REGULATION OF INTESTINAL UROGUANYLIN GUANYLIN RECEPTOR-MEDIATED RESPONSES BY MUCOSAL ACIDITY

Guanylin and uroguanylin are intestinal peptides that stimulate chlori de secretion by activating a common set of receptor-guanylate cyclase signaling molecules located on the mucosal surface of enterocytes, Hig h mucosal acidity, similar to the pH occurring within the fluid microc limate domain at the mucosal surface of the intestine, markedly enhanc es the cGMP accumulation responses of T84 human intestinal cells to ur oguanylin, In contrast, a mucosal acidity of pH 5.0 renders guanylin e ssentially inactive, T84 cells were used as a model epithelium to furt her explore the concept that mucosal acidity imposes agonist selectivi ty for activation of the intestinal receptors for uroguanylin and guan ylin, thus providing a rationale for the evolution of these related pe ptides, At an acidic mucosal pH of 5.0, uroguanylin is 100-fold more p otent than guanylin, but at an alkaline pH of 8.0 guanylin is more pot ent than uroguanylin in stimulating intracellular cGMP accumulation an d transepithelial chloride secretion, The relative affinities of urogu anylin and guanylin for binding to receptors on the mucosal surface of T84 cells is influenced dramatically by mucosal acidity, which explai ns the strong pH dependency of the cGMP and chloride secretion respons es to these peptides, The guanylin-binding affinities for peptide-rece ptor interaction were reduced by 100-fold at pH 5 versus pH 8, whereas the affinities of uroguanylin for these receptors were increased 10-f old by acidic pH conditions, Deletion of the N-terminal acidic amino a cids in uroguanylin demonstrated that these residues are responsible f or the increase in binding affinities that are observed for uroguanyli n at acidic pH. We conclude that guanylin and uroguanylin evolved dist inctly different structures, which enables both peptides to regulate, in a pH dependent fashion, the activity of receptors that control inte stinal salt and water transport via cGMP.