{"gene":"SLC26A6","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"SLC26A6 protein localizes to the apical surface of pancreatic ductal cells, suggesting a role as a luminal anion exchanger in the pancreas.","method":"Immunohistochemistry on pancreatic ductal cell lines Capan-1 and Capan-2","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implication, single lab","pmids":["11087667"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Functional expression in Xenopus oocytes; in vitro PDZ binding assay; immunofluorescence for membrane localization","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (oocyte transport assay, in vitro pulldown, mutagenesis), replicated functional and binding findings","pmids":["12444019"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Slc26a6 knockout mice; proximal tubule microperfusion; pH-sensitive dye BCPCF; Ussing chamber measurements of duodenal HCO3- secretion","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, multiple tissues and assays","pmids":["15574486"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Quantitative RT-PCR; immunohistochemistry; functional expression in HEK293 cells using BCECF intracellular pH measurements; pharmacological stimulation of alpha-adrenergic receptors","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, expression profiling plus functional assay plus regulation study in single paper","pmids":["15498800"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Isolated short-circuited ileal segments; radiotracer flux measurements; DIDS pharmacology; Slc26a6 knockout mice","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — KO model with defined transport phenotype, multiple flux measurements and pharmacological validation","pmids":["16373425"],"is_preprint":false},{"year":2006,"finding":"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.","method":"pH-sensitive dye BCECF in intact duodenal mucosa; PAT-1 KO, DRA KO, and AE4 KO mouse comparison; RT-PCR","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO comparison with multiple exchanger KOs, direct functional measurement in intact tissue","pmids":["17170027"],"is_preprint":false},{"year":2006,"finding":"SLC26A6 mediates PGE2-stimulated (but not forskolin-stimulated) duodenal HCO3- secretion in a CFTR-independent manner; carbachol-stimulated HCO3- secretion is partially SLC26A6 dependent.","method":"Ussing chamber measurements of murine duodenal mucosal HCO3- secretion; SLC26A6-/- mice; CFTR knockout mice; pharmacological stimulation with PGE2, forskolin, and carbachol","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined secretory phenotype, multiple secretagogues tested, CFTR KO comparison","pmids":["16472591"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Functional expression in Xenopus oocytes; PKC activator PMA; PKC-delta inhibitor rottlerin; surface biotinylation; immunofluorescence microscopy; ex vivo duodenal oxalate secretion assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (flux assays, surface biotinylation, localization imaging, in vivo correlate), specific PKC-delta implicated by isoform-selective inhibitor","pmids":["17151144"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Microperfused interlobular pancreatic ducts from Slc26a6 null and wild-type mice; BCECF pH measurements; semiquantitative RT-PCR for Slc26a3","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — KO model with direct functional measurement and compensatory expression analysis","pmids":["16901991"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Ussing chamber experiments with (36)Cl- and (22)Na+ flux measurements; Slc26a6-/- and NHE3-/- mouse jejunum; immunoblotting for NHE3","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — double KO genetic epistasis with direct ion flux measurements","pmids":["17763866"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro microperfused proximal tubule S3 segments; BCPCF-AM for intracellular pH; angiotensin II stimulation; immunoblotting and immunofluorescence for NHE3","journal":"American journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined functional phenotype, but mechanistic link between Slc26a6 and NHE3 activity is indirect (no physical interaction demonstrated)","pmids":["18046080"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Functional expression in Xenopus oocytes; radiotracer flux assays; electrophysiology; chimera studies between human and mouse SLC26A6","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution in oocytes with chimera domain-mapping and species comparison","pmids":["18174209"],"is_preprint":false},{"year":2008,"finding":"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.","method":"SLC26A6 promoter-luciferase reporter assays; deletion and mutation analysis; IFN-gamma treatment of Caco2 cells; RT-PCR and functional transport assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — promoter deletion and site-directed mutagenesis plus functional transport readout, single lab","pmids":["18655181"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown of SLC26A6; radiotracer and Ussing chamber unidirectional flux measurements; BCECF fluorometric pH measurements; surface biotinylation of PAT-1","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — siRNA KD with multiple orthogonal transport assays quantifying PAT-1 contribution","pmids":["20501439"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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","journal":"Acta physiologica (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple KO models with direct functional measurements, single lab","pmids":["20969732"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple KO models, pharmacological inhibitors, direct pH measurement, functional link to CAII interaction","pmids":["20150244"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — KO model plus multiple transport assays plus pharmacological and genetic manipulation of paracellular pathway","pmids":["22021714"],"is_preprint":false},{"year":2012,"finding":"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.","method":"RT-PCR; immunocytochemistry; Western blot; co-immunoprecipitation in mouse sperm; pharmacological inhibition during capacitation","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP interaction and localization demonstrated, but functional role of SLC26A6 specifically (vs. SLC26A3) in capacitation not fully resolved","pmids":["21976599"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted functional interaction in oocytes plus domain-mapping biochemistry plus in vivo null mouse confirmation","pmids":["23833257"],"is_preprint":false},{"year":2013,"finding":"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.","method":"RT-PCR isoform characterization; immunofluorescence confocal microscopy; patch-clamp technique with fast solution exchange in mouse cardiomyocytes","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 — direct electrophysiological measurement (patch-clamp) demonstrating electrogenicity in native cells","pmids":["23933580"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Enzymatic deglycosylation assays; site-directed mutagenesis of glycosylation sites; surface biotinylation; functional oxalate transport assays in transfected cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus enzymatic deglycosylation plus functional transport assay, multiple orthogonal methods","pmids":["27681177"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO model with direct functional measurements plus heterologous expression comparison of anion exchange specificities","pmids":["29530983"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Immunolocalization; ex vivo pancreas fluid secretion measurement; Slc26a6-null mice; HCO3--free conditions","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with defined secretory phenotype and HCO3- dependence test, single lab","pmids":["31532720"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with miRNA mimic plus mRNA/protein confirmation, single lab","pmids":["31042422"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — KO model with two independent CKD induction methods, direct oxalate measurement, and expression analysis","pmids":["32660969"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro cell expression of STAS domain mutants; protein expression and trafficking assays; functional transport assays; SLC13 citrate transport regulation assays","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — functional mutagenesis with multiple readouts (expression, trafficking, transport, regulatory interaction), single lab","pmids":["32317970"],"is_preprint":false},{"year":2021,"finding":"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.","method":"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","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 — HTS-identified selective inhibitor validated in both in vitro and in vivo functional assays","pmids":["34100381"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1-2 — functional mutagenesis with transport assay, surface expression, and dominant-negative co-transfection experiment","pmids":["35115415"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cryo-EM structure determination; reconstitution in proteoliposomes; functional transport assays; comparison with SLC26A9 structure","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure plus functional reconstitution with defined stoichiometry","pmids":["37351578"],"is_preprint":false},{"year":2024,"finding":"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.","method":"PAT1 knockout mice; DSS-induced colitis model; 16S rRNA sequencing; mass spectrometry metabolomics; Western blot for tight-junction proteins; co-housing experiments","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with multiple orthogonal readouts (microbiome, metabolome, barrier integrity, co-housing), but mechanistic link between oxalate transport and barrier/microbiome is indirect","pmids":["38735402"],"is_preprint":false},{"year":2018,"finding":"Helicobacter pylori infection downregulates duodenal SLC26A6 expression through a TGFβ-mediated p38 MAPK signaling pathway; TGFβ inhibitor SB431542 reverses H. pylori-induced SLC26A6 downregulation.","method":"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","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway inhibitor experiments in both in vivo and in vitro models, single lab","pmids":["30119655"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Slc26a6 knockout mice; I/R model; echocardiography; electrophysiology; hemodynamic monitoring; fluorescence microscopy for pHi; Ca2+ transients; sarcomere shortening; histochemistry","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with multiple in vivo, ex vivo, and cellular endpoints; single lab","pmids":["41462888"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter reporter assay plus multi-inhibitor pathway dissection in vivo and in vitro, single lab","pmids":["41938536"],"is_preprint":false}],"current_model":"SLC26A6 is a multifunctional apical membrane anion exchanger (Cl-/HCO3-, Cl-/oxalate, Cl-/OH-, Cl-/formate, Cl-/SO4(2-)) whose cryo-EM structure reveals an inward-facing conformation with a specialized ion-binding site mediating electroneutral Cl-/HCO3- and electrogenic Cl-/oxalate(2-) exchange; it is expressed in kidney proximal tubule, small intestine, pancreatic ducts and acini, heart, salivary glands, and other epithelia where it drives oxalate secretion (preventing hyperoxaluria and nephrolithiasis), bicarbonate secretion, and NaCl absorption—functions regulated by PKC-delta (causing membrane internalization), N-glycosylation (required for transport activity), carbonic anhydrase II interaction, PDZ scaffold proteins (NHERF/E3KARP), physical and functional interaction with CFTR, and transcriptional control by IRF-1, miR-125a-5p, and the CaSR-PKA-FOXO4 signaling axis."},"narrative":{"teleology":[{"year":2000,"claim":"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","pmids":["11087667"],"confidence":"Medium","gaps":["Functional transport activity not yet demonstrated","Expression in other epithelia not yet mapped"]},{"year":2002,"claim":"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","pmids":["12444019"],"confidence":"High","gaps":["Whether PDZ interactions affect transport activity in native tissues unknown","Full substrate specificity not yet catalogued"]},{"year":2004,"claim":"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","pmids":["15574486","15498800"],"confidence":"High","gaps":["Molecular basis of PKC-mediated inhibition (direct phosphorylation vs. trafficking) not resolved","Cardiac phenotype in KO mice not yet examined"]},{"year":2005,"claim":"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","pmids":["16373425"],"confidence":"High","gaps":["Contribution of other SLC26 family members to intestinal oxalate handling not fully excluded","Human relevance of mouse KO phenotype not yet confirmed"]},{"year":2006,"claim":"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","pmids":["17170027","17151144","16472591","16901991"],"confidence":"High","gaps":["Direct PKC-δ phosphorylation site on SLC26A6 not identified","Mechanism of compensatory Slc26a3 upregulation in pancreas unknown"]},{"year":2007,"claim":"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","pmids":["17763866","18046080"],"confidence":"High","gaps":["Physical interaction between SLC26A6 and NHE3 not directly demonstrated","Whether coupling is direct or mediated by shared scaffolds unclear"]},{"year":2008,"claim":"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","pmids":["18174209","18655181"],"confidence":"High","gaps":["Structural basis of species-specific electrogenicity differences not resolved at atomic level","In vivo relevance of IRF-1-mediated regulation not tested"]},{"year":2010,"claim":"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","pmids":["20150244","20969732","20501439"],"confidence":"High","gaps":["Whether CAII binds SLC26A6 directly or through a scaffold not determined","Molecular basis of CFTR–SLC26A6 functional coupling not fully elucidated"]},{"year":2013,"claim":"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","pmids":["23833257"],"confidence":"High","gaps":["Structural basis of STAS–NaDC-1 interaction not resolved","Whether this interaction occurs in human kidney proximal tubule not confirmed"]},{"year":2016,"claim":"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","pmids":["27681177"],"confidence":"High","gaps":["How glycosylation affects transporter conformation or substrate binding unknown","Whether glycosylation status varies across tissues not examined"]},{"year":2018,"claim":"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","pmids":["29530983","30119655"],"confidence":"High","gaps":["Physiological significance of salivary oxalate secretion unclear","Whether H. pylori-mediated downregulation contributes to hyperoxaluria not tested"]},{"year":2020,"claim":"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","pmids":["32660969","32317970"],"confidence":"High","gaps":["Whether pharmacological SLC26A6 activation could treat CKD-associated hyperoxaluria not tested","Clinical prevalence of STAS mutations in stone formers unknown"]},{"year":2021,"claim":"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","pmids":["34100381"],"confidence":"High","gaps":["Inhibitor selectivity across the full SLC26 family not completely profiled","Therapeutic utility in constipation or hyperoxaluria not yet evaluated"]},{"year":2022,"claim":"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","pmids":["35115415"],"confidence":"High","gaps":["Patient phenotype and family segregation details not fully elaborated in timeline","Whether other dominant-negative mutations exist is unknown"]},{"year":2023,"claim":"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","pmids":["37351578"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38735402"],"confidence":"Medium","gaps":["Whether the microbiome effect is secondary to altered luminal oxalate/pH or a direct epithelial signaling role is unknown","Human relevance not established"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,2,4,5,11,13,16,19,21,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7,14,19,20,21,22,27,28]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,2,4,5,8,9,11,13,16,19,21,28]}],"complexes":[],"partners":["NHERF1","SLC9A3R2","CA2","CFTR","SLC13A2","NHE3"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9BXS9","full_name":"Solute carrier family 26 member 6","aliases":["Anion exchange transporter","Pendrin-like protein 1","Pendrin-L1"],"length_aa":759,"mass_kda":83.0,"function":"Apical membrane anion-exchanger with wide epithelial distribution that plays a role as a component of the pH buffering system for maintaining acid-base homeostasis. Acts as a versatile DIDS-sensitive inorganic and organic anion transporter that mediates the uptake of monovalent anions like chloride, bicarbonate, formate and hydroxyl ion and divalent anions like sulfate and oxalate. Functions in multiple exchange modes involving pairs of these anions, which include chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate-sulfate and chloride-formate exchange. Apical membrane chloride-bicarbonate exchanger that mediates luminal chloride absorption and bicarbonate secretion by the small intestinal brush border membrane and contributes to intracellular pH regulation in the duodenal upper villous epithelium during proton-coupled peptide absorption, possibly by providing a bicarbonate import pathway. Also mediates intestinal chloride absorption and oxalate secretion, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Transepithelial oxalate secretion, chloride-formate, chloride-oxalate and chloride-bicarbonate transport activities in the duodenum are inhibited by PKC activation in a calcium-independent manner. The apical membrane chloride-bicarbonate exchanger also provides a major route for fluid and bicarbonate secretion into the proximal tubules of the kidney as well as into the proximal part of the interlobular pancreatic ductal tree, where it mediates electrogenic chloride-bicarbonate exchange with a chloride-bicarbonate stoichiometry of 1:2, and hence will dilute and alkalinize protein-rich acinar secretion. Also mediates the transcellular sulfate absorption and oxalate secretion across the apical membrane in the duodenum and the formate ion efflux at the apical brush border of cells in the proximal tubules of kidney. Plays a role in sperm capacitation by increasing intracellular pH Apical membrane chloride-bicarbonate exchanger. Its association with carbonic anhydrase CA2 forms a bicarbonate transport metabolon; hence maximizes the local concentration of bicarbonate at the transporter site","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BXS9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC26A6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000225697","cell_line_id":"CID001321","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001321","total_profiled":1310},"omim":[{"mim_id":"610130","title":"SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 1; SLC26A1","url":"https://www.omim.org/entry/610130"},{"mim_id":"610068","title":"SOLUTE CARRIER FAMILY 26 (ANION TRANSPORTER), MEMBER 6: SLC26A6","url":"https://www.omim.org/entry/610068"},{"mim_id":"603831","title":"PDZ DOMAIN-CONTAINING 1; PDZK1","url":"https://www.omim.org/entry/603831"},{"mim_id":"167030","title":"NEPHROLITHIASIS, CALCIUM OXALATE, 1; CAON1","url":"https://www.omim.org/entry/167030"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC26A6"},"hgnc":{"alias_symbol":["DKFZp586E1422"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXS9","domains":[{"cath_id":"-","chopping":"88-164_173-507","consensus_level":"medium","plddt":91.3894,"start":88,"end":507},{"cath_id":"3.30.750.24","chopping":"514-570_661-745","consensus_level":"high","plddt":89.5969,"start":514,"end":745}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXS9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXS9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXS9-F1-predicted_aligned_error_v6.png","plddt_mean":82.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC26A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC26A6"},"sequence":{"accession":"Q9BXS9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXS9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXS9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXS9"}},"corpus_meta":[{"pmid":"11087667","id":"PMC_11087667","title":"Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11087667","citation_count":163,"is_preprint":false},{"pmid":"15574486","id":"PMC_15574486","title":"Renal and intestinal transport defects in Slc26a6-null mice.","date":"2004","source":"American journal of physiology. 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[et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/26372434","citation_count":9,"is_preprint":false},{"pmid":"17120764","id":"PMC_17120764","title":"Anion exchangers in flux: functional differences between human and mouse SLC26A6 polypeptides.","date":"2006","source":"Novartis Foundation symposium","url":"https://pubmed.ncbi.nlm.nih.gov/17120764","citation_count":9,"is_preprint":false},{"pmid":"35116598","id":"PMC_35116598","title":"Systemic characterization of the SLC family genes reveals SLC26A6 as a novel oncogene in hepatocellular carcinoma.","date":"2021","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35116598","citation_count":8,"is_preprint":false},{"pmid":"30864378","id":"PMC_30864378","title":"Sex-independent expression of chloride/formate exchanger Cfex (Slc26a6) in rat pancreas, small intestine, and liver, and male-dominant expression in kidneys.","date":"2018","source":"Arhiv za higijenu rada i toksikologiju","url":"https://pubmed.ncbi.nlm.nih.gov/30864378","citation_count":8,"is_preprint":false},{"pmid":"31582903","id":"PMC_31582903","title":"Enhanced Activity by NKCC1 and Slc26a6 Mediates Acidic pH and Cl- Movement after Cardioplegia-Induced Arrest of db/db Diabetic Heart.","date":"2019","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/31582903","citation_count":7,"is_preprint":false},{"pmid":"34458928","id":"PMC_34458928","title":"SLC26A6 and NADC‑1: Future direction of nephrolithiasis and calculus‑related hypertension research (Review).","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34458928","citation_count":5,"is_preprint":false},{"pmid":"25907791","id":"PMC_25907791","title":"Bicarbonate exchangers SLC26A3 and SLC26A6 are localized at the apical membrane of porcine vas deferens epithelium.","date":"2015","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/25907791","citation_count":5,"is_preprint":false},{"pmid":"31539142","id":"PMC_31539142","title":"Novel SLC26A6 gene polymorphism rs184187143 is associated with diabetic ketoacidosis of gestational diabetes.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31539142","citation_count":4,"is_preprint":false},{"pmid":"31532720","id":"PMC_31532720","title":"Slc26a6 is an apical membrane anion exchanger that drives HCO3--dependent fluid secretion in murine pancreatic acinar cells.","date":"2019","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31532720","citation_count":4,"is_preprint":false},{"pmid":"39949394","id":"PMC_39949394","title":"The enigmatic SLC26A6 multifunctional anion transporter: recent advances in structure-function relationship, pathophysiological significance and novel pharmacological inhibitors.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39949394","citation_count":1,"is_preprint":false},{"pmid":"38349781","id":"PMC_38349781","title":"A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.","date":"2024","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38349781","citation_count":1,"is_preprint":false},{"pmid":"38543153","id":"PMC_38543153","title":"Unity Is Strength: The Mutual Alliance between CFTR and SLC26A6 as Therapeutic Opportunity in Cystic Fibrosis.","date":"2024","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38543153","citation_count":1,"is_preprint":false},{"pmid":"41462888","id":"PMC_41462888","title":"Ablation of Slc26a6 Mitigates Myocardial Ischemia/Reperfusion Injury.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41462888","citation_count":0,"is_preprint":false},{"pmid":"41938536","id":"PMC_41938536","title":"CaSR regulates SLC26A6 expression via the PKA-FOXO4 signaling axis to promote experimental calcium oxalate kidney stone formation in rats.","date":"2026","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41938536","citation_count":0,"is_preprint":false},{"pmid":"23596793","id":"PMC_23596793","title":"[Effects of weile powder on bicarbonate transporters CFTR SLC26A3 and SLC26A6 in gastric ulcers of rats].","date":"2013","source":"Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23596793","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38350,"output_tokens":8384,"usd":0.120405},"stage2":{"model":"claude-opus-4-6","input_tokens":12127,"output_tokens":4457,"usd":0.25809},"total_usd":0.378495,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SLC26A6 protein localizes to the apical surface of pancreatic ductal cells, suggesting a role as a luminal anion exchanger in the pancreas.\",\n      \"method\": \"Immunohistochemistry on pancreatic ductal cell lines Capan-1 and Capan-2\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implication, single lab\",\n      \"pmids\": [\"11087667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Functional expression in Xenopus oocytes; in vitro PDZ binding assay; immunofluorescence for membrane localization\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (oocyte transport assay, in vitro pulldown, mutagenesis), replicated functional and binding findings\",\n      \"pmids\": [\"12444019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Slc26a6 knockout mice; proximal tubule microperfusion; pH-sensitive dye BCPCF; Ussing chamber measurements of duodenal HCO3- secretion\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, multiple tissues and assays\",\n      \"pmids\": [\"15574486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative RT-PCR; immunohistochemistry; functional expression in HEK293 cells using BCECF intracellular pH measurements; pharmacological stimulation of alpha-adrenergic receptors\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, expression profiling plus functional assay plus regulation study in single paper\",\n      \"pmids\": [\"15498800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Isolated short-circuited ileal segments; radiotracer flux measurements; DIDS pharmacology; Slc26a6 knockout mice\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with defined transport phenotype, multiple flux measurements and pharmacological validation\",\n      \"pmids\": [\"16373425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"pH-sensitive dye BCECF in intact duodenal mucosa; PAT-1 KO, DRA KO, and AE4 KO mouse comparison; RT-PCR\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO comparison with multiple exchanger KOs, direct functional measurement in intact tissue\",\n      \"pmids\": [\"17170027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLC26A6 mediates PGE2-stimulated (but not forskolin-stimulated) duodenal HCO3- secretion in a CFTR-independent manner; carbachol-stimulated HCO3- secretion is partially SLC26A6 dependent.\",\n      \"method\": \"Ussing chamber measurements of murine duodenal mucosal HCO3- secretion; SLC26A6-/- mice; CFTR knockout mice; pharmacological stimulation with PGE2, forskolin, and carbachol\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined secretory phenotype, multiple secretagogues tested, CFTR KO comparison\",\n      \"pmids\": [\"16472591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Functional expression in Xenopus oocytes; PKC activator PMA; PKC-delta inhibitor rottlerin; surface biotinylation; immunofluorescence microscopy; ex vivo duodenal oxalate secretion assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (flux assays, surface biotinylation, localization imaging, in vivo correlate), specific PKC-delta implicated by isoform-selective inhibitor\",\n      \"pmids\": [\"17151144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Microperfused interlobular pancreatic ducts from Slc26a6 null and wild-type mice; BCECF pH measurements; semiquantitative RT-PCR for Slc26a3\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with direct functional measurement and compensatory expression analysis\",\n      \"pmids\": [\"16901991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Ussing chamber experiments with (36)Cl- and (22)Na+ flux measurements; Slc26a6-/- and NHE3-/- mouse jejunum; immunoblotting for NHE3\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double KO genetic epistasis with direct ion flux measurements\",\n      \"pmids\": [\"17763866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro microperfused proximal tubule S3 segments; BCPCF-AM for intracellular pH; angiotensin II stimulation; immunoblotting and immunofluorescence for NHE3\",\n      \"journal\": \"American journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined functional phenotype, but mechanistic link between Slc26a6 and NHE3 activity is indirect (no physical interaction demonstrated)\",\n      \"pmids\": [\"18046080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Functional expression in Xenopus oocytes; radiotracer flux assays; electrophysiology; chimera studies between human and mouse SLC26A6\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution in oocytes with chimera domain-mapping and species comparison\",\n      \"pmids\": [\"18174209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"SLC26A6 promoter-luciferase reporter assays; deletion and mutation analysis; IFN-gamma treatment of Caco2 cells; RT-PCR and functional transport assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter deletion and site-directed mutagenesis plus functional transport readout, single lab\",\n      \"pmids\": [\"18655181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of SLC26A6; radiotracer and Ussing chamber unidirectional flux measurements; BCECF fluorometric pH measurements; surface biotinylation of PAT-1\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with multiple orthogonal transport assays quantifying PAT-1 contribution\",\n      \"pmids\": [\"20501439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO models with direct functional measurements, single lab\",\n      \"pmids\": [\"20969732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO models, pharmacological inhibitors, direct pH measurement, functional link to CAII interaction\",\n      \"pmids\": [\"20150244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model plus multiple transport assays plus pharmacological and genetic manipulation of paracellular pathway\",\n      \"pmids\": [\"22021714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR; immunocytochemistry; Western blot; co-immunoprecipitation in mouse sperm; pharmacological inhibition during capacitation\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP interaction and localization demonstrated, but functional role of SLC26A6 specifically (vs. SLC26A3) in capacitation not fully resolved\",\n      \"pmids\": [\"21976599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted functional interaction in oocytes plus domain-mapping biochemistry plus in vivo null mouse confirmation\",\n      \"pmids\": [\"23833257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR isoform characterization; immunofluorescence confocal microscopy; patch-clamp technique with fast solution exchange in mouse cardiomyocytes\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological measurement (patch-clamp) demonstrating electrogenicity in native cells\",\n      \"pmids\": [\"23933580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Enzymatic deglycosylation assays; site-directed mutagenesis of glycosylation sites; surface biotinylation; functional oxalate transport assays in transfected cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus enzymatic deglycosylation plus functional transport assay, multiple orthogonal methods\",\n      \"pmids\": [\"27681177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with direct functional measurements plus heterologous expression comparison of anion exchange specificities\",\n      \"pmids\": [\"29530983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Immunolocalization; ex vivo pancreas fluid secretion measurement; Slc26a6-null mice; HCO3--free conditions\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with defined secretory phenotype and HCO3- dependence test, single lab\",\n      \"pmids\": [\"31532720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with miRNA mimic plus mRNA/protein confirmation, single lab\",\n      \"pmids\": [\"31042422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with two independent CKD induction methods, direct oxalate measurement, and expression analysis\",\n      \"pmids\": [\"32660969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro cell expression of STAS domain mutants; protein expression and trafficking assays; functional transport assays; SLC13 citrate transport regulation assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mutagenesis with multiple readouts (expression, trafficking, transport, regulatory interaction), single lab\",\n      \"pmids\": [\"32317970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — HTS-identified selective inhibitor validated in both in vitro and in vivo functional assays\",\n      \"pmids\": [\"34100381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Whole exome sequencing; cell culture expression of mutant SLC26A6; functional oxalate transport assay; surface expression assay; co-transfection dominant-negative assay; in silico analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional mutagenesis with transport assay, surface expression, and dominant-negative co-transfection experiment\",\n      \"pmids\": [\"35115415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination; reconstitution in proteoliposomes; functional transport assays; comparison with SLC26A9 structure\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure plus functional reconstitution with defined stoichiometry\",\n      \"pmids\": [\"37351578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"PAT1 knockout mice; DSS-induced colitis model; 16S rRNA sequencing; mass spectrometry metabolomics; Western blot for tight-junction proteins; co-housing experiments\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple orthogonal readouts (microbiome, metabolome, barrier integrity, co-housing), but mechanistic link between oxalate transport and barrier/microbiome is indirect\",\n      \"pmids\": [\"38735402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Helicobacter pylori infection downregulates duodenal SLC26A6 expression through a TGFβ-mediated p38 MAPK signaling pathway; TGFβ inhibitor SB431542 reverses H. pylori-induced SLC26A6 downregulation.\",\n      \"method\": \"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\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway inhibitor experiments in both in vivo and in vitro models, single lab\",\n      \"pmids\": [\"30119655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Slc26a6 knockout mice; I/R model; echocardiography; electrophysiology; hemodynamic monitoring; fluorescence microscopy for pHi; Ca2+ transients; sarcomere shortening; histochemistry\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple in vivo, ex vivo, and cellular endpoints; single lab\",\n      \"pmids\": [\"41462888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter reporter assay plus multi-inhibitor pathway dissection in vivo and in vitro, single lab\",\n      \"pmids\": [\"41938536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC26A6 is a multifunctional apical membrane anion exchanger (Cl-/HCO3-, Cl-/oxalate, Cl-/OH-, Cl-/formate, Cl-/SO4(2-)) whose cryo-EM structure reveals an inward-facing conformation with a specialized ion-binding site mediating electroneutral Cl-/HCO3- and electrogenic Cl-/oxalate(2-) exchange; it is expressed in kidney proximal tubule, small intestine, pancreatic ducts and acini, heart, salivary glands, and other epithelia where it drives oxalate secretion (preventing hyperoxaluria and nephrolithiasis), bicarbonate secretion, and NaCl absorption—functions regulated by PKC-delta (causing membrane internalization), N-glycosylation (required for transport activity), carbonic anhydrase II interaction, PDZ scaffold proteins (NHERF/E3KARP), physical and functional interaction with CFTR, and transcriptional control by IRF-1, miR-125a-5p, and the CaSR-PKA-FOXO4 signaling axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunohistochemistry in Capan-1 and Capan-2 pancreatic ductal cell lines\",\n      \"pmids\": [\"11087667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional transport activity not yet demonstrated\", \"Expression in other epithelia not yet mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Functional expression in Xenopus oocytes with flux assays; in vitro PDZ binding assay; truncation mutagenesis\",\n      \"pmids\": [\"12444019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDZ interactions affect transport activity in native tissues unknown\", \"Full substrate specificity not yet catalogued\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Slc26a6-null mice with proximal tubule microperfusion, Ussing chamber duodenal HCO₃⁻ secretion, and HEK293 cell pH measurements with pharmacological PKC activation\",\n      \"pmids\": [\"15574486\", \"15498800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of PKC-mediated inhibition (direct phosphorylation vs. trafficking) not resolved\", \"Cardiac phenotype in KO mice not yet examined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Radiotracer flux in isolated short-circuited ileal segments from Slc26a6-null mice with DIDS pharmacology\",\n      \"pmids\": [\"16373425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of other SLC26 family members to intestinal oxalate handling not fully excluded\", \"Human relevance of mouse KO phenotype not yet confirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"17170027\", \"17151144\", \"16472591\", \"16901991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PKC-δ phosphorylation site on SLC26A6 not identified\", \"Mechanism of compensatory Slc26a3 upregulation in pancreas unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ussing chamber ³⁶Cl⁻/²²Na⁺ flux measurements in Slc26a6⁻/⁻ and NHE3⁻/⁻ jejunum; microperfused S3 proximal tubule segments from Slc26a6-null mice\",\n      \"pmids\": [\"17763866\", \"18046080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical interaction between SLC26A6 and NHE3 not directly demonstrated\", \"Whether coupling is direct or mediated by shared scaffolds unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Human–mouse chimera studies in Xenopus oocytes with electrophysiology; SLC26A6 promoter-luciferase deletion/mutation analysis in Caco-2 cells\",\n      \"pmids\": [\"18174209\", \"18655181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of species-specific electrogenicity differences not resolved at atomic level\", \"In vivo relevance of IRF-1-mediated regulation not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pat-1 KO and CAII KO mouse intestinal pH measurements; comparison of Pat-1 KO, DRA KO, and Cftr KO duodenal preparations\",\n      \"pmids\": [\"20150244\", \"20969732\", \"20501439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CAII binds SLC26A6 directly or through a scaffold not determined\", \"Molecular basis of CFTR–SLC26A6 functional coupling not fully elucidated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-expression in Xenopus oocytes with domain-mapping pulldowns; Slc26a6-null mouse urinary hypocitraturia phenotype\",\n      \"pmids\": [\"23833257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAS–NaDC-1 interaction not resolved\", \"Whether this interaction occurs in human kidney proximal tubule not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Site-directed mutagenesis of glycosylation sites; enzymatic deglycosylation of surface-expressed protein; functional oxalate transport assays\",\n      \"pmids\": [\"27681177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How glycosylation affects transporter conformation or substrate binding unknown\", \"Whether glycosylation status varies across tissues not examined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"29530983\", \"30119655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of salivary oxalate secretion unclear\", \"Whether H. pylori-mediated downregulation contributes to hyperoxaluria not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"32660969\", \"32317970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pharmacological SLC26A6 activation could treat CKD-associated hyperoxaluria not tested\", \"Clinical prevalence of STAS mutations in stone formers unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"High-throughput screen of 50,000 compounds using halide-sensing fluorescent protein; closed intestinal loop fluid absorption assay in mice\",\n      \"pmids\": [\"34100381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor selectivity across the full SLC26 family not completely profiled\", \"Therapeutic utility in constipation or hyperoxaluria not yet evaluated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-exome sequencing; functional transport assay and surface expression in transfected cells; co-transfection dominant-negative assay\",\n      \"pmids\": [\"35115415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Patient phenotype and family segregation details not fully elaborated in timeline\", \"Whether other dominant-negative mutations exist is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM structure determination; reconstitution in proteoliposomes with functional transport assays; structural comparison with SLC26A9\",\n      \"pmids\": [\"37351578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"PAT1-KO mice with DSS colitis; 16S rRNA sequencing; metabolomics; tight-junction protein Western blot; co-housing experiments\",\n      \"pmids\": [\"38735402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the microbiome effect is secondary to altered luminal oxalate/pH or a direct epithelial signaling role is unknown\", \"Human relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2, 4, 5, 11, 13, 16, 19, 21, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7, 14, 19, 20, 21, 22, 27, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 2, 4, 5, 8, 9, 11, 13, 16, 19, 21, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NHERF1\",\n      \"SLC9A3R2\",\n      \"CA2\",\n      \"CFTR\",\n      \"SLC13A2\",\n      \"NHE3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}