PAT-1 (Slc26a6) is the predominant apical membrane Cl⁻/HCO₃⁻ exchanger in the upper villous epithelium of the murine duodenum

<jats:p> Basal HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion across the duodenum has been shown in several species to principally involve the activity of apical membrane Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchanger(s). To investigate the identity of relevant anion exchanger(s), experiments were performed using wild-type (WT) mice and mice with gene-targeted deletion of the following Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchangers localized to the apical membrane of murine duodenal villi: Slc26a3 [down-regulated in adenoma (DRA)], Slc26a6 [putative anion transporter 1 (PAT-1)], and Slc4a9 [anion exchanger 4 (AE4)]. RT-PCR of the isolated villous epithelium demonstrated PAT-1, DRA, and AE4 mRNA expression. Using the pH-sensitive dye BCECF, anion exchange rates were measured across the apical membrane of epithelial cells in the upper villus of the intact duodenal mucosa. Under basal conditions, Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchange activity was reduced by 65–80% in the PAT-1(−) duodenum, 30–40% in the DRA(−) duodenum, and <5% in the AE4(−) duodenum compared with the WT duodenum. SO<jats:sub>4</jats:sub><jats:sup>2−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchange was eliminated in the PAT-1(−) duodenum but was not affected in the DRA(−) and AE4(−) duodenum relative to the WT duodenum. Intracellular pH (pH<jats:sub>i</jats:sub>) was reduced in the PAT-1(−) villous epithelium but increased to WT levels in the absence of CO<jats:sub>2</jats:sub>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> or during methazolamide treatment. Further experiments under physiological conditions indicated active pH<jats:sub>i</jats:sub> compensation in the PAT-1(−) villous epithelium by combined activities of Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup> exchanger 1 and Cl<jats:sup>−</jats:sup>-dependent transport processes at the basolateral membrane. We conclude that 1) PAT-1 is the major contributor to basal Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> and SO<jats:sub>4</jats:sub><jats:sup>2−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchange across the apical membrane and 2) PAT-1 plays a role in pH<jats:sub>i</jats:sub> regulation in the upper villous epithelium of the murine duodenum. </jats:p>