Isoforms of the anion exchanger SLC26A6 (PAT1) mediate chloride and sulfate transport and have functional PDZ interaction domains

The solute carrier gene family SLC26 consists of tissue-specific anion exchanger genes, three of them associated with distinct human recessive disorders. By a genome-driven approach, several new SLC26 family members have been identified, including a kidney and pancreas-specific gene, SLC26A6. We report the functional characterization of SLC26A6 and two new alternatively spliced variants, named SLC26A6c and SLC26A6d. Immunofluorescence studies on transiently transfected cells indicated membrane localization and that both N- and C-terminal tails of the SLC26A6 variants are located intracellularly, suggesting a topology with an even number of transmembrane domains. Functional expression of the three proteins in Xenopus oocytes demonstrated chloride and sulfate transport activity. In addition, the transport of sulfate and chloride was inhibited by DIDS and bicarbonate. We demonstrated also that the C-terminus of SLC26A6 binds to the first and second PDZ domains of the E3KARP and NHERF proteins in vitro. Truncation of the last three amino acids (TRL) of SLC26A6 abrogated the interaction, but did not affect transport function. These results demonstrate that SLC26A6 and its two splice variants can function as anion transporters linked to PDZ-interaction pathways. Our results support the general concept of microdomain organization for ion transport, and suggest a mechanism for CFTR-mediated SLC26A6 upregulation in pancreatic duct cells. These results demonstrate that SLC26A6 isoforms are novel anion exchangers interacting with PDZ-domain proteins. SLC26A6 is a strong candidate for a CFTR-directed luminal Cl - /HCO 3 - -exchanger in ductal pancreas.