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2 Renal Division, West Roxbury Veterans Affairs Medical Center and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; 1 Division of Nephrology, Nashville Veterans Affairs Medical Center, and Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Departments of 3 Physiology and Biophysics and 4 Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106-4970
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We report the molecular and
functional characterization of murine Slc26a6, the putative apical
chloride-formate exchanger of the proximal tubule. The Slc26a6
transcript is expressed in several tissues, including kidney.
Alternative splicing of the second exon generates two distinct
isoforms, denoted Slc26a6a and Slc26a6b, which differ in the inclusion
of a 23-residue NH2-terminal extension. Functional
comparison with murine Slc26a1, the basolateral oxalate exchanger of
the proximal tubule, reveals a number of intriguing differences.
Whereas Slc26a6 is capable of Cl
, SO
in the presence
and absence of HCO
/HCO/OH exchanger; simultaneous membrane
hyperpolarization during these experimental maneuvers reveals that
HCO transport mediated by
Slc26a6 is electrogenic. Cis-inhibition and efflux
experiments indicate that Slc26a6 can mediate the exchange of both
Cl and SO/formate/oxalate and Cl/base exchanger
and reveal significant mechanistic differences between apical and
basolateral oxalate exchangers of the proximal tubule.
oxalate; proximal tubule; formate; anion exchange; chloride
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ANION EXCHANGE AT THE
PLASMA membrane is primarily mediated by the products of two
structurally distinct gene families; the anion exchanger (AE) genes,
which form a subset of the bicarbonate transporter, SLC4
superfamily (41, 52), and the SLC26 or
"sulfate permease" gene family (10, 33). The mammalian
SLC26 gene family has emerged over the last seven years
through a combination of expression cloning (4),
subtractive cDNA cloning (61), and positional
characterization of human disease genes (10). Evolving physiological roles for specific family members include transepithelial salt transport (10, 45), thyroidal iodide transport
(46), development and function of the inner ear (10,
61), sulfation of extracellular matrix (43), and
the renal excretion of both bicarbonate (42) and oxalate
(17). The various substrates transported by the SLC26
anion exchangers include sulfate (SO), iodide (I), formate, oxalate,
hydroxyl ion (OH), and bicarbonate
(HCO
The SLC26 gene family is highly conserved across evolution, with
identifiable homologues in bacteria, fungi, yeast, plants, and animals
(10). The Drosophila genome contains at least
nine family members, and the existence of new mammalian paralogs has been suspected for some time (10). The cloning of several
of these new genes has been recently reported (19, 30, 31, 53,
54), and the family appears to encompass 10 members and 1 pseudogene (Mount DB, unpublished observations). Physiological interest in the characterization of novel family members was stimulated in particular by the observation that SLC26A4 can function as a
Cl/formate exchanger (45), because
Cl/formate exchange is thought to play a pivotal role in
the transepithelial transport of NaCl by the renal proximal tubule
(56, 57). However, Slc26a4 is not expressed in the
proximal tubule but is instead found at the apical membrane of
-intercalated cells, where it appears to play a role in renal
bicarbonate excretion (42). The sixth member of the gene
family, SLC26A6, was recently cloned in both humans
(SLC26A6) (30, 54) and mice
(Slc26a6, also known as CFEX) (19). Functional
characterization of Slc26a6 indicates that it can mediate both
Cl/formate and Cl/Cl exchange
(19), whereas the human ortholog was nonfunctional (54). The immunolocalization of SLC26A6 and Slc26a6
indicates expression at the apical membrane of epithelial cells
(19, 30) and suggests that this gene encodes the proximal
tubule Cl/formate exchanger. Important unresolved issues
include whether SLC26A6 also mediates Cl/oxalate exchange
and Cl/base exchange (Cl/OH
and/or Cl/HCO/base exchange functions in
transepithelial NaCl absorption by the proximal tubule
(24). Moreover, the ability of SLC26 proteins to function
as Cl/base exchangers identifies Slc26a6 as a candidate
for both the apical Cl/base exchanger of the proximal
tubule and the apical CFTR-dependent bicarbonate transporter(s) in the
lung (26), submandibular gland (27), and
exocrine pancreas (7, 27). We report the initial exploration of these issues, in addition to a functional comparison of
the murine Slc26a1 and Slc26a6 anion exchangers.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Molecular characterization of Slc26a6 and Slc26a1. Human SLC26A6 exons were initially identified in the draft sequences of the BAC clone RP11-148G20 and the PAC clone RP4-751E10, using tblastn searches of the HTGS database with the SLC26A1-4 proteins. A blastn search of the mouse expressed sequence tag (EST) database using the extracted human exon contig yielded a Sugano mouse IMAGE clone (2076921), with 5'- and 3'-EST entries that exhibited modest homology to the NH2 and COOH termini of known SLC26 proteins. This full-length cDNA was obtained from Research Genetics (Birmingham, AL), sequenced on both strands using fluorescent dye terminator chemistry (Applied Biosystems), and submitted to GenBank (AF248494, 3/23/00). A blastn search of the Celera mouse genomic database yielded a 500-kb contig containing the 11-kb Slc26a6 gene, and a subsequent blastn search of the mouse EST database using a 1.7-kb region between the start of the 2076921 EST and the 3'-untranslated region (UTR) of the upstream gene yielded three RIKEN 5'-ESTs that overlap with 2076921 but have a different 5'-end. This alternative 5'-end was cloned by RT-PCR from mouse intestine total RNA, using a sense primer in exon 1a (5'-TACACGAGTTACCCTCTGAGG-3') and an antisense primer from within exon 4 (5'-TACAGACCAAACATAGGAGGC-3'), as described (37). The two amplified PCR fragments obtained (see Fig. 2) were subcloned into pCR2.1 (Invitrogen) and sequenced. Finally, for the purpose of functional comparison to Slc26a6, we identified and sequenced a full-length mouse Slc26a1 EST (IMAGE clone 1450460).
The analysis of nucleotide and amino acid sequence utilized Vector NTI 6.0 (Informax), supplemented by GRAIL (http://compbio.ornl.gov/Grail-1.3/), Phosphobase (http://www.cbs. dtu.dk/databases/PhosphoBase/), MattInspector (http://transfac. gbf.de/cgi-bin/matSearch/matsearch.pl), TESS (http://www. cbil.upenn.edu/cgi-bin/tess/tess33?RQ=SEA-FR-Query), and Prosite (http://www.expasy.ch/prosite/). Genomic localization of Slc26a1 and Slc26a6 exploited Celera genomic contigs encompassing the two genes, the UniSTS website (NCBI), and the Mouse Genome Database (MGD; http://www. informatics.jax.org/mgihome/).Northern blot analysis. RNA was extracted from C57BL/6J mice using guanidine isothiocyanate and cesium chloride. Total RNA (10 µg/lane) was size-fractionated by electrophoresis (5% formaldehyde, 1% agarose), transferred to a nylon membrane (Stratagene), and probed sequentially with 32P-labeled randomly primed probes corresponding to full-length GAPDH and a 3'-probe from Slc26a6 (nucleotides 2339-2673 of Slc26a6b). Hybridization was performed overnight at 42°C in Express-Hyb solution (Clontech), and membranes were washed twice for 10 min at room temperature in 2× SSCP/0.1% SDS and twice for 1 h at 65°C in 0.1× SSCP/0.1% SDS.
Expression of Slc26a1 and Slc26a6 in Xenopus laevis oocytes. The entire inserts of the Slc26a6b and Slc26a1 cDNAs were transferred to the pGEMHE X. laevis expression vector (29) using EcoRI and XbaI. The Slc26a6b and Slc26a1 expression constructs were linearized using NheI and NotI, respectively, and cRNA was transcribed in vitro using T7 RNA polymerase and mMESSAGE mMACHINE kits (Ambion). Defolliculated oocytes were injected with 25-50 nl of water or a solution containing cRNA at a concentration of 0.5 µg/µl (12.5-25 ng/oocyte), using a Nanoliter-2000 injector (WPI Instruments, Sarasota, FL). Oocytes were incubated at 17°C in 50% Leibovitz's L-15 media supplemented with Pen-Strep (1,000 U/ml) and glutamine for 2-3 days before uptake assays.
For sulfate uptakes, oocytes were preincubated for 20 min in chloride-free uptake medium [100 mM N-methyl-D-glucamine (NMDG)-gluconate, 2 mM potassium gluconate, 1 mM calcium gluconate, 1 mM magnesium gluconate, 10 mM HEPES-Tris, pH 6.0 or pH 7.5, as indicated], followed by a 60-min uptake in the same medium with 1 mM K235SO4. The cells were then washed three times in uptake buffer with 5 mM nonradioactive K2SO4 to remove tracer activity in the extracellular fluid. The oocytes were dissolved individually in 10% SDS, and tracer activity was determined by scintillation counting. Cl, formate, and oxalate uptakes were assayed using the
same Cl-free uptake solutions, substituting 8.3 mM
36Cl, 500 µM [14C]oxalate, or
50 µM [14C]formate for labeled sulfate. For sulfate
exchange (see Fig. 5C) and cis-inhibition (Fig.
5A), the concentration of NMDG-gluconate in the uptake
solution was adjusted to maintain isotonic osmolality, which was
experimentally confirmed using a Fiske 110 osmometer. Cis-inhibition experiments used the Na+ salts of
the relevant anions. All radioisotopes were from New England Nuclear
(Boston, MA).
The uptake experiments all included 12-18 oocytes in each
experimental group, statistical significance was defined as two-tailed (P < 0.05), and results are reported as means ± SE.
Oocyte electrophysiology.
Oocytes were studied 3-11 days postinjection. The
CO2/HCO solutions,
gluconate replaced Cl. All solutions were titrated to pH
7.5 and continuously bubbled with CO2-balanced
O2 to maintain PCO2 and pH.
Ion-selective microelectrodes were prepared and calibrated, and
experiments were performed as previously described for NBC
(40) and NDAE1 (41). All pH electrodes had
slopes of at least 
56 mV/decade concentration change. Where statistical tests were indicated, a two-tailed Student's
t-test assuming unequal variances was used. P
values <0.05 were considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Molecular biology. Sequence comparison indicates that the murine Slc26a6 and human SLC26A6 orthologs share only 78% identity at the amino acid level, much lower than the median of 86% for human and mouse orthologous pairs (32). However, the murine and human genes are clearly orthologous, such that both are flanked at the 5'-ends by the FMI-1/MEGF-2 gene and at the 3'-end by the UQCRC1 and ColA7 genes (13, 28). The gene and sequence tagged site content of these contigs confirm that the human SLC26A6 gene is on chromosome 3p21 (30) and the murine gene is in the syntenic segment of chromosome 9, at ~61 cM. In particular, the murine ColA7 gene is physically linked ~40 kb 3' of Slc26a6 and is known to be localized on mouse chromosome 9 at 61.0 cM (UniSTS marker 859381) (28).
The Slc26a6 and SLC26A6 genes share a similar organization, encompassing 21 coding exons and ~10 kb of genomic DNA. Both genes include an alternative 5' noncoding exon (exon 1b, 945 nucleotides 5' of coding exon 2 in Slc26a6). Nonquantitative RT-PCR using primers in exons 1a and 4 (see Fig. 2A) suggests that the isoform in which exon 1b has been spliced out, denoted Slc26a6a, is expressed at a lower level than Slc26a6b; our functional experiments utilized a Slc26a6b construct. The identity of the two RT-PCR fragments (see Fig. 2A) was verified by subcloning and sequencing of the amplified bands. The intron-exon boundaries in Slc26a6 were determined by comparison of the various Slc26a6 cDNAs to the murine Celera contig, and all of the donor and acceptor sites were found to conform to consensus splice sites (39) (Table 1). The inclusion of exon 1b in the longer Slc26a6b transcript results in a frame shift and a start codon within exon 2. The predicted Slc26a6b protein is thus 23 amino acids shorter than Slc26a6a (Fig. 1). The start codons in exon 1a and exon 2 are both predicted Kozak sites (21), with purines at position3 and G at position +4. However, it is conceivable that the Kozak site in exon 2 is in fact
preferred for translation initiation in both the Slc26a6a and Slc26a6b
transcripts; formal proof that the start codon in exon 1a is utilized
will require the generation of an antibody to the putative
NH2-terminal extension of the Slc26a6a protein. Slc26a6b is
essentially identical to the sequence of mouse "CFEX" (19), except for codons 2 (glutamate in Slc26a6b, glycine
in CFEX), 65 (valine in Slc26a6b, indeterminate in CFEX), and 549 (proline in Slc26a6b, arginine in CFEX). Exon 1b is conserved in the
human genomic sequence; the cDNA reported by Waldegger et al.
(54) corresponds to SLC26A6a, whereas that reported by Lohi et al. (30) corresponds to SLC26A6b. The functional
significance of the alternative NH2 terminus in the
Slc26a6a isoform is not yet known; however, note is made of the
conservation of the sequence, TQALLS, in mice, humans, and pigs
(Fig. 1 and data not shown, porcine SLC26A6a). The murine Slc26a6b
isoform lacking the NH2-terminal extension is functional
(see Figs. 4-7); hence, this sequence is not required for
transport activity.
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Anion transport in X. laevis oocytes. We have characterized the physiological properties of mouse Slc26a6b and Slc26a1 in X. laevis oocytes using similar protocols to those published for SLC26A1 (4, 25, 43), SLC26A2 (43), SLC26A3 (36), and SLC26A4 (45, 46).
Figure 4 illustrates the uptake of 35SO
by oocytes injected with Slc26a1 and Slc26a6, as a function of extracellular pH and extracellular Cl or
SO- and Na+-independent sulfate
transport (148 ± 9 and 237 ± 37 pmol · oocyte1 · h1 at pH
7.4 and 6.0, respectively, vs. 2.0 ± 0.2 and 5.8 ± 0.9 pmol · oocyte1 · h1 in
water-injected controls), as does Slc26a6 (605 ± 40 and 625 ± 53 pmol · oocyte1 · h1
at pH 7.4 and 6.0, respectively). The difference in
35SO1 · h1 at pH
7.4 vs. 101 ± 10 pmol · oocyte1 · h1 at pH
6.0 for Slc26a6 in the presence of DIDS). In contrast, Cl
uptake in Slc26a6/CFEX-expressing oocytes was reported by Knauf et al.
(19) to be highly sensitive to 100 µM DIDS, with no
significant difference between pH 7.4 and 6.5; this higher sensitivity
may have masked an effect of extracellular pH. It is also likely that DIDS sensitivities of Slc26a6 and other members of the family are
highly dependent on both the concentration and the identity of the
transported anion (16), although we note that SLC26A3 and
SLC26A4 are also only modestly sensitive to DIDS (1, 46).
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(Fig. 4B), although, again, there was no consistent
difference between pH 7.4 and 6.0 for Slc26a6-injected groups
(4,345 ± 243 and 4,193 ± 109 pmol · oocyte1 · h1 at pH
7.4 and 6.0, respectively, vs. 106 ± 12 and 99 ± 16 pmol · oocyte1 · h1 in
water-injected controls). In contrast to Slc26a6, Slc26a1-injected oocytes did not take up 36Cl; this is in
agreement with transport studies using basolateral membrane vesicles
from renal cortex, which indicate that the basolateral SO (23). We
considered that Slc26a1 might require the presence of extracellular
SO; however, Slc26a1
mediates minimal Cl uptake in either the presence or
the absence of 25 mM SO, closer to the values for
Slc26a6 in the absence of Cl (Fig. 4C). In
contrast, 35SO (Fig. 4C), consistent with
the ability of this exchanger to mediate 36Cl
uptake (Fig. 4B). The increase in
35SO.
A shared property of the SLC26 anion exchangers is
cis-inhibition of the uptake of a given ion by other
substrates (19, 36, 43, 45). To assess the repertoire of
substrates capable of cis-inhibiting Cl uptake
by Slc26a6, we incubated Slc26a6-injected oocytes with sulfate,
formate, halides, nitrate, and lactate; all but lactate significantly
inhibit 36Cl uptake (Fig.
5A). A similar profile was
obtained for SO, but neither
oxalate (45) nor SO, formate, and oxalate;
the residual 35SO
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1 · h1 in
water-injected controls, Fig.
6A) and formate (45 ± 5 vs. 7 pmol · oocyte1 · h1
in water-injected controls, Fig. 6B). In contrast, Slc26a1
mediates the transport of oxalate (72 ± 2 pmol · oocyte1 · h1, Fig.
6A), as reported for rat Slc26a1 (17), but not
formate (7 pmol · oocyte1 · h1, Fig.
6B).
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(Fig.
4C) has been observed before (43) but not
explored in detail. To extend this observation, we first examined the
effect of several monovalent ions (halides, formate, and lactate) on
35SO (Fig.
7A). Although the ability of Slc26a1 to transport all of these monovalent ions has not been examined, it transports neither Cl (Fig. 4B) nor formate (Fig. 6B).
Moreover, I and Br are both
cis-inhibitory for both SO uptake via Slc26a6, indicating that they are potential
substrates, as shown directly for SLC26A4 in the case of
I (46); by extension, these are not likely
substrates for Slc26a1. The activation of Slc26a1 by impermeant anions
is not unique to SO and other anions (Fig. 7B). Slc26a6 serves
as a control for the latter experiment, in that oxalate transport by
oocytes injected with this cRNA is strongly cis-inhibited by
these anions (Fig. 7B).
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Oocyte intracellular pH and electrophysiology.
To determine whether Slc26a6 functions as a
Cl/HCO. The
initial addition of CO2/HCO0.46 ± 0.01, n = 8) at an initial rate of 46.0 × 104 pH units/s
(382 ± 19 × 105 pH units/s,
n = 8). The initial pHi of Slc26a6 oocytes
is essentially the same as that of water-injected control
(water-injected, 7.26 ± 0.03, n = 8; Slc26a6,
7.29 ± 0.03, n = 10); addition of 5%
CO2/33 mM HCO0.46 ± 0.02, n = 10) at an initial rate of 35.0 × 104 pH units/s (387 ± 15 × 105 pH units/s, n = 10). Slc26a6 oocytes
are depolarized (26.3 ± 4.5 mV, n = 10)
compared with control oocytes (44.8 ± 4.3 mV, n = 8). The addition of HCO
replacement (gluconate) does not affect pHi of the
water-injected control (+6.0 ± 2.2 × 105 pH
units/s, n = 8; Fig. 8A). However, Fig.
8B illustrates that Cl removal increases
pHi of a Slc26a6 oocyte at the rate of 44 × 105 pH units/s (+72 ± 8.8 × 105
pH units/s, n = 10; Fig. 8B), which ceases
after Cl readdition. Surprisingly, this gluconate
replacement evokes a 37-mV hyperpolarization (22.7 ± 2.9 mV,
n = 9; vs. +0.2 ± 2.0 mV, n = 8 for controls). A second Cl removal in Fig. 8B
alkalinizes the cell at 28 × 105 pH units/s
(+41 ± 6.2 × 105 pH units/s,
n = 8) and reproduces the hyperpolarization
(18.6 ± 3.8 mV, n = 8). In all the experiments
with Slc26a6-injected oocytes, the second alkalinization induced by
Cl removal, which occurs at a higher pHi, has
a lower rate (+72 × 105 pH units/s for the first
alkalinization and +41 × 105 vs. +6.0 × 105 pH units/s for the single Cl removal in
water-injected oocytes).
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)pHi for
Slc26a6 is +0.53 ± 0.07, n = 10] (40,
41). This overshoot is not observed in controls
(pHi for controls is +0.02 ± 0.04, n = 8) (40, 41).
Because Slc26a6 clearly functions as a
Cl/HCO/OH exchanger. For these experiments, we
continuously bubbled all the non-HCO removal of
control oocytes (Fig. 9A) does not change pHi
(2.1 ± 1.8 × 105 pH units/s,
n = 7) or membrane potential (+1.1 ± 1.7 mV,
n = 14). Nevertheless, this same maneuver alkalinized
(+27 ± 6.4 × 105 pH units/s,
n = 6) and hyperpolarized (9.1 ± 3.0 mV,
n = 11; P < 0.008) Slc26a6 oocytes
(Fig. 9B). Cl readdition to the bath stopped
the alkalinization and returned membrane potential to the initial
value. However, the readdition of Cl evoked a large
transient depolarization (+39.6 ± 4.9 mV, n = 11 for Slc26a6 vs. 4.6 ± 0.9 mV, n = 14 for
controls; P < 0.000002) followed by a smaller
sustained depolarization.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We report here the molecular and functional characterization of
Slc26a1 and Slc26a6, the first and sixth members of the murine Slc26
gene family of anion exchangers. We have also reported on the
chromosomal localization and genomic structure of the two genes, along
with evidence of alternative splicing of both transcripts. Immunolocalization and functional characterization recently identified Slc26a6 as the putative Cl/formate exchanger of the renal
proximal tubular epithelium (19), and our data indicate
that Slc26a6 can also mediate SO/oxalate, Cl/OH, and
Cl/HCO
The sequence comparison of mouse Slc26a6 reveals that the closest characterized relative is prestin (Slc26a5), with 39% identity at the amino acid level, whereas Slc26a1 is closest to Slc26a2 (DTDST, 47% identity). The COOH-terminal domains of both Slc26a1 and Slc26a6 contain predicted sulfate transporter and anti-sigma (STAS) domains, recently defined by virtue of homology between the SLC26 gene family and bacterial anti-sigma factor antagonists (2). Structural predictions suggest a role for the STAS domain in nucleotide binding and/or hydrolysis (2). With the exception of a COOH-terminal type I PDZ interaction motif (51) (see below), analysis of the Slc26a6 protein with motif-based algorithms (44, 60) does not reveal other protein-signaling domains or motifs. Mouse and rat Slc26a1 (4) predict a COOH-terminal type I PDZ binding motif (S-A-L); however, this motif is not conserved in the human protein (GenBank AF297659). Analysis using both the Prosite and Phosphobase (22) databases reveals that Slc26a1 and Slc26a6 are both potential substrates for a number of protein kinases, including tyrosine kinases, protein kinase A, and protein kinase C (Fig. 1).
We utilized heterologous expression in X. laevis oocytes for
the functional characterization of Slc26a1 and Slc26a6. Isotopic flux
studies indicate that Slc26a6 is a versatile anion exchanger, capable
of transporting SO, formate, and
oxalate, whereas Slc26a1 transports only SO in both the presence and absence of
HCO/HCO/OH exchanger (Figs. 8 and 9). While this
manuscript was in review, Wang et al. (58) reported that
Slc26a6-injected X. laevis oocytes can mediate
Cl/HCO uptake by Slc26a6 by a
more acidic extracellular medium (Fig. 4B) is somewhat
surprising, given that this protein can mediate Cl/OH exchange (Fig. 9). However, similar
findings for the pH dependency of Slc26a6 Cl uptake were
reported by Knauf et al. (19).
Slc26a6 shares the ability to mediate Cl/base exchange
with Slc26a3 (34) and Slc26a4 (42, 49).
However, the electrophysiology of this mode of anion transport has not
been studied in the SLC26 anion exchangers. We have found that removal
of extracellular Cl in the presence of
HCO; 2) the entry of another anion with
HCO ion that
exits. We cannot rule out the possibility that Slc26a6 overexpression
somehow evokes an otherwise silent conductance natively present in the
oocyte, and future experiments will examine the nature of these
Cl-suppressed voltage or current changes. However,
unmasking an otherwise silent conductance in response to Slc26a6
expression seems unlikely, because there is not a precedent in the
literature for a "Cl-inhibited anion current" as
measured in our experiments.
Although complete functional characterization is lacking for many of
the SLC26 anion exchangers, the range of substrates intrinsic to
Slc26a6 is tentatively only matched by that of SLC26A3 (DRA) (5,
34, 36, 54). Of note, however, formate transport has not
been reported for SLC26A3, and only low-level oxalate, Cl, and SO or formate but does transport
SO,
I, and formate, but not divalent anions such as
SO
The data reported here reveal that transport of the divalent anions
SO and formate.
This is, presumably, not simply a matter of the valence of anionic
charge, because HCO (Fig. 4C). This is suggestive of
H+-SO, and
HCO
The finding that Slc26a6 functions in the exchange of formate and
oxalate for both Cl and SO/formate exchange functions in transepithelial
reabsorption of NaCl by the proximal tubule (57) and some
segments of the distal nephron (55). The
perfusion of proximal tubules with luminal oxalate also stimulates
transepithelial salt transport, although in this case
Na+-SO/formate and Cl/oxalate
exchange, given that previous studies using renal brush-border vesicles
suggested the existence of two separate distinct transporters, one
capable of only Cl/formate exchange and the other capable
of both Cl/formate and Cl/oxalate exchange
(16). The Cl/formate/oxalate exchanger
activity in brush-border vesicles has a higher affinity for oxalate
over formate (16); although kinetic studies of Slc26a6 are
lacking, the greater efficacy of oxalate in both
cis-inhibition of 36Cl uptake
(Fig. 5A) and trans-stimulation of
35SO/formate
exchange, Cl/oxalate exchange in apical membrane vesicles
is thought to be electrogenic (16), compatible perhaps
with the observation that Cl/HCO/formate
exchange in the proximal tubule awaits the characterization of Slc26a6
knockout mice, along with the full pharmacological characterization of
the Slc26a6 in its various transport modes (16). A second
unresolved issue is how the luminal exchange of Cl with
formate and oxalate is specifically coupled to
Na+/H+ exchange and
Na+-SO/formate exchange
(Fig. 5).
Finally, another longstanding issue in the transcellular transport of
NaCl by the proximal tubule has been the relative importance of apical
Cl/formate/oxalate exchange and Cl/base
exchange, particularly Cl/OH exchange.
Whereas several groups have reported the presence of apical
Cl/base exchange in both vesicle and whole tubule
preparations, this has not been reproduced in many other studies
(reviewed in Ref. 24). Data shown in Fig. 9 indicate that
Slc26a6 can clearly mediate Cl/OH exchange.
Again, clarification of the quantitative role of Slc26a6 in apical
Cl/OH exchange in the proximal tubule
awaits the characterization of Slc26a6-null mice.
The expression pattern and substrate specificity of Slc26a6 suggests
that it may mediate several modes of anion exchange in a number of
tissues. For example, there is evidence for Cl/formate
exchange in vascular smooth muscle and cardiac myocytes (50), consistent with the expression of Slc26a6 in heart
and skeletal muscle (Fig. 2). The role of Slc26a6 in
Cl/HCO/HCO/HCO/HCO
Finally, the ability of Slc26a1 and Slc26a6 to mediate oxalate exchange
suggests important roles for these transporters in oxalate homeostasis.
Thus there is evidence for DIDS-sensitive Cl/oxalate,
OH/oxalate, and formate/oxalate exchange in brush-border
vesicles from rabbit ileum (20), and Slc26a6 is heavily
expressed in small intestine (Fig. 2). Slc26a1 and Slc26a6 are
expressed at the basolateral (17) and apical
(19) membranes, respectively, of the proximal tubule, a
major site of renal oxalate secretion (47). Hyperexcretion
of oxalate is an important factor in the pathogenesis of renal stones,
and increased red cell oxalate transport has been shown to segregate
with oxalate excretion in certain kindreds with nephrolithiasis
(3); although red cell oxalate transport has generally
been attributed to AE1 (15), this has not to our knowledge
been verified by heterologous expression, and the relative role of
specific anion exchangers in oxalate transport is as yet unknown.
However, it is evident that dietary absorption of oxalate, potentially
via SLC26A6, is an important determinant of urinary excretion
(14). Given this physiology, variation in the human
SLC26A1 and/or SLC26A6 genes may be an important
determinant of the risk for nephrolithiasis.
| |
ACKNOWLEDGEMENTS |
|---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants K11-DK-02103 (D. B. Mount), PO1-DK-038226 (D. B. Mount), RO1-DK-57708 (D. B. Mount), and RO1-DK-56218 (M. F. Romero) and by a Howard Hughes Medical Institute grant to Case Western Reserve University (M. F. Romero). D. B. Mount is supported by an Advanced Career Development Award from the Department of Veterans Affairs; Q. Xie was supported by NIDDK training grant T32-DK-07569-12.
| |
FOOTNOTES |
|---|
* Q. Xie and R. Welch contributed equally to this study.
The nucleotide sequences for Slc26a6a, Slc26a6b, SLC26A6a, and Slc26a1 have been submitted to the GenBank/EBI Data Bank with the accession nos. AY049076, AF248494, AF416721, and AF349043.
Address for reprint requests and other correspondence: D. B. Mount, Dept. of Veterans Affairs Medical Center, 1400 VFW Pkwy., West Roxbury, MA, 02132 (E-mail: dmount{at}rics.bwh.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
May 29, 2002;10.1152/ajprenal.00079.2002
Received 25 February 2002; accepted in final form 25 May 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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T. Nakada, K. Zandi-Nejad, Y. Kurita, H. Kudo, V. Broumand, C. Y. Kwon, A. Mercado, D. B. Mount, and S. Hirose Roles of Slc13a1 and Slc26a1 sulfate transporters of eel kidney in sulfate homeostasis and osmoregulation in freshwater Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R575 - R585. [Abstract] [Full Text] [PDF]
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J. E. Simpson, L. R. Gawenis, N. M. Walker, K. T. Boyle, and L. L. Clarke Chloride conductance of CFTR facilitates basal Cl-/HCO3- exchange in the villous epithelium of intact murine duodenum Am J Physiol Gastrointest Liver Physiol, June 1, 2005; 288(6): G1241 - G1251. [Abstract] [Full Text] [PDF]
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Z. Wang, T. Wang, S. Petrovic, B. Tuo, B. Riederer, S. Barone, J. N. Lorenz, U. Seidler, P. S. Aronson, and M. Soleimani Renal and intestinal transport defects in Slc26a6-null mice Am J Physiol Cell Physiol, April 1, 2005; 288(4): C957 - C965. [Abstract] [Full Text] [PDF]
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B. V Alvarez, D. M Kieller, A. L Quon, D. Markovich, and J. R Casey Slc26a6: a cardiac chloride-hydroxyl exchanger and predominant chloride-bicarbonate exchanger of the mouse heart J. Physiol., December 15, 2004; 561(3): 721 - 734. [Abstract] [Full Text] [PDF]
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R. M. Pelis and J. L. Renfro Role of tubular secretion and carbonic anhydrase in vertebrate renal sulfate excretion Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R491 - R501. [Abstract] [Full Text] [PDF]
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S. Barone, H. Amlal, J. Xu, M. Kujala, J. Kere, S. Petrovic, and M. Soleimani Differential Regulation of Basolateral Cl-/HCO3- Exchangers SLC26A7 and AE1 in Kidney Outer Medullary Collecting Duct J. Am. Soc. Nephrol., August 1, 2004; 15(8): 2002 - 2011. [Abstract] [Full Text] [PDF]
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S. Petrovic, S. Barone, A. M. Weinstein, and M. Soleimani Activation of the apical Na+/H+ exchanger NHE3 by formate: a basis of enhanced fluid and electrolyte reabsorption by formate in the kidney Am J Physiol Renal Physiol, August 1, 2004; 287(2): F336 - F346. [Abstract] [Full Text] [PDF]
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R. Pedrosa, P. A. Jose, and P. Soares-da-Silva Defective D1-like receptor-mediated inhibition of the Cl-/HCO3- exchanger in immortalized SHR proximal tubular epithelial cells Am J Physiol Renal Physiol, June 1, 2004; 286(6): F1120 - F1126. [Abstract] [Full Text] [PDF]
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S. Petrovic, S. Barone, J. Xu, L. Conforti, L. Ma, M. Kujala, J. Kere, and M. Soleimani SLC26A7: a basolateral Cl-/HCO3- exchanger specific to intercalated cells of the outer medullary collecting duct Am J Physiol Renal Physiol, January 1, 2004; 286(1): F161 - F169. [Abstract] [Full Text] [PDF]
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S. Petrovic, L. Ma, Z. Wang, and M. Soleimani Identification of an apical Cl-/HCO-3 exchanger in rat kidney proximal tubule Am J Physiol Cell Physiol, September 1, 2003; 285(3): C608 - C617. [Abstract] [Full Text] [PDF]
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M. N Chernova, L. Jiang, B. E Shmukler, C. W Schweinfest, P. Blanco, S. D Freedman, A. K Stewart, and S. L Alper Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes J. Physiol., May 15, 2003; 549(1): 3 - 19. [Abstract] [Full Text] [PDF]
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H. Lohi, G. Lamprecht, D. Markovich, A. Heil, M. Kujala, U. Seidler, and J. Kere Isoforms of SLC26A6 mediate anion transport and have functional PDZ interaction domains Am J Physiol Cell Physiol, March 1, 2003; 284(3): C769 - C779. [Abstract] [Full Text] [PDF]
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