Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology

The guanylin family of bioactive peptides consists of three endogenous pept ides, including guanylin, uroguanylin and lymphoguanylin, and one exogenous peptide toxin produced by enteric bacteria. These small cysteine-rich pept ides activate cell-surface receptors, which have intrinsic guanylate cyclas e activity, thus modulating cellular function via the intracellular second messenger, cyclic GMP. Membrane guanylate cyclase-C is an intestinal recept or for guanylin and uroguanylin that is responsible for stimulation of Cl- and HCO3- secretion into the intestinal lumen. Guanylin and uroguanylin are produced within the intestinal mucosa to serve in a paracrine mechanism fo r regulation of intestinal fluid and electrolyte secretion. Enteric bacteri a secrete peptide toxin mimics of uroguanylin and guanylin that activate th e intestinal receptors in an uncontrolled fashion to produce secretory diar rhea. Opossum kidney guanylate cyclase is a key receptor in the kidney that may be responsible for the diuretic and natriuretic actions of uroguanylin in vivo. Uroguanylin serves in an endocrine axis linking the intestine and kidney where its natriuretic and diuretic actions contribute to the mainte nance of Na+ balance following oral ingestion of NaCl. Lymphoguanylin is hi ghly expressed in the kidney and myocardium where this unique peptide may a ct locally to regulate cyclic GMP levels in target cells. Lymphoguanylin is also produced in cells of the lymphoid-immune system where other physiolog ical functions may be influenced by intracellular cyclic GMP. Observations of nature are providing insights into cellular mechanisms involving guanyli n peptides in intestinal diseases such as colon cancer and diarrhea and in chronic renal diseases or cardiac disorders such as congestive heart failur e where guanylin and/or uroguanylin levels in the circulation and/or urine are pathologically elevated. Guanylin peptides are clearly involved in the regulation of salt and water homeostasis, but new findings indicate that th ese novel peptides have diverse physiological roles in addition to those pr eviously documented for control of intestinal and renal function. Published by Elsevier Science B.V.