Gene-targeted disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) in mice results in an intestinal disease phenotype that is remarkably similar to bowel disease in cystic fibrosis patients. In the intestinal segment downstream from the stomach (i.e., the duodenum), CFTR plays an important role in bicarbonate secretion that protects the epithelium from acidic gastric effluent. In this report, we examine the role of CFTR in cAMP-stimulated bicarbonate secretion in the murine duodenum and the mechanisms of acid-base transport that are revealed in CFTR knockout (CF) mice. Ion substitution, channel blocker and pH stat studies comparing duodena from wild-type and CF mice indicate that CFTR mediates a HCO3 - conductance across the apical membrane of the epithelium. In the presence of a favorable cellto-lumen HCO3 - gradient, the CFTR-mediated HCO3 - current accounts for about 80% of stimulated HCO3 - secretion. Exposure of the duodenal mucosa to acidic pH reveals another role of CFTR in facilitating HCO3 - secretion via an electroneutral, 4,4’-diisothiocyanatostilbene-2,2’ disulfonic acid (DIDS) sensitiveCl- /HCO3 - exchange process. In CF duodenum, other apical membrane acid-base transporters retain function, thereby affording limited control of transepithelial pH. Activity of a Cl- - dependent anion exchanger provides nearconstant HCO3 - secretion in CF intestine, but under basal conditions the magnitude of secretion is lessened by simultaneous activity of a Na+ /H+ exchanger (NHE). During cAMP stimulation of CF duodenum, a small increase in net base secretion is measured but the change results from cAMP inhibition of NHE activity rather than increased HCO3 - secretion. Interestingly, a small inward current that is sensitive to the anion channel blocker, 5-nitro- 2(3-phenylpropyl amino)-benzoate (NPPB), is also activated during cAMP stimulation of the CFTR-null intestine but the identity of the current is yet to be resolved. Studies to identify the proteins involved in non-CFTR mediated HCO3 - secretion are on-going and potentially will provide targets to correct deficient HCO3 - secretion in the CF intestine.
Lane L Clarke, Xavier Stien, Nancy M Walker