The SLC26 gene family of multifunctional anion exchangers

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Abstract
The ten-member SLC26 gene family encodes anion exchangers capable of transporting a wide variety of monovalent and divalent anions. The physiological role(s) of individual paralogs is evidently due to variation in both anion specificity and expression pattern. Three members of the gene family are involved in genetic disease; SLC26A2 in chondrodysplasias, SLC26A3 in chloride-losing diarrhea, and SLC26A4 in Pendred syndrome and hereditary deafness (DFNB4). The analysis of Slc26a4-null mice has significantly enhanced the understanding of the roles of this gene in both health and disease. Targeted deletion of Slc26a5 has in turn revealed that this paralog is essential for electromotor activity of cochlear outer hair cells and thus for cochlear amplification. Anions transported by the SLC26 family, with variable specificity, include the chloride, sulfate, bicarbonate, formate, oxalate and hydroxyl ions. The functional versatility of SLC26A6 identifies it as the primary candidate for the apical Cl−-formate/oxalate and Cl−-base exchanger of brush border membranes in the renal proximal tubule, with a central role in the reabsorption of Na+-Cl− from the glomerular ultrafiltrate. At least three of the SLC26 exchangers mediate electrogenic Cl−-HCO3 − and Cl−-OH− exchange; the stoichiometry of Cl−-HCO3 − exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports ≥2 Cl− ions per HCO3 − ion, whereas SLC26A6 transports ≥2 HCO3 − ions per Cl− ion. SLC26 Cl−-HCO3 − and Cl−-OH− exchange is activated by the cystic fibrosis transmembrane regulator (CFTR), implicating defective regulation of these exchangers in the reduced HCO3 − transport seen in cystic fibrosis and related disorders; CFTR-independent activation of these exchangers is thus an important and novel goal for the future therapy of cystic fibrosis.