title: The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function.
abstract: CFTR has been recognized to function as both an anion channel and a key regulator of Slc26 anion transporters in heterologous expression systems. Whether this regulatory relationship between CFTR and Slc26 transporters is seen in native intestine, and whether this effect is coupled to CFTR transport function or other features of this protein, has not been studied. The duodena of anesthetized CFTR-, NHE3-, Slc26a6-, and Scl26a3-deficient mice and wild-type (WT) littermates were perfused, and duodenal bicarbonate (HCO(3)(-)) secretion (DBS) and fluid absorptive or secretory rates were measured. The selective NHE3 inhibitor S1611 or genetic ablation of NHE3 significantly reduced fluid absorptive rates and increased DBS. Slc26a6 (PAT1) or Slc26a3 (DRA) ablation reduced the S1611-induced DBS increase and reduced fluid absorptive rates, suggesting that the effect of S1611 or NHE3 ablation on HCO(3)(-) secretion may be an unmasking of Slc26a6- and Slc26a3-mediated Cl(-)/HCO(3)(-) exchange activity. In the absence of CFTR expression or after application of the CFTR(inh)-172, fluid absorptive rates were similar to those of WT, but S1611 induced virtually no increase in DBS, demonstrating that CFTR transport activity, and not just its presence, is required for Slc26-mediated duodenal HCO(3)(-) secretion. A functionally active CFTR is an absolute requirement for Slc26-mediated duodenal HCO(3)(-) secretion, but not for Slc26-mediated fluid absorption, in which these transporters operate in conjunction with the Na(+)/H(+) exchanger NHE3. This suggests that Slc26a6 and Slc26a3 need proton recycling via NHE3 to operate in the Cl(-) absorptive mode and Cl(-) exit via CFTR to operate in the HCO(3)(-) secretory mode.
authors.affiliation: Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
authors.forename: Anurag Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.forename: Mingmin
authors.initials: M
authors.lastname: Chen
authors.forename: Fang
authors.initials: F
authors.lastname: Xiao
authors.forename: Anja
authors.initials: A
authors.lastname: Krabbenhöft
authors.forename: Regina
authors.initials: R
authors.lastname: Engelhardt
authors.forename: Olof
authors.initials: O
authors.lastname: Nylander
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004386:Duodenum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018181:Mice, Inbred CFTR; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D000076988:Sulfate Transporters; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D017920:Antiporters; D001565:Benzoates; D001639:Bicarbonates; D012333:RNA, Messenger; C489860:Slc26a3 protein, mouse; C466900:Slc26a6 protein, mouse; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator