Differential role of cyclic GMP-dependent protein kinase II in ion transport in murine small intestine and colon

Background & Aims: The aim of this study was to determine the role of guano sine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase (cGK) type Ii in intestinal fluid homeostasis under basal conditions and following exp osure to cGMP-linked secretagogues, e.g,, Escherichia coil heat-stable ente rotoxin (STa) and guanylin. Methods: Fluid and ion transport was determined in different segments of the intestine of wildtype and cGK Il-deficient mi ce by ligated loop assays in vivo, and by short-circuit current and isotope flux measurements in vitro, Results: Small intestinal fluid absorption in vivo was enhanced in cGK Il-deficient mice under basal conditions and in th e presence of STa. Furthermore, STa, guanylin, and 8-pCPT-cGMP stimulation of electrogenic anion secretion and inhibition of Na+ absorption in vitro w ere markedly reduced in the small intestine from cGK II -/- mice but not in proximal colon, The type III phosphodiesterase inhibitor amrinone mimicked STa action in cGK II -/- mice, and also stimulated ion secretion in humans , Conclusions: This study shows that the cGMP/cGK II pathway regulates flui d homeostasis in the small intestine under basal conditions and mediates ST a effects by both increasing anion secretion and inhibiting Na+ absorption. It also demonstrates the presence of a cGK II-independent pathway for STa/ cGMP-provoked secretion predominantly in the colon, which possibly involves a cGMP-inhibitable phosphodiesterase and/or activation of the cAMP-depende nt protein kinase pathway.