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(-)-HCO(3)(-) and Cl(-)-
OH(-) exchange; the stoichiometry of Cl(-)-HCO(3)(-) exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports >/=2 Cl(-)
ions per HCO(3)(-) ion, whereas SLC26A6 transports >/=2 HCO(3)(-)
ions per Cl(-) ion. SLC26 Cl(-)-HCO(3)(-) and Cl(-)-
OH(-) exchange is activated by the
cystic fibrosis transmembrane regulator (CFTR), implicating defective regulation of these exchangers in the reduced HCO(3)(-) 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.