The SLC26 gene family of multifunctional anion exchangers

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(-)-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.

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…53,54 This ion transporter also exchanges other anions such as HCO À , OH À , I À or formate. 55 Variations in this gene, as a second prevalent cause of HL, can contribute to both syndromic (Pendred syndrome, PS) and ARNSHL (DFNB4). 56,57 PS is associated with severe sensorineural HL and thyroid symptoms ranging from small changes in thyroid size to a large extent goiter.…”

Involvement of FpTRP26, a thioredoxin‐related protein, in oxalic acid‐resistance of the brown‐rot fungus Fomitopsis palustris

“…FpTRP26 was deduced to be a soluble protein according to the PSORT program (http://psort.hgc.jp/). Thus, FpTRP26 cannot be a membrane-bound OA-transporter such as the multifunctional anion exchanger SLC26, found in humans [19]. This possible protein-protein interaction of FpTRP26 can be postulated in analogy with the assumption for the DUF 1000 domain of TRP32.…”

Increased sulfate uptake by E. coli overexpressing the SLC26-related SulP protein Rv1739c from Mycobacterium tuberculosis

“…Inherited human diseases are associated with mutations in multiple members of both superfamilies (Mount et al 2004;Romero et al 2004;Alper 2006;Kere 2006). However, the transmembrane domain structure of neither family is currently known.…”

“…However, the transmembrane domain structure of neither family is currently known. SLC26-related SulP genes are widely distributed among bacterial species (Felce et al 2004;Price et al 2004), in addition to the widespread expression of SLC26 genes among eukaryotic organisms (Mount et al 2004). Vertebrate SLC26 polypeptides transport a wide range of anions, including Cl − , HCO 3 − , iodide, formate, oxalate, and sulfate, and have been implicated in teleost kidney sulfate excretion and osmoregulation (Renfro et al 1999;Nakada et al 2005;Katoh et al 2006).…”

“…Overexpression screening of several bacterial SulP genes revealed inducible, stable accumulation of M. tuberculosis Rv1739c and E. coli ychM. In view of the importance of the SulP gene family in plant (Yoshimoto et al 2007) and yeast (Shibagaki et al 2006), and fish biology (Renfro et al 1999;Nakada et al 2005;Katoh et al 2006), and the significance of the SLC26 gene superfamily in mammalian biology (Mount et al 2004;Markovich et al 2007), and the proposed importance of sulfate in M. tuberculosis pathogenicity (Schelle et al 2006;Fan et al 2007), we investigated further the function of Rv1739c (Fig. 1A) as a candidate sulfate transporter of mycobacteria.…”