Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42−/OH−/Cl− Exchanger Regulated by Extracellular Cl−

Ohana, Ehud; Shcheynikov, Nikolay; Park, Meeyoung; Muallem, Shmuel

doi:10.1074/jbc.m111.297192

Cited by 50 publications

(56 citation statements)

References 56 publications

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“…On the other hand, slc26a6 and NaDC-1 can be readily co-immunoprecipitated (see Figure 2D and discussion below). Finally, inhibition of NaDC-1 was not restricted to slc26a6 because the 2Cl -/1HCO 3 2 exchanger slc26a3 6,7 similarly inhibited NaDC-1 activity ( Figure 2B), although the SO 4 22 /OH 2 /Cl 2 exchanger slc26a2 23 did not (Supplemental Figure 3). …”

Section: Resultsmentioning

confidence: 97%

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

Ohana

Shcheynikov

Moe

et al. 2013

Journal of the American Society of Nephrology

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The combination of hyperoxaluria and hypocitraturia can trigger Ca 2+ -oxalate stone formation, even in the absence of hypercalciuria, but the molecular mechanisms that control urinary oxalate and citrate levels are not understood completely. Here, we examined the relationship between the oxalate transporter SLC26A6 and the citrate transporter NaDC-1 in citrate and oxalate homeostasis. Compared with wildtype mice, Slc26a6-null mice exhibited increased renal and intestinal sodium-dependent succinate uptake, as well as urinary hyperoxaluria and hypocitraturia, but no change in urinary pH, indicating enhanced transport activity of NaDC-1. When co-expressed in Xenopus oocytes, NaDC-1 enhanced Slc26a6 transport activity. In contrast, Slc26a6 inhibited NaDC-1 transport activity in an activity dependent manner to restricted tubular citrate absorption. Biochemical and physiologic analysis revealed that the STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediated both the physical and functional interactions of these transporters. These findings reveal a molecular pathway that senses and tightly regulates oxalate and citrate levels and may control Ca 2+-oxalate stone formation.

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Section: Resultsmentioning

confidence: 97%

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

Ohana

Shcheynikov

Moe

et al. 2013

Journal of the American Society of Nephrology

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“…Mutations within this motif altered Cl − transport and coupling in ClCs (34,35). Recently, we reported that regulation of slc26a2 by extracellular Cl − is altered by mutations in slc26a2 GXXXP motif (36). NBCe1-B has three GXXXP motifs in the N terminus (Fig.…”

Section: Imentioning

confidence: 97%

“…The present study has uncovered a previously unidentified function of Cl − in as a signaling ion that regulates the activity of other transporters, including transporters that do not transport Cl − , such as the NBCs. The regulation seems to be mediated by sites containing GXXXP motifs, which have been associated with Cl − sensing and transport in other transporters (32)(33)(34)(35)(36). In the ClC channels, residues in the GXXXP motifs from several regions are brought together to form the Cl − binding sites (32).…”

Section: CLmentioning

confidence: 99%

Intracellular Cl ⁻ as a signaling ion that potently regulates Na ⁺ /HCO3 ⁻ transporters

Shcheynikov

Son

Hong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cl− is a major anion in mammalian cells involved in transport processes that determines the intracellular activity of many ions and plasma membrane potential. Surprisingly, a role of intracellular Clas a signaling ion has not been previously evaluated. Here we report that Cl − in functions as a regulator of cellular Na + and HCO 3 − concentrations and transepithelial transport through modulating the activity of several electrogenic Na− transporters. We describe the molecular mechanism(s) of this regulation by physiological Cl − in concentrations highlighting the role of GXXXP motifs in Cl − sensing. Regulation of the ubiquitous Na + -HCO3 − cotransport (NBC)e1-B is mediated by two GXXXP-containing sites; regulation of NBCe2-C is dependent on a single GXXXP motif; and regulation of NBCe1-A depends on a cryptic GXXXP motif. In the basal state NBCe1-B is inhibited by high Cl

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“…Previous studies of N-glycan sites have focused on a few members of the SLC26 family. SLC26A2 (DTDST) expressed in HEK cells showed two bands of 120 and 80 kDa with the upper band predominating (24,37), as did the protein in isolated rat proximal tubule microvillus membrane vesicles (9). Previous N-glycosylation studies of SLC26A3 identified N-glycosylation sites at closely spaced positions Asn153, 161, and 165, showing that this loop region is extracellular (20).…”

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confidence: 89%

“…For a recent review on SLC26 family members, see also Alper and Sharma (1). SLC26A1 and A2 transport sulfate, oxalate, and glyoxalate in an exchange mode with chloride (6,19,37,45,49,50,68). SLC26A1 (Sat-1) is located in the basolateral membrane of hepatocytes, enterocytes, and proximal tubular epithelial cells, while SLC26A2 (DTDST) is found in chrondrocytes and in the apical membrane of colonic epithelial cells and renal proximal cells.…”

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confidence: 99%

N-glycosylation and topology of the human SLC26 family of anion transport membrane proteins

Xia

Reithmeier

2014

American Journal of Physiology-Cell Physiology

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Li J, Xia F, Reithmeier RA. N-glycosylation and topology of the human SLC26 family of anion transport membrane proteins. Am J Physiol Cell Physiol 306: C943-C960, 2014. First published March 19, 2014 doi:10.1152/ajpcell.00030.2014.-The human solute carrier (SLC26) family of anion transporters consists of 10 members (SLCA1-11, SLCA10 being a pseudogene) that encode membrane proteins containing ϳ12 transmembrane (TM) segments with putative N-glycosylation sites (-NXS/T-) in extracellular loops and a COOHterminal cytosolic STAS domain. All 10 members of the human SLC26 family, FLAG-tagged at the NH2 terminus, were transiently expressed in HEK-293 cells. While most proteins were observed to contain both high-mannose and complex oligosaccharides, SLC26A2 was mainly in the complex form, SLC26A4 in the high-mannose form, and SLC26A8 was not N-glycosylated. Mutation of the putative N-glycosylation sites showed that most members contain multiple N-glycosylation sites in the second extracytosolic (EC) loop, except SLC26A11, which was N-glycosylated in EC loop 4. Immunofluorescence staining of permeabilized cells localized the proteins to the plasma membrane and the endoplasmic reticulum, with SLC26A2 highly localized to the plasma membrane. N-glycosylation was not a necessary requirement for cell surface expression as the localization of nonglycosylated proteins was similar to their wild-type counterparts, although a lower level of cell-surface biotinylation was observed. No immunostaining of intact cells was observed for any SLC26 members, demonstrating that the NH2-terminal FLAG tag was located in the cytosol. Topological models of the SLC26 proteins that contain an even number of transmembrane segments with both the NH2 and COOH termini located in the cytosol and utilized N-glycosylation sites defining the positions of two EC loops are presented. anion transport; calnexin; congenital chloride-losing diarrhea; CLD; membrane glycoproteins; membrane protein topology; membrane protein trafficking; D-glycosylation; SLC26; solute carrier THE SLC26 FAMILY OF ANION transporters is found in all kingdoms of life indicating a fundamental importance of these membrane proteins in biology. The human SLC26 family (Table 1) of anion transporters consists of 10 members (SLC26A1-11, A10 being a pseudo gene) (18,36,62,63). The human SLC26 proteins contain ϳ750 residues but range in size from 606 residues (SLC26A11) to 970 residues (SLC26A8). The proteins all consist of two major domains: a NH 2 -terminal membrane domain with ϳ12 putative transmembrane (TM) segments and a COOH-terminal STAS (sulfate transporter antagonist of anti-sigma factor) domain located in the cytosol (53). Structures of the STAS domain of several bacterial members of the SLC26 family have been obtained (4, 54), as well as the structure of a modified version of the STAS domain of rat SLC26A5 protein (40). All of the core structures resemble the Bacillus anti-sigma factor antagonist SpoIIAA, a 110 amino acid phospho-protein with an alpha/beta topology consisting of ...

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Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42−/OH−/Cl− Exchanger Regulated by Extracellular Cl−

Abstract: Background: Slc26a2 is an SO 4 2Ϫ transporter, mutations in which cause diastrophic dysplasia. How Slc26a2 transports SO 4

Cited by 50 publications

References 56 publications

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

Intracellular Cl ⁻ as a signaling ion that potently regulates Na ⁺ /HCO3 ⁻ transporters

N-glycosylation and topology of the human SLC26 family of anion transport membrane proteins

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Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42−/OH−/Cl− Exchanger Regulated by Extracellular Cl−

Abstract: Background: Slc26a2 is an SO 4 2Ϫ transporter, mutations in which cause diastrophic dysplasia. How Slc26a2 transports SO 4

Cited by 50 publications

References 56 publications

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

Intracellular Cl − as a signaling ion that potently regulates Na + /HCO3 − transporters

N-glycosylation and topology of the human SLC26 family of anion transport membrane proteins

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Intracellular Cl ⁻ as a signaling ion that potently regulates Na ⁺ /HCO3 ⁻ transporters