FROM TOXINS TO MEDICINES: THE GUANYLIN CASE

MANASSÉS C. FONTELES(1)

(1)Universidade Presbiteriana Mackenzie and Universidade Estadual do Ceará - Brazil

Our laboratory described in 1983 the first evidence of guanylin like peptides, when studing renal effects promoted by semipurified extracts of E. coli toxins, originated from fecal materials of children with diarrhea in Ceará, Brazil. This represents the evidence that many toxins can generate medicines that can be used to treat many diseases. The guanylin family of bioactive peptides consists of four endogenous peptides, including guanylin, uroguanylin, lymphoguanylin and renoguanylin, and one exogenous peptide toxin produced by enteric bacteria E. coli (Sta). This thermo stable toxin is the main responsible for traveler’s diarrhea.  These small cysteine-rich peptides activate cell-surface receptors, which have intrinsic guanylate cyclase activity, thus modulating cellular function via the intracellular second messenger, cyclic GMP. Membrane guanylate cyclase-C is an intestinal receptor 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 for regulation of intestinal fluid and electrolyte secretion. Enteric bacteria secrete peptide toxin that mimics  uroguanylin and guanylin and activates the intestinal receptors in an uncontrolled fashion to produce secretory diarrhea. Opossum kidney guanylate cyclase is a key receptor in the renal tissues that may be responsible for the diuretic and natriuretic actions of uroguanylin in vivo and in vitro. Uroguanylin serves as  an  endocrine  axis linking the intestine to the kidney where its natriuretic and diuretic actions contribute to the maintenance of Na balance following oral ingestion of NaCl. Lymphoguanylin is highly expressed in the kidney, myocardium and lymphoid tissues, where this unique peptide may act locally to regulate cyclic GMP levels in target cells. It is also produced by cells of the immune system where other physiological functions may be influenced by intracellular cyclic GMP. Observations of several species provided insights into cellular mechanisms involving guanylin peptides in intestinal diseases, such as colon cancer, diarrhea and in chronic renal diseases or cardiac disorders such as congestive heart failure, 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 these novel peptides have diverse physiological roles, in addition to those previously documented for control of intestinal and renal function, that may contribute to the physiopathology of salt sensitive hypertension and even cancer treatment as a promoter of apoptosis.