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. 2008 Nov 17;587(Pt 10):2179–2185. doi: 10.1113/jphysiol.2008.164863

Diverse transport modes by the solute carrier 26 family of anion transporters

Ehud Ohana 1, Dongki Yang 1, Nikolay Shcheynikov 1, Shmuel Muallem 1
PMCID: PMC2697291  PMID: 19015189

Abstract

The solute carrier 26 (SLC26) transporters are anion transporters with diverse substrate specificity. Several members are ubiquitous while others show limited tissue distribution. They are expressed in many epithelia and to the extent known, play a central role in anion secretion and absorption. Members of the family are primarily Cl− transporters, although some members transport mainly SO42−, Cl−, HCO3− or I−. A defining feature of the family is their functional diversity. Slc26a1 and Slc26a2 function as specific SO42− transporters while Slc26a4 functions as an electroneutral Cl−/I−/HCO3− exchanger. Slc26a3 and Slc26a6 function as coupled electrogenic Cl−/HCO3− exchangers or as bona fide anion channels. SLC26A7 and SLC26A9 function exclusively as Cl− channels. This short review discusses the functional diversity of the SLC26 transporters.

A crucial function of most epithelia is Cl− absorption and HCO3− secretion that is coupled to fluid secretion. This controls the electrolyte composition and pH of the fluid secreted by exocrine cells (Melvin et al. 2005; Steward et al. 2005; Blouquit-Laye & Chinet, 2007). Vectorial Cl− absorption and HCO3− secretion are mediated by HCO3− entry at the basolateral membrane that is mostly mediated by the pNBC1 (NBCe1-B) isoform of the Na+–HCO3− cotransporter family and to a lesser extent by the combined action of the Na+/H+ exchanger NHE1 and the Cl−/HCO3− exchanger AE2 (Zhao et al. 1994; Melvin et al. 2005; Steward et al. 2005; Bachmann et al. 2006). The nature of the transporters mediating HCO3− exit at the luminal membrane remained elusive until the discovery of the SLC26 family of anion transporters (Dorwart et al. 2008). Although the first member of the family to be identified was the liver SO42− transporter SLC26a1 (Bissig et al. 1994), the breakthrough in appreciating the function of the family in Cl− absorption and HCO3− secretion was made with the discovery that congenital Cl− diarrhoea is caused by mutations in SLC26A3 (Höglund et al. 1996) and that SLC26a3 is expressed in the luminal membrane of colonic epithelium where it functions as a Cl− and HCO3− transporter (Moseley et al. 1999) that can mediate Cl−/HCO3− exchange activity (Melvin et al. 1999). It then became clear that the previously identified SO42− transporter SLC26A2, which is mutated in dystrophic dysplasia (DTDST) (Hastbacka et al. 1994), belongs to the same family. Subsequent identification of SLC26A4 as the transporter mutated in Pendred syndrome (Everett et al. 1997) and of SLC26A5 (Prestin) as the protein mediating electromotility of outer hair cells in the cochlea (Zheng et al. 2000) was followed by identification of the remaining members of the family, mostly by database searches (Dorwart et al. 2008).

By convention, upper and lower case letters are used to, respectively, refer to the human and mouse transporters. The human family of SLC26 transporters is coded by 11 genes, although SLC26A10 is probably a pseudogene. Homologues of the family are found in many species, from the human to Drosophila to Arabidopsis (Dorwart et al. 2008). The family of SLC26 transporters is relatively new and many structural and functional features of all members of the family are still not well understood. The current knowledge of the general features of the transporters and their potential cellular function has been summarized in several recent reviews (Markovich & Aronson, 2007; Sindićet al. 2007; Dorwart et al. 2008). Here, we will only highlight the intriguingly diverse transport modes of members of the family. Members of the family can be grouped into three general categories: the SO42− transporters SLC26A1 and SLC26A2; the Cl−/HCO3− exchangers SLC26A3, SLC26A4 and SLC26A6; and the ion channels SLC26A7 and SLC26A9 (Dorwart et al. 2008). The mammalian SLC26A5 was reported to not function as a transporter, although the invertebrate Slc26a5 does (Detro-Dassen et al. 2007; Schaechinger & Oliver, 2007). However, recent study suggests that SLC26A5 may mediate Cl−/formate exchange (J. Santos-Sacchi, personal communication). The transport function of SLC26A8 and SLC26A11 is not known.

The SO42− transporters

SLC26A1 is a basolateral membrane SO42− (Karniski et al. 1998; Regeer et al. 2003) and oxalate (Xie et al. 2002) transporter and does not transport Cl−, OH− or HCO3− (Karniski et al. 1998; Regeer et al. 2003). The mechanism of SO42− and oxalate transport by SLC26A1 is not known. SLC26A1-mediated SO42− uptake is enhanced by extracellular halides and acidic extracellular pH (Xie et al. 2002), suggesting that SLC26A1 does not function as a SO42−/Cl− exchanger. The physiological role for SLC26A1 is not well understood, but it has been suggested to play a role in SO42− homeostasis and sulphation of proteoglycans in the liver (Quondamatteo et al. 2006) and in oxalate homeostasis in the kidney (Pritchard & Renfro, 1983; Kuo & Aronson, 1988).

SLC26A2 is ubiquitous and is expressed at high level in all epithelia examined and in connective tissues (Hastbacka et al. 1994; Haila et al. 2001). SLC26A2 functions as a SO42− transporter and provides SO42− for proteoglycan sulphation, which is needed for cartilage development (Hastbacka et al. 1996; Forlino et al. 2005). Accordingly, mutations in the SLC26A2 gene cause diastrophic dysplasia (Hastbacka et al. 1994). It was proposed that SLC26A2 functions as a SO42−/Cl− exchanger, but not as a SO42−/HCO3− exchanger (Satoh et al. 1998). However, preliminary results from our laboratory suggest that SO42− transport by SLC26A2 may not be coupled to Cl− transport and that SLC26A2 may function as an electroneutral SO42−–2H+ cotransporter (or SO42−/2OH− exchanger). In addition, SLC26A2 did not appear to generate ionic current in the presence of any of the anions tested, including NO3− and SCN− (N. Shcheynikov & S Muallem, unpublished observations).

The anion exchangers

The most intriguing members of the family are the anion exchangers SLC26A3, SLC26A4 and SLC26A6. SLC26A3 and SLC26A6 are expressed in the luminal membrane of many epithelia (Höglund et al. 1996, 2001; Haila et al. 2000; Lohi et al. 2002, 2003) and play a central role in Cl− absorption and HCO3− secretion in several epithelia, including that of the intestine (Jacob et al. 2002; Simpson et al. 2007) and of the pancreas (Wang et al. 2006). SLC26A4 is expressed at high levels in the luminal membrane of follicular cells in the thyroid, in the inner ear (Everett et al. 1997; Royaux et al. 2000), in the renal cortical collecting duct (Royaux et al. 2001; Soleimani et al. 2001) and in the salivary gland ducts (Shcheynikov et al. 2008), where it participates in transcellular I− transport and in Cl−/HCO3− exchange.

Slc26a3, Slc26a4 and Slc26a6 function as obligatory Cl−/HCO3− exchangers, but with different stoichiometries (Shcheynikov et al. 2006a,b, 2008). The coupled exchange is evident from the stimulation of Cl− fluxes by HCO3− and stimulation of HCO3− fluxes by Cl−. However, Slc26a3 functions as a 2Cl−/1HCO3− exchanger (Ko et al. 2002; Shcheynikov et al. 2006b), and Slc26A4 as a 1Cl−/1HCO3− exchanger (Shcheynikov et al. 2008), while Slc26a6 functions as a 1Cl−/2HCO3− exchanger (Ko et al. 2002; Shcheynikov et al. 2006b). This is illustrated in Fig. 1A, D and G, which shows the mode of Cl−/HCO3− exchange of the respective transporters, as determined by simultaneous measurement of Cl− and HCO3− fluxes in Xenopus oocytes.

Figure 1. Cl−/HCO3− exchange and channel function of slc26a3, SLC26A4 and slc26a6.

Figure 1

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The transporters were expressed in Xenopus oocytes and Cl−/HCO3− exchange or anion current were measured as described in the respective publications. The results in A and B were modified from Shcheynikov et al. (2006b) and show Cl−/HCO3− exchange (A) and NO3− and SCN− current (B) in the absence of pHi changes (C) by Slc26a3. The results in D–F were modified mostly from Shcheynikov et al. (2008) and show Cl−/HCO3− exchange (D), I−/Cl− exchange at two membrane potentials (E) and I−/HCO3− exchange (F) by SLC26A4. The results in panels G–I were modified from Shcheynikov et al. (2006b) and show Cl−/HCO3− exchange (G), NO3− and SCN− current (H) in the absence of pHi changes (I) by Slc26a6.

The SLC26 exchangers can also transport other anions of physiological relevance. A special case is SLC26A4, which functions as a Cl−/HCO3−, Cl−/I− and I−/HCO3− exchanger (Fig. 1D and F; Shcheynikov et al. 2008). SLC26A4 has a relatively high affinity for I− and prefers I− over Cl− and HCO3− as the transported ion. This is illustrated in Fig. 1E, which shows that SLC26A4 can transport I− in media containing 110 mm Cl− and 1 mm I−. Cl−, HCO3− and I− transport by SLC26A4 is electroneutral, as is apparent from the 1Cl−/1HCO3− exchange stoichiometry and the same rate of I−/Cl− exchange at membrane potentials of −100 and +40 mV (Fig. 1D and E). All modes of transport are relevant physiologically. Mutations in SLC26A4 cause Pendred syndrome, which is associated with goitre as a result of impaired I− organification in the thyroid (Everett et al. 1997; Campbell et al. 2001). This is probably due to impaired HCO3−/I− and Cl−/I− exchange, and consequently limited I− secretion into the follicular space. Pendred syndrome is also associated with hearing loss (Coyle et al. 1996; Everett et al. 1997; Campbell et al. 2001), and deletion of Slc26a4 in mice revealed that the renal Slc26a4 modulates vascular volume and arterial pH (Wall et al. 2004; Wall, 2005). These functions are probably mediated by the Cl−/HCO3− exchange function of SLC26A4. Accordingly, Slc26a4 mediates HCO3− secretion by epithelial cells of the inner ear to alkalinize the pH of the endolymphatic fluid (Wangemann et al. 2007).

Measurement of Cl−, NO3− and SCN− transport in the absence of HCO3− revealed an unexpected function of Slc26a3 and Slc26a6. Both transporters showed a channel-like activity and generated large currents (Shcheynikov et al. 2006b). The Cl− current by Slc26a3 and Slc26a6 expressed in oocytes was about 0.5 μA and was associated with small or no Cl−/OH− exchange with Slc26a3 and Slc26a6, respectively (Ko et al. 2002). Strikingly, Slc26a3 and Slc26a6 mediate large NO3− and SCN− currents that are not coupled to OH− or HCO3− transport (Ko et al. 2002; Shcheynikov et al. 2006b). Several features of the currents are illustrated in Fig. 1B, C, H and I, which shows the large NO3− and very large SCN− currents mediated by Slc26a3 and Slc26a6 with minimal changes in pHi. The outward current appeared on addition of NO3− and SCN− to the extracellular media, while the inward currents developed more slowly, reflecting the rate of entry of the conducted anions into the oocytes. The slow rates of current development and extent of the inward NO3− and SCN− currents by Slc26a6 relative to that mediated by Slc26a3, indicate lower permeability of Slc26a6 to these anions. These findings suggest that the same transporter (Slc26a3 and Slc26a6) can function either as an obligatory coupled exchanger or as an ion channel, depending on the transported ion. This property is reminiscent of the behaviour of several neurotransmitter transporters (Fairman & Amara, 1999; Torres & Amara, 2007) and of Na+ transport by the Na+–HCO3− cotransporter NBCe1 (Choi et al. 2000).

How can the same transporter function as a coupled transporter and as an ion channel? A clue might be provided by the function of the bacterial ClC-ec1. ClC-ec1 functions as a 2Cl−/H+ exchanger, but mutating Glu148 or Tyr445 in the ion-conducting pathway converts it to a Cl− channel (Accardi et al. 2004). By analogy, it is possible that a similar mechanism regulates the Slc26a3 and Slc26a6 pores to hinder the movement of Cl− through the transporters with HCO3− facilitating the movement of Cl− through the pore to generate coupled transport. In this case, Cl− may be occluded in the pore with HCO3− releasing the occluded state while itself entering the pore and being transported, as occurs with other coupled transporters. The residues that hinder the movement of Cl− may not interact with NO3− and SCN−, allowing their flow through the pore to result in an uncoupled conductive transport. Unlike Cl−, NO3− and SCN− do not become occluded and flow freely through the pore to generate the current. Another scenario is a change of the pore conformation by NO3− and SCN− to convert Slc26a3 and Slc26a6 from coupled transporters to channels.

The anion channels

The two established SLC26 transporters that function exclusively as channels are SLC26A7 and SLC26A9. Current measurement in Xenopus oocytes and HEK cells transfected with SLC26A7 showed that SLC26A7 functions as a Cl− channel (Kim et al. 2005). As illustrated in Fig. 2A, the extent of the SLC26A7 current is not affected by HCO3−, indicating that SLC26A7 is not permeable to HCO3− and thus does not function as a Cl−/HCO3− exchanger. Accordingly, no Cl−/HCO3− exchange activity could be measured with SLC26A7 (Fig. 2B). However, HCO3− increases the selectivity of SLC26A7 for Cl− (Fig. 2A) due to regulation of the channel function of SLC26A7 by intracellular H+, raising the possibility that SLC26A7 may function as a pHi sensor (Kim et al. 2005).

Figure 2. Cl− channel activity and lack of Cl−/HCO3− exchange by SLC26A7 and SLC26A9.

Figure 2

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The results in A and B were modified from Kim et al. (2005) and show Cl− channel activity in Hepes- and in HCO3−-buffered media (A) and the minimal Cl−/HCO3− exchange activity (B) by SLC26A7. The results in C and D were modified from Dorwart et al. (2007) and show Cl− channel activity in Hepes- and in HCO3−-buffered media (C) and the minimal Cl−/HCO3− exchange activity (D) by SLC26A9.

Initial characterization of SLC26A9 transport properties by measurement of pHi suggested that SLC26A9 functions as a Cl−/HCO3− exchanger (Xu et al. 2005). On the other hand, current measurement in Xenopus oocytes and HEK or COS-7 cells expressing SLC26A9 revealed that SLC26A9 functions as a Cl− channel with minimal permeability to HCO3− (Dorwart et al. 2007; Loriol et al. 2008). Figure 2C illustrates the Cl− channel function of SLC26A9 and the lack of effect of HCO3− on the current, and Fig. 2D shows that SLC26A9 does not function as a Cl−/HCO3− exchanger. However, a recent study reported that HCO3− slightly stimulated Cl− channel activity by SLC26A9 (Loriol et al. 2008). How HCO3− may influence channel activity is not known at present, although it does not appear to be mediated by changes in pHi.

This brief review emphasizes the remarkable functional diversity of the SLC26 transporters, suggesting diverse physiological roles for these transporters that has yet to be fully understood. The basis for the functional diversity in terms of substrate specificity and transport modes is not known at present. The SLC26 transporters show only limited sequence similarity among members of the family, including those with similar transport modes, which is not sufficient to deduce functional specificity. However, the functional diversity of the SLC26 transporters, from coupled electroneutral exchangers to electrogenic exchangers to ion channels, offers a good model to study the structural basis of different transport functions. Within the family, the most intriguing are Slc26a3 and Slc26a6 that can function both as coupled transporters and as anion channels. Deciphering the underlying structural basis for these functions should also impact our understanding of the function of other anion transporters like the CLC family, members of which can function as electrogenic Cl−/H+ exchangers and as Cl− channels (Miller, 2006).

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