Affinage

SLC26A6

Solute carrier family 26 member 6 · UniProt Q9BXS9

Length
759 aa
Mass
83.0 kDa
Annotated
2026-04-28
63 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC26A6 is a multifunctional apical membrane anion exchanger that mediates Cl⁻/HCO₃⁻, Cl⁻/oxalate, Cl⁻/OH⁻, Cl⁻/formate, and Cl⁻/SO₄²⁻ exchange across epithelial surfaces of the intestine, kidney proximal tubule, pancreatic ducts and acini, salivary glands, and heart, where it drives oxalate secretion, bicarbonate secretion, NaCl absorption, and intracellular pH regulation (PMID:15574486, PMID:16373425, PMID:16901991, PMID:29530983, PMID:15498800). Its cryo-EM structure reveals an inward-facing conformation with a remodeled ion-binding site that confers coupled anion exchange (electroneutral Cl⁻/HCO₃⁻ and electrogenic Cl⁻/oxalate²⁻) rather than uncoupled channel activity, with transport activity critically dependent on N-glycosylation and regulated by PKC-δ–mediated membrane internalization, interaction with carbonic anhydrase II, and PDZ scaffold proteins NHERF/E3KARP (PMID:37351578, PMID:27681177, PMID:17151144, PMID:20150244, PMID:12444019). SLC26A6 physically and functionally interacts with NaDC-1 (SLC13A2) via its STAS domain to reciprocally regulate citrate transport, and cooperates with NHE3 for electroneutral NaCl absorption; Slc26a6-null mice develop hyperoxaluria due to loss of intestinal oxalate secretion, and a dominant-negative R507W mutation in humans causes loss of oxalate transport function (PMID:23833257, PMID:17763866, PMID:22021714, PMID:35115415). Transcriptional regulation of SLC26A6 is mediated by IFN-γ/IRF-1, miR-125a-5p, TGFβ/p38 MAPK, and a CaSR–PKA–FOXO4 signaling axis (PMID:18655181, PMID:31042422, PMID:30119655, PMID:41938536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 Medium

    Identifying where SLC26A6 resides in polarized epithelia was prerequisite to understanding its physiological role; immunolocalization placed it at the apical surface of pancreatic ductal cells, suggesting a luminal anion exchange function.

    Evidence Immunohistochemistry in Capan-1 and Capan-2 pancreatic ductal cell lines

    PMID:11087667

    Open questions at the time
    • Functional transport activity not yet demonstrated
    • Expression in other epithelia not yet mapped
  2. 2002 High

    Demonstrating that SLC26A6 has intrinsic anion transport activity and identifying its PDZ-mediated scaffold interactions established it as a DIDS-sensitive Cl⁻/SO₄²⁻ exchanger with a C-terminal TRL motif binding NHERF and E3KARP.

    Evidence Functional expression in Xenopus oocytes with flux assays; in vitro PDZ binding assay; truncation mutagenesis

    PMID:12444019

    Open questions at the time
    • Whether PDZ interactions affect transport activity in native tissues unknown
    • Full substrate specificity not yet catalogued
  3. 2004 High

    Knockout mouse studies resolved the in vivo roles of Slc26a6, showing it mediates oxalate-stimulated NaCl absorption in kidney proximal tubule, HCO₃⁻ secretion in duodenum, and Cl⁻/HCO₃⁻ and Cl⁻/OH⁻ exchange in the heart, where it is the predominant anion exchanger inhibited by PKC.

    Evidence Slc26a6-null mice with proximal tubule microperfusion, Ussing chamber duodenal HCO₃⁻ secretion, and HEK293 cell pH measurements with pharmacological PKC activation

    PMID:15498800 PMID:15574486

    Open questions at the time
    • Molecular basis of PKC-mediated inhibition (direct phosphorylation vs. trafficking) not resolved
    • Cardiac phenotype in KO mice not yet examined
  4. 2005 High

    The discovery that Slc26a6-null mice have increased ileal oxalate absorption and fourfold greater urinary oxalate excretion established SLC26A6 as the principal intestinal oxalate secretory transporter and a gatekeeper against hyperoxaluria.

    Evidence Radiotracer flux in isolated short-circuited ileal segments from Slc26a6-null mice with DIDS pharmacology

    PMID:16373425

    Open questions at the time
    • Contribution of other SLC26 family members to intestinal oxalate handling not fully excluded
    • Human relevance of mouse KO phenotype not yet confirmed
  5. 2006 High

    Multiple studies established SLC26A6 as the dominant apical Cl⁻/HCO₃⁻ exchanger in duodenal villous epithelium and pancreatic ducts, showed PKC-δ–mediated membrane internalization as the mechanism of transport inhibition, and distinguished PGE2-stimulated HCO₃⁻ secretion as SLC26A6-dependent but CFTR-independent.

    Evidence Comparison of PAT-1, DRA, and AE4 KO mice in intact duodenal mucosa; surface biotinylation and immunofluorescence with PKC-δ inhibitor rottlerin in oocytes; Ussing chamber with secretagogues in SLC26A6⁻/⁻ and CFTR⁻/⁻ mice; microperfused pancreatic ducts from Slc26a6-null mice

    PMID:16472591 PMID:16901991 PMID:17151144 PMID:17170027

    Open questions at the time
    • Direct PKC-δ phosphorylation site on SLC26A6 not identified
    • Mechanism of compensatory Slc26a3 upregulation in pancreas unknown
  6. 2007 High

    Functional epistasis experiments with NHE3 revealed that SLC26A6 cooperates with NHE3 for electroneutral NaCl absorption in the jejunum and functionally regulates NHE3 activity in the proximal tubule, establishing a coupled transport paradigm.

    Evidence Ussing chamber ³⁶Cl⁻/²²Na⁺ flux measurements in Slc26a6⁻/⁻ and NHE3⁻/⁻ jejunum; microperfused S3 proximal tubule segments from Slc26a6-null mice

    PMID:17763866 PMID:18046080

    Open questions at the time
    • Physical interaction between SLC26A6 and NHE3 not directly demonstrated
    • Whether coupling is direct or mediated by shared scaffolds unclear
  7. 2008 High

    Species-specific differences between human and mouse SLC26A6 in oxalate transport kinetics and electrogenicity were mapped to both transmembrane and C-terminal domains, while IFN-γ/IRF-1 was identified as a transcriptional repressor acting through a promoter ISRE element.

    Evidence Human–mouse chimera studies in Xenopus oocytes with electrophysiology; SLC26A6 promoter-luciferase deletion/mutation analysis in Caco-2 cells

    PMID:18174209 PMID:18655181

    Open questions at the time
    • Structural basis of species-specific electrogenicity differences not resolved at atomic level
    • In vivo relevance of IRF-1-mediated regulation not tested
  8. 2010 High

    Functional interaction with carbonic anhydrase II was shown to be required for SLC26A6-mediated pH buffering during peptide absorption, and CFTR was found to modulate SLC26A6 activity in the lower villous epithelium, expanding the regulatory network.

    Evidence Pat-1 KO and CAII KO mouse intestinal pH measurements; comparison of Pat-1 KO, DRA KO, and Cftr KO duodenal preparations

    PMID:20150244 PMID:20501439 PMID:20969732

    Open questions at the time
    • Whether CAII binds SLC26A6 directly or through a scaffold not determined
    • Molecular basis of CFTR–SLC26A6 functional coupling not fully elucidated
  9. 2013 High

    The STAS domain of SLC26A6 was identified as the mediator of reciprocal physical and functional interaction with NaDC-1, whereby SLC26A6 inhibits citrate reabsorption—linking oxalate and citrate homeostasis in a single molecular complex.

    Evidence Co-expression in Xenopus oocytes with domain-mapping pulldowns; Slc26a6-null mouse urinary hypocitraturia phenotype

    PMID:23833257

    Open questions at the time
    • Structural basis of STAS–NaDC-1 interaction not resolved
    • Whether this interaction occurs in human kidney proximal tubule not confirmed
  10. 2016 High

    N-glycosylation at two sites in the second extracellular loop was shown to be critical for SLC26A6 transport activity but not for surface delivery, establishing post-translational glycosylation as a functional requirement.

    Evidence Site-directed mutagenesis of glycosylation sites; enzymatic deglycosylation of surface-expressed protein; functional oxalate transport assays

    PMID:27681177

    Open questions at the time
    • How glycosylation affects transporter conformation or substrate binding unknown
    • Whether glycosylation status varies across tissues not examined
  11. 2018 High

    SLC26A6's tissue repertoire was extended to salivary gland acinar cells where it mediates oxalate and HCO₃⁻ exchange, and H. pylori infection was found to downregulate duodenal SLC26A6 via TGFβ/p38 MAPK signaling, revealing a disease-relevant transcriptional mechanism.

    Evidence Slc26a6⁻/⁻ mouse submandibular gland acinar cell transport assays and salivary oxalate measurements; H. pylori infection model with TGFβ and p38 inhibitors in mice and SCBN cells

    PMID:29530983 PMID:30119655

    Open questions at the time
    • Physiological significance of salivary oxalate secretion unclear
    • Whether H. pylori-mediated downregulation contributes to hyperoxaluria not tested
  12. 2020 High

    Intestinal SLC26A6 was established as a critical extrarenal oxalate clearance route that is upregulated in chronic kidney disease, and STAS domain mutations were shown to impair transport and NaDC-1 regulation, linking SLC26A6 dysfunction to calcium oxalate stone susceptibility.

    Evidence CKD induction in Slc26a6-null mice with plasma oxalate measurement; in vitro expression of STAS mutants D23H/D673N and R621G with trafficking and transport assays

    PMID:32317970 PMID:32660969

    Open questions at the time
    • Whether pharmacological SLC26A6 activation could treat CKD-associated hyperoxaluria not tested
    • Clinical prevalence of STAS mutations in stone formers unknown
  13. 2021 High

    Development of a selective small-molecule inhibitor (PAT1inh-B01, IC50 ~350 nM) confirmed SLC26A6 as the predominant anion exchanger driving fluid absorption in mouse ileum and provided a pharmacological tool to dissect SLC26A6 function in vivo.

    Evidence High-throughput screen of 50,000 compounds using halide-sensing fluorescent protein; closed intestinal loop fluid absorption assay in mice

    PMID:34100381

    Open questions at the time
    • Inhibitor selectivity across the full SLC26 family not completely profiled
    • Therapeutic utility in constipation or hyperoxaluria not yet evaluated
  14. 2022 High

    A human R507W mutation was shown to cause dominant-negative loss of SLC26A6 oxalate transport, establishing a direct genetic mechanism for human disease through suppression of wild-type transporter activity when co-expressed.

    Evidence Whole-exome sequencing; functional transport assay and surface expression in transfected cells; co-transfection dominant-negative assay

    PMID:35115415

    Open questions at the time
    • Patient phenotype and family segregation details not fully elaborated in timeline
    • Whether other dominant-negative mutations exist is unknown
  15. 2023 High

    The cryo-EM structure of human SLC26A6 resolved how a remodeled ion-binding site in the mobile transmembrane domain confers coupled anion exchange selectivity (vs. uncoupled Cl⁻ channel activity in SLC26A9), with reconstituted proteoliposomes confirming 1:1 stoichiometry for electroneutral Cl⁻/HCO₃⁻ and electrogenic Cl⁻/oxalate²⁻ exchange.

    Evidence Cryo-EM structure determination; reconstitution in proteoliposomes with functional transport assays; structural comparison with SLC26A9

    PMID:37351578

    Open questions at the time
    • Outward-facing conformation not captured
    • Structural basis of substrate discrimination between oxalate and other divalent anions not fully resolved
    • How STAS domain interactions with partners modulate the transport cycle structurally unknown
  16. 2024 Medium

    Loss of SLC26A6 was found to disrupt gut microbiome composition and barrier integrity, with transferable dysbiosis increasing colitis susceptibility—revealing an unexpected link between apical anion exchange and intestinal homeostasis beyond ion transport.

    Evidence PAT1-KO mice with DSS colitis; 16S rRNA sequencing; metabolomics; tight-junction protein Western blot; co-housing experiments

    PMID:38735402

    Open questions at the time
    • Whether the microbiome effect is secondary to altered luminal oxalate/pH or a direct epithelial signaling role is unknown
    • Human relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the outward-facing structural conformation, the direct phosphorylation site(s) mediating PKC-δ regulation, the structural basis of STAS domain interactions with NaDC-1 and CFTR, and whether SLC26A6 loss-of-function mutations cause a defined Mendelian hyperoxaluria/nephrolithiasis syndrome in humans.
  • No outward-facing structure available
  • PKC-δ phosphorylation site(s) on SLC26A6 not mapped
  • No human genetic cohort study confirming SLC26A6 as a Mendelian disease gene

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 10 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 10
Pathway
R-HSA-382551 Transport of small molecules 12
Partners
CA2CFTRNHE3NHERF1SLC13A2SLC9A3R2

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 SLC26A6 protein localizes to the apical surface of pancreatic ductal cells, suggesting a role as a luminal anion exchanger in the pancreas. Immunohistochemistry on pancreatic ductal cell lines Capan-1 and Capan-2 Genomics Medium 11087667
2002 SLC26A6 and its splice variants SLC26A6c and SLC26A6d mediate Cl- and SO4(2-) transport activity (inhibited by DIDS and HCO3-), and the COOH terminus of SLC26A6 binds to the first and second PDZ domains of NHE3 regulatory proteins E3KARP and NHERF in vitro; truncation of the last three amino acids (TRL) abrogates PDZ interaction without affecting transport function. Functional expression in Xenopus oocytes; in vitro PDZ binding assay; immunofluorescence for membrane localization American journal of physiology. Cell physiology High 12444019
2004 Slc26a6 mediates oxalate-stimulated NaCl absorption and contributes to apical membrane Cl-/base exchange in the kidney proximal tubule; it also plays an important role in HCO3- secretion in the duodenum. Slc26a6 knockout mice; proximal tubule microperfusion; pH-sensitive dye BCPCF; Ussing chamber measurements of duodenal HCO3- secretion American journal of physiology. Cell physiology High 15574486
2004 Slc26a6 functions as a Cl-/HCO3- exchanger and Cl-/OH- exchanger in the myocardium; it is the predominant such exchanger in the mouse heart. Alpha-adrenergic stimulation (via protein kinase C) inhibits SLC26A6 Cl-/HCO3- exchange activity. Quantitative RT-PCR; immunohistochemistry; functional expression in HEK293 cells using BCECF intracellular pH measurements; pharmacological stimulation of alpha-adrenergic receptors The Journal of physiology High 15498800
2005 Slc26a6 mediates a significant fraction of apical oxalate efflux in exchange for Cl- in the ileum (secretory direction); Slc26a6-null mice show increased net ileal oxalate absorption and approximately fourfold greater urinary oxalate excretion compared to wild type. Isolated short-circuited ileal segments; radiotracer flux measurements; DIDS pharmacology; Slc26a6 knockout mice American journal of physiology. Gastrointestinal and liver physiology High 16373425
2006 PAT-1 (Slc26a6) is the predominant contributor to basal Cl-/HCO3- exchange (65-80% of activity) and entirely responsible for SO4(2-)/HCO3- exchange across the apical membrane of the upper villous epithelium of the murine duodenum; its deletion reduces intracellular pH. pH-sensitive dye BCECF in intact duodenal mucosa; PAT-1 KO, DRA KO, and AE4 KO mouse comparison; RT-PCR American journal of physiology. Gastrointestinal and liver physiology High 17170027
2006 SLC26A6 mediates PGE2-stimulated (but not forskolin-stimulated) duodenal HCO3- secretion in a CFTR-independent manner; carbachol-stimulated HCO3- secretion is partially SLC26A6 dependent. Ussing chamber measurements of murine duodenal mucosal HCO3- secretion; SLC26A6-/- mice; CFTR knockout mice; pharmacological stimulation with PGE2, forskolin, and carbachol Gastroenterology High 16472591
2006 PKC activation (specifically PKC-delta) inhibits multiple modes of Slc26a6-mediated anion exchange (Cl/formate, Cl/oxalate, and Cl/Cl) by redistributing Slc26a6 from the plasma membrane to intracellular compartments, reducing surface-available transporter without affecting total expression. Functional expression in Xenopus oocytes; PKC activator PMA; PKC-delta inhibitor rottlerin; surface biotinylation; immunofluorescence microscopy; ex vivo duodenal oxalate secretion assay American journal of physiology. Cell physiology High 17151144
2006 Slc26a6 mediates the HCO3- efflux mode of apical Cl-/HCO3- exchange in pancreatic interlobular duct cells (unidirectional toward HCO3- export); Slc26a6 deletion leads to compensatory upregulation of Slc26a3 (DRA) in the pancreas. Microperfused interlobular pancreatic ducts from Slc26a6 null and wild-type mice; BCECF pH measurements; semiquantitative RT-PCR for Slc26a3 American journal of physiology. Gastrointestinal and liver physiology High 16901991
2007 Slc26a6 acts in concert with NHE3 to mediate electroneutral NaCl absorption in the small intestine; its deletion reduces net Cl- and Na+ fluxes and Cl- absorption during glucose-driven transport. Ussing chamber experiments with (36)Cl- and (22)Na+ flux measurements; Slc26a6-/- and NHE3-/- mouse jejunum; immunoblotting for NHE3 Pflugers Archiv : European journal of physiology High 17763866
2007 Slc26a6 deletion downregulates apical NHE3 (Na+/H+ exchanger) activity in the straight segment (S3) of the proximal tubule, reducing intracellular pH, without altering NHE3 protein abundance or distribution. In vitro microperfused proximal tubule S3 segments; BCPCF-AM for intracellular pH; angiotensin II stimulation; immunoblotting and immunofluorescence for NHE3 American journal of nephrology Medium 18046080
2008 Human SLC26A6 mediates oxalate/Cl- exchange in Xenopus oocytes with a much higher K1/2 for extracellular Cl- (~62 mM) compared to mouse slc26a6 (~8 mM), and human SLC26A6-mediated oxalate transport appears electroneutral whereas mouse slc26a6-mediated exchange is electrogenic; these differences map to both transmembrane and C-terminal cytoplasmic domains. Functional expression in Xenopus oocytes; radiotracer flux assays; electrophysiology; chimera studies between human and mouse SLC26A6 The Journal of physiology High 18174209
2008 IFN-gamma decreases SLC26A6 mRNA expression and Cl-/HCO3- exchanger function in intestinal cells via an IRF-1 binding site (ISRE) located in the -414/-214 region of the SLC26A6 promoter; mutation of this ISRE abrogates IFN-gamma inhibitory effects. SLC26A6 promoter-luciferase reporter assays; deletion and mutation analysis; IFN-gamma treatment of Caco2 cells; RT-PCR and functional transport assays Journal of cellular biochemistry Medium 18655181
2009 PAT-1 (SLC26A6) at the apical membrane of Caco-2 BBe1 cells mediates bidirectional Cl-/oxalate exchange with DIDS EC50 ~5 µM and mucosal Cl- EC50 <20 mM; siRNA knockdown reduces oxalate, Cl-, and HCO3- exchange fluxes by 50%, 35%, and 50% respectively. siRNA knockdown of SLC26A6; radiotracer and Ussing chamber unidirectional flux measurements; BCECF fluorometric pH measurements; surface biotinylation of PAT-1 American journal of physiology. Gastrointestinal and liver physiology High 20501439
2010 Pat-1 (Slc26a6) mediates Cl-(IN)/HCO3-(OUT) exchange in the lower villous epithelium of murine duodenum; this activity is masked during glucose transport and is dependent on concurrent membrane association with CFTR for inhibition by membrane depolarization. BCECF measurements in intact duodenal mucosa; Pat-1 KO, DRA KO, Cftr KO, and DRA/Cftr double KO mouse comparison; Ussing chamber short-circuit current Acta physiologica (Oxford, England) Medium 20969732
2010 Pat-1 (Slc26a6) Cl-/HCO3- exchange contributes to intracellular pH regulation during H+-dipeptide (Pept1-mediated) transport; Pat-1 interacts with carbonic anhydrase II (CAII), and both Pat-1 and CAII are required for the Cl-(OUT)/HCO3-(IN) exchange that buffers epithelial acidification during peptide absorption. Ussing chamber short-circuit current; microfluorometry for pH; Pat-1 KO and CAII KO mouse intestine; pharmacological inhibition of NHE3, Cl-/HCO3- exchange, and CA activity American journal of physiology. Gastrointestinal and liver physiology High 20150244
2011 SLC26A6 mediates transcellular secretory flux of oxalate in the duodenum; absorptive oxalate flux is predominantly passive and paracellular (similar to mannitol), while secretory oxalate flux is DIDS-sensitive, saturable, and SLC26A6-dependent. In Slc26a6-null mice, secretory flux is reduced to passive levels. Simultaneous radiotracer flux measurements of [(14)C]oxalate and [(3)H]mannitol; DIDS pharmacology; Slc26a6-null mice; ZO-1 knockdown in epithelial cell lines; claudin modulation Journal of the American Society of Nephrology : JASN High 22021714
2012 SLC26A6, SLC26A3, and SLC9A3R1 are expressed in mouse sperm, localize to the midpiece, and physically interact with each other and with CFTR; CFTR and SLC26A3 mediate the Cl- increase induced by db-cAMP in sperm capacitation. RT-PCR; immunocytochemistry; Western blot; co-immunoprecipitation in mouse sperm; pharmacological inhibition during capacitation Biology of reproduction Medium 21976599
2013 The STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediate physical and functional interaction; Slc26a6 inhibits NaDC-1 citrate transport activity in an activity-dependent manner while NaDC-1 enhances Slc26a6 transport activity when co-expressed in Xenopus oocytes; Slc26a6-null mice show increased NaDC-1 transport activity with urinary hyperoxaluria and hypocitraturia. Co-expression in Xenopus oocytes; biochemical interaction (pulldown); domain mapping using STAS domain and NaDC-1 intracellular loop; Slc26a6-null mouse phenotyping; sodium-dependent succinate uptake assays Journal of the American Society of Nephrology : JASN High 23833257
2013 Cardiac Slc26a6 mediates electrogenic Cl-/HCO3- and electrogenic Cl-/oxalate exchange in cardiomyocytes; four cardiac isoforms (C-a, C-b, C-c, C-d) are expressed in both atrial and ventricular myocytes, with Slc26a6 present in the plasma membrane. RT-PCR isoform characterization; immunofluorescence confocal microscopy; patch-clamp technique with fast solution exchange in mouse cardiomyocytes Cardiovascular research High 23933580
2016 N-glycosylation at two sites in the putative second extracellular loop of SLC26A6 is critically important for chloride-dependent oxalate transport function; glycosylation is not essential for cell surface delivery but affects trafficking/maintenance in the plasma membrane. Enzymatic deglycosylation of surface-expressed SLC26A6 strongly reduces oxalate transport activity. Enzymatic deglycosylation assays; site-directed mutagenesis of glycosylation sites; surface biotinylation; functional oxalate transport assays in transfected cells American journal of physiology. Cell physiology High 27681177
2018 Slc26a6 localizes to the apical membrane of submandibular salivary gland acinar cells where it mediates Cl-/oxalate exchange (and Cl-/HCO3- exchange); Slc26a6-/- mice show significantly reduced Cl-/oxalate and Cl-/HCO3- exchange in acinar cells and reduced oxalate secretion in submandibular saliva, without affecting HCO3- secretion. RNA sequencing; Western blot; CHO-K1 cell transfection with Slc26a6 and comparison exchangers; isolated acinar cell transport assays; salivary oxalate and HCO3- measurement in Slc26a6-/- mice The Journal of biological chemistry High 29530983
2019 Slc26a6 localizes to the apical membrane of pancreatic exocrine acinar cells and mediates the HCO3--dependent component of fluid secretion (~35%); fluid secretion in Slc26a6-null mice is independent of HCO3-, while wild-type secretion is HCO3- dependent. Immunolocalization; ex vivo pancreas fluid secretion measurement; Slc26a6-null mice; HCO3--free conditions American journal of physiology. Cell physiology Medium 31532720
2019 miR-125a-5p directly targets the 3'-UTR of SLC26A6 (PAT1) mRNA and reduces both mRNA and protein levels of PAT-1 in intestinal epithelial cells. In silico 3'-UTR analysis; dual luciferase reporter assay with PAT-1 3'-UTR; miRNA mimic transfection; RT-PCR and Western blot in Caco-2 cells American journal of physiology. Cell physiology Medium 31042422
2020 Slc26a6-mediated enteric oxalate secretion is upregulated in chronic kidney disease (CKD) models, with increased Slc26a6 mRNA and protein expression in the intestine of CKD mice; Slc26a6-null mice with CKD show significantly elevated plasma oxalate, demonstrating that intestinal Slc26a6 is a critical extrarenal route for oxalate clearance. CKD induction by high oxalate diet or aristolochic acid; qPCR; immunohistochemistry; Western blot for intestinal Slc26a6; fecal and plasma oxalate measurement by oxalate oxidase assay in WT and Slc26a6-null mice Journal of the American Society of Nephrology : JASN High 32660969
2020 STAS domain mutations of SLC26A6 (D23H/D673N and R621G) impair SLC26A6 protein expression, membrane trafficking, and/or transport activity, and differentially impair regulation of NaDC-1/SLC13-mediated citrate transport, linking the SLC26A6 STAS domain to control of citrate homeostasis and Ca2+-oxalate stone susceptibility. In vitro cell expression of STAS domain mutants; protein expression and trafficking assays; functional transport assays; SLC13 citrate transport regulation assays Frontiers in pharmacology Medium 32317970
2021 A selective small-molecule inhibitor (PAT1inh-B01, IC50 ~350 nM) of SLC26A6 blocks PAT1-mediated anion exchange without inhibiting SLC26A3; in mice, it inhibits fluid absorption by ~50% in midjejunum and >80% in ileum, demonstrating PAT1 as the predominant anion exchanger in mouse ileum. High-throughput small-molecule screen (50,000 compounds) using halide-sensing fluorescent protein; closed intestinal loop fluid absorption assay in mice; comparison with SLC26A3 inhibitor JCI insight High 34100381
2022 A heterozygous missense mutation R507W in SLC26A6 causes dominant-negative loss of function: the mutant protein has dramatically reduced Cl--dependent oxalate transport activity and reduced membrane surface expression, and when co-expressed with wild-type SLC26A6, it strongly suppresses wild-type transport activity. Whole exome sequencing; cell culture expression of mutant SLC26A6; functional oxalate transport assay; surface expression assay; co-transfection dominant-negative assay; in silico analysis Journal of medical genetics High 35115415
2023 Cryo-EM structure of human SLC26A6 reveals an inward-facing conformation similar to SLC26A9; a remodeled ion binding site in the mobile transmembrane domain unit accounts for altered anion selectivity (coupled Cl-/HCO3- and Cl-/oxalate exchanger vs. uncoupled Cl- channel in SLC26A9); structural studies in proteoliposomes support 1:1 stoichiometry giving electroneutral Cl-/HCO3- and electrogenic Cl-/oxalate2- exchange. Cryo-EM structure determination; reconstitution in proteoliposomes; functional transport assays; comparison with SLC26A9 structure eLife High 37351578
2024 Loss of SLC26A6 (PAT1) disrupts gut microbiome composition (dysbiosis), reduces butyrate and butyrate-producing bacteria, decreases tight-junction protein expression and gut-barrier integrity, and increases susceptibility to DSS-induced colitis; co-housing experiments transferred the barrier-deficient phenotype to wild-type mice. PAT1 knockout mice; DSS-induced colitis model; 16S rRNA sequencing; mass spectrometry metabolomics; Western blot for tight-junction proteins; co-housing experiments Gastroenterology Medium 38735402
2018 Helicobacter pylori infection downregulates duodenal SLC26A6 expression through a TGFβ-mediated p38 MAPK signaling pathway; TGFβ inhibitor SB431542 reverses H. pylori-induced SLC26A6 downregulation. H. pylori infection of C57BL/6 mice and human duodenal epithelial cells (SCBN); Western blot and RT-PCR for SLC26A6 and TGFβ; TGFβ inhibitor and p38 MAPK inhibitor (SB203580) treatment BMC microbiology Medium 30119655
2025 Ablation of Slc26a6 in mice protects the heart from ischemia/reperfusion injury; Slc26a6-null cardiomyocytes show elevated intracellular pH (less acidic), smaller infarct size, reduced troponin I, and better systolic and diastolic function compared to wild type, demonstrating that Slc26a6 acts as an acid loader via Cl-/HCO3- exchange in the myocardium. Slc26a6 knockout mice; I/R model; echocardiography; electrophysiology; hemodynamic monitoring; fluorescence microscopy for pHi; Ca2+ transients; sarcomere shortening; histochemistry Biomedicines Medium 41462888
2026 CaSR activates PKA, which phosphorylates FOXO4, leading to upregulation of SLC26A6 transcription; FOXO4 directly regulates the SLC26A6 promoter as confirmed by dual-luciferase reporter assay. This CaSR-PKA-FOXO4 signaling axis drives SLC26A6-mediated urinary oxalate excretion and calcium oxalate stone formation. In vivo CaOx stone model in rats; CaSR agonist/inhibitor, PKA inhibitor, FOXO4 inhibitor treatment; Western blot; immunohistochemistry; RT-qPCR; dual-luciferase reporter assay for FOXO4-SLC26A6 promoter interaction; NRK-52E cell culture Frontiers in cell and developmental biology Medium 41938536

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger. Genomics 163 11087667
2004 Renal and intestinal transport defects in Slc26a6-null mice. American journal of physiology. Cell physiology 148 15574486
2005 Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice. American journal of physiology. Gastrointestinal and liver physiology 144 16373425
2002 Isoforms of SLC26A6 mediate anion transport and have functional PDZ interaction domains. American journal of physiology. Cell physiology 106 12444019
2006 PAT-1 (Slc26a6) is the predominant apical membrane Cl-/HCO3- exchanger in the upper villous epithelium of the murine duodenum. American journal of physiology. Gastrointestinal and liver physiology 84 17170027
2006 Involvement of the anion exchanger SLC26A6 in prostaglandin E2- but not forskolin-stimulated duodenal HCO3- secretion. Gastroenterology 75 16472591
2001 Cloning and characterization of SLC26A6, a novel member of the solute carrier 26 gene family. Genomics 73 11247665
2011 Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion. Journal of the American Society of Nephrology : JASN 72 22021714
2012 Participation of the Cl-/HCO(3)- exchangers SLC26A3 and SLC26A6, the Cl- channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. Biology of reproduction 67 21976599
2008 Species differences in Cl- affinity and in electrogenicity of SLC26A6-mediated oxalate/Cl- exchange correlate with the distinct human and mouse susceptibilities to nephrolithiasis. The Journal of physiology 61 18174209
2013 SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis. Journal of the American Society of Nephrology : JASN 60 23833257
2004 Slc26a6: a cardiac chloride-hydroxyl exchanger and predominant chloride-bicarbonate exchanger of the mouse heart. The Journal of physiology 60 15498800
2006 Effect of Slc26a6 deletion on apical Cl-/HCO3- exchanger activity and cAMP-stimulated bicarbonate secretion in pancreatic duct. American journal of physiology. Gastrointestinal and liver physiology 56 16901991
2007 Sodium and chloride absorptive defects in the small intestine in Slc26a6 null mice. Pflugers Archiv : European journal of physiology 53 17763866
2008 Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis. American journal of kidney diseases : the official journal of the National Kidney Foundation 43 18951670
2006 Regulation of anion exchanger Slc26a6 by protein kinase C. American journal of physiology. Cell physiology 37 17151144
2021 Short-Chain Fatty Acids Reduced Renal Calcium Oxalate Stones by Regulating the Expression of Intestinal Oxalate Transporter SLC26A6. mSystems 36 34783577
2009 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: siRNA knockdown of SLC26A6 reveals the role and properties of PAT-1. American journal of physiology. Gastrointestinal and liver physiology 28 20501439
2015 Sulfate and thiosulfate inhibit oxalate transport via a dPrestin (Slc26a6)-dependent mechanism in an insect model of calcium oxalate nephrolithiasis. American journal of physiology. Renal physiology 27 26538444
2013 In-vivo functional study on the involvement of CFTR, SLC26A6, NHE-1 and CA isoenzymes II and XII in uterine fluid pH, volume and electrolyte regulation in rats under different sex-steroid influence. International journal of medical sciences 27 23869188
2014 Mechanisms of Cl(-) uptake in rainbow trout: cloning and expression of slc26a6, a prospective Cl(-)/HCO3(-) exchanger. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 24 25446148
2018 The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells. The Journal of biological chemistry 22 29530983
2015 Slc26a3/Dra and Slc26a6 in Murine Ameloblasts. Journal of dental research 22 26394631
2018 High expression of SLC26A6 in the kidney may contribute to renal calcification via an SLC26A6-dependent mechanism. PeerJ 20 30002986
2016 In Silico Screening and Molecular Dynamic Study of Nonsynonymous Single Nucleotide Polymorphisms Associated with Kidney Stones in the SLC26A6 Gene. The Journal of urology 20 26812303
2012 Urinary metabolic phenotyping the slc26a6 (chloride-oxalate exchanger) null mouse model. Journal of proteome research 20 22594923
2012 Progesterone downregulates oestrogen-induced expression of CFTR and SLC26A6 proteins and mRNA in rats' uteri. Journal of biomedicine & biotechnology 20 23226939
2005 SLC26A6 and SLC26A7 anion exchangers have a distinct distribution in human kidney. Nephron. Experimental nephrology 20 15956810
2017 Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis. American journal of physiology. Gastrointestinal and liver physiology 18 28526688
2010 Putative anion transporter-1 (Pat-1, Slc26a6) contributes to intracellular pH regulation during H+-dipeptide transport in duodenal villous epithelium. American journal of physiology. Gastrointestinal and liver physiology 18 20150244
2010 Functional activity of Pat-1 (Slc26a6) Cl(−)/HCO₃(−) exchange in the lower villus epithelium of murine duodenum. Acta physiologica (Oxford, England) 18 20969732
2018 Helicobacter pylori infection downregulates duodenal CFTR and SLC26A6 expressions through TGFβ signaling pathway. BMC microbiology 17 30119655
2016 The role of the rectum in osmoregulation and the potential effect of renoguanylin on SLC26a6 transport activity in the Gulf toadfish (Opsanus beta). American journal of physiology. Regulatory, integrative and comparative physiology 17 27030664
2008 Analysis of the 206M polymorphic variant of the SLC26A6 gene encoding a Cl- oxalate transporter in patients with primary hyperparathyroidism. European journal of endocrinology 17 19029225
2020 Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease. Journal of the American Society of Nephrology : JASN 16 32660969
2014 Genistein induces increase in fluid pH, Na+ and HCO3(-) concentration, SLC26A6 and SLC4A4 (NBCe1)-B expression in the uteri of ovariectomized rats. International journal of molecular sciences 16 24434640
2016 N-glycosylation critically regulates function of oxalate transporter SLC26A6. American journal of physiology. Cell physiology 15 27681177
2022 Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis. Journal of medical genetics 14 35115415
2008 Characterization of the 5'-flanking region and regulation of expression of human anion exchanger SLC26A6. Journal of cellular biochemistry 14 18655181
2013 Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes. Cardiovascular research 13 23933580
2021 SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine. JCI insight 12 34100381
2007 Slc26a6 (PAT1) deletion downregulates the apical Na+/H+ exchanger in the straight segment of the proximal tubule. American journal of nephrology 12 18046080
2023 Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange. eLife 11 37351578
2020 Novel Human Polymorphisms Define a Key Role for the SLC26A6-STAS Domain in Protection From Ca2+-Oxalate Lithogenesis. Frontiers in pharmacology 11 32317970
2024 A Direct Link Implicating Loss of SLC26A6 to Gut Microbial Dysbiosis, Compromised Barrier Integrity, and Inflammation. Gastroenterology 10 38735402
2019 miR-125a-5p: a novel regulator of SLC26A6 expression in intestinal epithelial cells. American journal of physiology. Cell physiology 10 31042422
2016 Involvement of Cl(-)/HCO3(-) exchanger SLC26A3 and SLC26A6 in preimplantation embryo cleavage. Scientific reports 10 27346053
2022 Estrogen treatment reduced oxalate transporting activity and enhanced migration through the involvement of SLC26A6 in lung cancer cells. Toxicology in vitro : an international journal published in association with BIBRA 9 35500753
2015 Genetic analysis of the bicarbonate secreting anion exchanger SLC26A6 in chronic pancreatitis. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 9 26372434
2006 Anion exchangers in flux: functional differences between human and mouse SLC26A6 polypeptides. Novartis Foundation symposium 9 17120764
2021 Systemic characterization of the SLC family genes reveals SLC26A6 as a novel oncogene in hepatocellular carcinoma. Translational cancer research 8 35116598
2018 Sex-independent expression of chloride/formate exchanger Cfex (Slc26a6) in rat pancreas, small intestine, and liver, and male-dominant expression in kidneys. Arhiv za higijenu rada i toksikologiju 8 30864378
2019 Enhanced Activity by NKCC1 and Slc26a6 Mediates Acidic pH and Cl- Movement after Cardioplegia-Induced Arrest of db/db Diabetic Heart. Mediators of inflammation 7 31582903
2021 SLC26A6 and NADC‑1: Future direction of nephrolithiasis and calculus‑related hypertension research (Review). Molecular medicine reports 5 34458928
2015 Bicarbonate exchangers SLC26A3 and SLC26A6 are localized at the apical membrane of porcine vas deferens epithelium. Physiological reports 5 25907791
2019 Slc26a6 is an apical membrane anion exchanger that drives HCO3--dependent fluid secretion in murine pancreatic acinar cells. American journal of physiology. Cell physiology 4 31532720
2019 Novel SLC26A6 gene polymorphism rs184187143 is associated with diabetic ketoacidosis of gestational diabetes. European review for medical and pharmacological sciences 4 31539142
2025 The enigmatic SLC26A6 multifunctional anion transporter: recent advances in structure-function relationship, pathophysiological significance and novel pharmacological inhibitors. Frontiers in pharmacology 1 39949394
2024 A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts. American journal of physiology. Gastrointestinal and liver physiology 1 38349781
2024 Unity Is Strength: The Mutual Alliance between CFTR and SLC26A6 as Therapeutic Opportunity in Cystic Fibrosis. Pharmaceuticals (Basel, Switzerland) 1 38543153
2026 CaSR regulates SLC26A6 expression via the PKA-FOXO4 signaling axis to promote experimental calcium oxalate kidney stone formation in rats. Frontiers in cell and developmental biology 0 41938536
2025 Ablation of Slc26a6 Mitigates Myocardial Ischemia/Reperfusion Injury. Biomedicines 0 41462888
2013 [Effects of weile powder on bicarbonate transporters CFTR SLC26A3 and SLC26A6 in gastric ulcers of rats]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine 0 23596793