title: Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum.
abstract: 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 ³⁵SO₄²⁻ and ³⁶Cl⁻ 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 μmol·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 μM), bumetanide (100 μM), 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.
authors: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA. jwhittamore@pathology.ufl.edu
authors: Jonathan M
authors: JM
authors: Whittamore
authors: Robert W
authors: RW
authors: Freel
authors: Marguerite
authors: M
authors: Hatch
mesh_terms: D000042:Absorption; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002034:Bumetanide / Q000494:pharmacology; D002432:Cecum / Q000187:drug effects / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D004232:Diuretics / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D017920:Antiporters; D002712:Chlorides; D004232:Diuretics; C489860:Slc26a3 protein, mouse; C483904:Slc36a1 protein, mouse; D000076988:Sulfate Transporters; D013431:Sulfates; D027981:Symporters; D002034:Bumetanide
keywords: PAT1; Slc26a6; epithelial ion transport; large intestine
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