating excess NaCl in the urine. Uroguanylin, in part icular, may be a prototypical "intestinal natriuretic hormone.".