CHLORIDE SECRETION IN RESPONSE TO GUANYLIN IN COLONIC EPITHELIA FROM NORMAL AND TRANSGENIC CYSTIC-FIBROSIS MICE

1 Guanylin, a 15 amino acid endogenous gut peptide, increased the shor t circuit current (SCC) in the epithelium of the mouse colon, but only when applied to the apical and not the basolateral surface. 2 By use of selective blockers of epithelial ion transport and modification of the bathing solution, it was concluded that guanylin increased electro genic chloride secretion but also had a minor effect on electrogenic s odium absorption. In addition there were small residual currents which remained unresolved. 3 The threshold concentration of guanylin causin g a SCC increase was less than 50 nM, but at concentrations 40 times g reater no indication of a maximally effective concentration was found. 4 Two guanylin isomers with the same amino acid sequence but with the disulphide bridges joined in an alternate fashion showed no activity. Thus only guanylin with the greatest structural homology to heat stab le enterotoxin (STa) showed biological activity. 5 The action of guany lin was virtually eliminated in colonic epithelia from transgenic cyst ic. fibrosis (CF) mice. As these animals lack the chloride channel cod ed by the CF gene sequence, it is likely that the final effector proce ss in murine colonic epithelia involves the CFTR (cystic fibrosis tran smembrane conductance regulator) chloride channel. 6 Opportunistic inf ections of the gut generating STa lead to diarrhoeal conditions via an action of the toxin on apical guanylin receptors. Thus, as discussed, the CF heterozygote may have a genetic advantage in this circumstance .