Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum

Inorganic sulfate (SO42-) is essential for a multitude of physiological processes. The specific molecular pathway has been identified for uptake from the small intestine but is virtually unknown for the large bowel, although there is evidence for absorption involving Na+-independent anion exchange. A leading candidate is the apical chloride/bicarbonate (Cl-/HCO3-) exchanger DRA (down-regulated in adenoma; Slc26a3), primarily linked to the Cl- transporting defect in congenital chloride diarrhea. The present study set out to characterize transepithelial (SO42-)-S-35 and Cl-36(-) fluxes across the isolated, short-circuited cecum from wild-type (WT) and knockout (KO) mice and subsequently to define the contribution of DRA. The cecum demonstrated simultaneous net SO42- secretion (-8.39 +/- 0.88 nmol.cm(-2).h(-1)) and Cl- absorption (10.85 +/- 1.41 mu mol.cm(-2).h(-1)). In DRA-KO mice, SO42- secretion was reversed to net absorption via a 60% reduction in serosal to mucosal SO42- flux. Similarly, net Cl- absorption was abolished and replaced by secretion, indicating that DRA represents a major pathway for transcellular SO42- secretion and Cl- absorption. Further experiments including the application of DIDS (500 mu M), bumetanide (100 mu M), and substitutions of extracellular Cl- or HCO3-/CO2 helped to identify specific ion dependencies and driving forces and suggested that additional anion exchangers were operating at both apical and basolateral membranes supporting SO42- transport. In conclusion, DRA contributes to SO42- secretion via DIDS-sensitive HCO3-/SO42- exchange, in addition to being the principal DIDS-resistant Cl-/HCO3- exchanger. With DRA linked to the pathogenesis of other gastrointestinal diseases extending its functional characterization offers a more complete picture of its role in the intestine.