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MUCOSAL BIOLOGY

Functional coupling of the downregulated in adenoma Cl^–/base exchanger DRA and the apical Na⁺/H⁺ exchangers NHE2 and NHE3

¹Department of Medicine, University of Chicago, Chicago, Illinois; and ²Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 23 May 2008 ; accepted in final form 26 November 2008

Non-nutrient-dependent salt absorption across the brush-border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na⁺/H⁺ (aNHE) and anion exchange transport, with the latter suspected of being mediated by DRA (downregulated in adenoma; SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine whether DRA and NHE activities can be coupled, we measured ²²Na⁺ and ³⁶Cl^– uptake in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms NHE2 and NHE3, increased ³⁶Cl^– uptake was observed. Inhibition of DRA activity by niflumic acid was greater than that by DIDS as well as by the NHE inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl^–/base exchange and apical NHE.

anion exchange; electroneutral NaCl transport; intestinal transport; endocytosis; diarrheal diseases; sodium absorption; congenital chloridorrhea; SLC26A3; SLC26; synaptotagmin; clathrin; membrane biotinylation

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