(Journal Article): Intestinal Bicarbonate Secretion in Cystic Fibrosis Mice
Clarke LL, Stien X, Walker NM (Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri. Columbia, MO, USA,
clarkel@missouri.edu
)
IN:
JOP. J Pancreas (Online)
2001; 02(4 Suppl.):263-267
ABSTRACT: 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 HCO(3)(-) conductance across the apical membrane of the epithelium. In the presence of a favorable cell-to-lumen HCO(3)(-) gradient, the CFTR-mediated HCO(3)(-) current accounts for about 80% of stimulated HCO(3)(-) secretion. Exposure of the duodenal mucosa to acidic pH reveals another role of CFTR in facilitating HCO(3)(-) secretion via an electroneutral, 4,4'-diisothiocyanato-stilbene-2,2' disulfonic acid (DIDS) sensitive Cl(-)/HCO(3)(-) 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 near-constant HCO(3)(-) 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 HCO(3)(-) 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 HCO(3)(-) secretion are on-going and potentially will provide targets to correct deficient HCO(3)(-) secretion in the CF intestine.
TYPE OF PUBLICATION: Round Table
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