title: Role of down-regulated in adenoma anion exchanger in HCO3- secretion across murine duodenum.
abstract: OBJECTIVE
  The current model of duodenal HCO(3)(-) secretion proposes that basal secretion results from Cl(-)/HCO(3)(-) exchange, whereas cyclic adenosine monophosphate (cAMP)-stimulated secretion depends on a cystic fibrosis transmembrane conductance regulator channel (Cftr)-mediated HCO(3)(-) conductance. However, discrepancies in applying the model suggest that Cl(-)/HCO(3)(-) exchange also contributes to cAMP-stimulated secretion. Of 2 candidate Cl(-)/HCO(3)(-) exchangers, studies of putative anion transporter-1 knockout (KO) mice find little contribution of putative anion transporter-1 to basal or cAMP-stimulated secretion. Therefore, the role of down-regulated in adenoma (Dra) in duodenal HCO(3)(-) secretion was investigated using DraKO mice.
  
  
  METHODS
  Duodenal HCO(3)(-) secretion was measured by pH stat in Ussing chambers. Apical membrane Cl(-)/HCO(3)(-) exchange was measured by microfluorometry of intracellular pH in intact villous epithelium. Dra expression was assessed by immunofluorescence.
  
  
  RESULTS
  Basal HCO(3)(-) secretion was reduced approximately 55%-60% in the DraKO duodenum. cAMP-stimulated HCO(3)(-) secretion was reduced approximately 50%, but short-circuit current was unchanged, indicating normal Cftr activity. Microfluorimetry of villi demonstrated that Dra is the dominant Cl(-)/HCO(3)(-) exchanger in the lower villous epithelium. Dra expression increased from villous tip to crypt. DraKO and wild-type villi also demonstrated regulation of apical Na(+)/H(+) exchange by Cftr-dependent cell shrinkage during luminal Cl(-) substitution.
  
  
  CONCLUSIONS
  In murine duodenum, Dra Cl(-)/HCO(3)(-) exchange is concentrated in the lower crypt-villus axis where it is subject to Cftr regulation. Dra activity contributes most basal HCO(3)(-) secretion and approximately 50% of cAMP-stimulated HCO(3)(-) secretion. Dra Cl(-)/HCO(3)(-) exchange should be considered in efforts to normalize HCO(3)(-) secretion in duodenal disorders such as ulcer disease and cystic fibrosis.
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Walker
authors.forename: Janet E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Brazill
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Gill
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Schweinfest
authors.forename: Lane L
authors.initials: LL
authors.lastname: Clarke
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000235:genetics* / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters / Q000493:pharmacokinetics; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004386:Duodenum / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076988:Sulfate Transporters
chemical_list: D000143:Acids; D017920:Antiporters; D001639:Bicarbonates; D027963:Chloride-Bicarbonate Antiporters; C489860:Slc26a3 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D000242:Cyclic AMP