Dual role of CFTR in cAMP-stimulated HCO3- secretion across murine duodenum

The role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cAMP-stimulated HCO3- secretion across the murine duodenum was investigated. Serosal-to-mucosal flux of HCO3- (J(s-->m) in mu eq.cm(-2).h(-1)) and short-circuit current (I-sc; in mu eq.cm(-2).h(-1)) were measured by the pH stat method in duodenum from CFTR knockout [CFTR(-)] and normal [CFTR(+)] mice. Under control conditions, forskolin increased J(s-->m) and I-sc (+1.7 and +3.5, respectively) across the CFTR(+) but not CFTR(-) duodenum. Both the forskolin-stimulated Delta J(s-->m) and Delta I-sc were abolished by the CFTR channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate, whereas inhibition of luminal Cl-/HCO3- exchange by luminal Cl- removal or DIDS reduced the J(s-->m) by similar to 18% without a consistent effect on the Delta I-sc. Methazolamide also reduced the J(s-->m) by 39% but did not affect the Delta I-sc. When carbonic anhydrase-dependent HCO3- secretion was isolated by using a CO2-gassed, HCO3- free Ringer bath, forskolin stimulated the J(s-->m) and I-sc (+0.7 and +2.0; respectively) across CFTR(+) but not CFTR(-) duodenum. Under these conditions, luminal Cl- substitution or DIDS abolished the J(s-->m) but not the Delta I-sc. It was concluded that cAMP-stimulated HCO3- secretion across the duodenum involves 1) electrogenic secretion via a CFTR HCO3- conductance and 2) electroneutral secretion via a CFTR-dependent Cl-/HCO3- exchange process that is closely associated with the carbonic anhydrase activity of the epithelium.