{"gene":"SLC26A6","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2000,"finding":"SLC26A6 protein localizes to the apical surface of pancreatic ductal cells, as determined by immunohistochemistry, suggesting a role as a luminal anion exchanger.","method":"Immunohistochemistry on pancreatic ductal cell lines (Capan-1 and Capan-2)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunolocalization without functional transport assay in the same study; replicated in subsequent work","pmids":["11087667"],"is_preprint":false},{"year":2002,"finding":"SLC26A6 and its splice variants SLC26A6c and SLC26A6d function as anion transporters mediating Cl- and SO4(2-) transport when expressed in Xenopus oocytes; transport is inhibited by DIDS and HCO3-. The NH2- and COOH-terminal tails are intracellular, consistent with an even number of transmembrane domains.","method":"Functional expression in Xenopus oocytes; immunofluorescence for topology","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — heterologous expression assay with pharmacological inhibition; replicated across multiple subsequent studies","pmids":["12444019"],"is_preprint":false},{"year":2002,"finding":"The COOH-terminus of SLC26A6 binds to the first and second PDZ domains of E3KARP (NHE3 kinase A regulatory protein) and NHERF proteins in vitro; truncation of the last three amino acids (TRL) abolishes this interaction without affecting transport function.","method":"In vitro PDZ domain binding assay; truncation mutagenesis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with mutagenesis in single study; functional consequence of PDZ interaction not fully characterized in vivo","pmids":["12444019"],"is_preprint":false},{"year":2004,"finding":"Slc26a6-null mice show abolished oxalate-stimulated NaCl absorption in kidney proximal tubules and a 58% decrease in apical membrane Cl-/base exchange activity, establishing Slc26a6 as the mediator of oxalate-stimulated NaCl transport and a major contributor to proximal tubule Cl-/base exchange.","method":"Gene knockout mice; in vitro microperfusion of proximal tubules; pH-sensitive dye BCPCF","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple defined physiological readouts; replicated by subsequent studies","pmids":["15574486"],"is_preprint":false},{"year":2004,"finding":"Slc26a6 deletion reduces baseline HCO3- secretion (~30%) in the duodenum, as measured in Ussing chambers, but does not affect forskolin-stimulated HCO3- secretion.","method":"Slc26a6 knockout mice; Ussing chamber HCO3- secretion measurements","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with quantitative functional readout; replicated in subsequent duodenal studies","pmids":["15574486"],"is_preprint":false},{"year":2004,"finding":"Slc26a6 (SLC26A6) functions as a Cl-/HCO3- exchanger and Cl-/OH- exchanger in the heart; it is the predominant Cl-/HCO3- and Cl-/OH- exchanger in mouse ventricular myocytes. Alpha-adrenergic receptor activation (via PKC) inhibits SLC26A6 Cl-/HCO3- exchange activity.","method":"Quantitative RT-PCR; immunohistochemistry; intracellular pH fluorescence measurements (BCECF) in HEK293 cells transfected with SLC26A6; pharmacological stimulation with alpha-adrenergic agonists","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (expression profiling, heterologous functional assay, pharmacological modulation); replicated in later cardiac studies","pmids":["15498800"],"is_preprint":false},{"year":2005,"finding":"PAT1 (Slc26a6) mediates a significant fraction of oxalate efflux (secretion) across the apical membrane of the distal ileum in exchange for Cl-, as demonstrated by the reversal of net oxalate transport from secretion to absorption in Slc26a6-null mice and DIDS sensitivity.","method":"Slc26a6 knockout mice; Ussing chamber radiotracer flux measurements; pharmacological inhibition with DIDS","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with quantitative unidirectional flux measurements; multiple orthogonal approaches; replicated across labs","pmids":["16373425"],"is_preprint":false},{"year":2006,"finding":"PAT-1 (Slc26a6) is the predominant contributor (65-80%) to basal Cl-/HCO3- exchange and the sole mediator of SO4(2-)/HCO3- exchange across the apical membrane of the upper villous epithelium of the murine duodenum.","method":"Gene-targeted deletion mice (PAT-1-, DRA-, AE4-); pH-sensitive dye BCECF fluorescence in intact duodenal mucosa","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — comparative KO strategy with three exchangers, quantitative functional readout, multiple deletion lines","pmids":["17170027"],"is_preprint":false},{"year":2006,"finding":"SLC26A6-mediated PGE2-stimulated duodenal HCO3- secretion is CFTR-independent, whereas forskolin-stimulated HCO3- secretion is completely SLC26A6-independent and CFTR-dependent, establishing distinct transport pathways for different secretagogues.","method":"SLC26A6-/- and CFTR-/- mouse duodenal mucosa in Ussing chambers; pharmacological stimulation with PGE2, forskolin, and carbachol","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double KO epistasis with quantitative functional readout; clearly dissects two mechanistic pathways","pmids":["16472591"],"is_preprint":false},{"year":2006,"finding":"PKC-delta activation inhibits multiple modes of Slc26a6-mediated anion exchange (Cl/formate, Cl/oxalate, Cl/Cl) and causes redistribution of Slc26a6 from the plasma membrane to an intracellular compartment, reducing surface-biotinylation-accessible protein.","method":"Functional expression in Xenopus oocytes; surface biotinylation; immunofluorescence microscopy; PKC-delta-selective inhibitor rottlerin; PMA stimulation; mouse duodenal oxalate secretion assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (oocyte functional assay, surface biotinylation, immunofluorescence, in vivo secretion assay) in single study","pmids":["17151144"],"is_preprint":false},{"year":2006,"finding":"Slc26a6 deletion in pancreatic ducts shows HCO3- efflux is mediated by Slc26a6 (HCO3-efflux mode decreased in null mice), while HCO3-influx mode is upregulated in null mice. Compensatory >5-fold upregulation of Slc26a3 (DRA) expression occurs in Slc26a6 knockout pancreas.","method":"Slc26a6 knockout mice; pH-sensitive dye BCECF in microperfused interlobular pancreatic ducts; semiquantitative RT-PCR","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with directional transport measurements in native tissue; demonstrates unidirectionality of Slc26a6-mediated HCO3- transport","pmids":["16901991"],"is_preprint":false},{"year":2007,"finding":"Slc26a6 acts in concert with NHE3 in electroneutral NaCl absorption in the small intestinal jejunum; net Cl- and Na+ fluxes are significantly reduced in Slc26a6-/- animals, and Slc26a6 also mediates Cl- absorption during glucose-driven salt absorption.","method":"Slc26a6-/- and NHE3-/- knockout mice; Ussing chambers with 36Cl- and 22Na+ flux measurements; NHE3 immunofluorescence and immunoblot","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO comparison with isotopic flux measurements establishes functional coupling between SLC26A6 and NHE3","pmids":["17763866"],"is_preprint":false},{"year":2007,"finding":"Slc26a6 deletion reduces apical Na+/H+ exchanger (NHE3) activity in the straight segment (S3) of the kidney proximal tubule, decreasing intracellular pH and blunting formate-induced alkalinization, without affecting NHE3 protein abundance or distribution.","method":"In vitro microperfusion of proximal tubule S3 segments; BCPCF-AM pH measurements; immunoblotting and immunofluorescence for NHE3","journal":"American journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with functional readout in native tissue; indirect functional coupling to NHE3 activity, single lab","pmids":["18046080"],"is_preprint":false},{"year":2008,"finding":"Human SLC26A6 mediates oxalate/Cl- exchange with different kinetics than mouse Slc26a6: human SLC26A6 has a K1/2 for extracellular Cl- of ~62 mM (vs. 8 mM for mouse), and human SLC26A6-mediated oxalate transport appears electroneutral whereas mouse Slc26a6 mediates electrogenic oxalate/Cl- exchange. These differences are determined by both transmembrane and C-terminal cytoplasmic domains.","method":"Heterologous expression in Xenopus oocytes; isotopic flux assays; electrophysiology; human-mouse chimera studies","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Xenopus oocytes with domain-swap chimeras and electrophysiology; multiple orthogonal methods establishing mechanistic species differences","pmids":["18174209"],"is_preprint":false},{"year":2008,"finding":"The SLC26A6 variant V206M (p.Val206Met) shows ~30% reduction in oxalate transport activity when expressed in Xenopus oocytes, though heterozygosity for this variant does not measurably affect plasma or urine oxalate in hyperoxaluria patients.","method":"Functional expression of SLC26A6 variants in Xenopus laevis oocytes; oxalate transport assay","journal":"American journal of kidney diseases","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — heterologous functional expression with defined variant; single lab, limited clinical correlation","pmids":["18951670"],"is_preprint":false},{"year":2008,"finding":"The SLC26A6 promoter region -214/-44 harbors cis-acting elements required for maximal promoter activity; IFN-gamma decreases SLC26A6 mRNA, function, and promoter activity via an IRF-1 binding site (ISRE) located at -318/-300 bp, and mutation of this ISRE abrogates IFN-gamma inhibition.","method":"Promoter-luciferase reporter assays; deletion analysis; site-directed mutagenesis of ISRE; IFN-gamma treatment of Caco-2 cells","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with mutagenesis identifies regulatory element; single lab","pmids":["18655181"],"is_preprint":false},{"year":2009,"finding":"PAT-1 (SLC26A6) at the apical membrane of Caco-2BBe1 cells mediates oxalate, Cl-, and HCO3- exchange; siRNA knockdown reduces PAT-1 protein >60% and decreases unidirectional oxalate fluxes ~50%, Cl- fluxes ~35%, and Cl-/HCO3- exchange ~50%. PAT-1-mediated oxalate exchange is inhibited by mucosal DIDS (EC50 ~5 µM) and by mucosal Cl- (EC50 <20 mM). Vectorial oxalate transport depends principally on counterion gradients.","method":"siRNA knockdown in Caco-2BBe1 monolayers; radiotracer flux measurements; Ussing chambers; BCECF fluorometry","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA KD with multiple quantitative functional readouts in a native epithelial model; multiple orthogonal methods","pmids":["20501439"],"is_preprint":false},{"year":2010,"finding":"Pat-1 (Slc26a6) contributes to Cl-/HCO3- exchange in the lower villus epithelium; its activity is masked during glucose absorption due to membrane depolarization, but is active during electroneutral mannose absorption. Pat-1-dependent Cl-/HCO3- exchange activity is inhibited by membrane depolarization only when CFTR is co-expressed.","method":"Pat-1 KO, DRA KO, CFTR KO, and DRA/CFTR double-KO mice; BCECF fluorometry; Ussing chamber Isc measurements","journal":"Acta physiologica (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO comparisons with quantitative functional readout; establishes CFTR-dependent modulation of Pat-1 activity","pmids":["20969732"],"is_preprint":false},{"year":2010,"finding":"Pat-1 (Slc26a6) Cl-/HCO3- exchange contributes to intracellular pH regulation in villous epithelium during H+-dipeptide absorption via Pept1. This involves interaction with carbonic anhydrase II (CAII), and both Pat-1 and CAII are required for increased Cl-(OUT)/HCO3-(IN) exchange during glycyl-sarcosine exposure.","method":"Pat-1 KO and CAII KO mice; Ussing chambers; BCECF microfluorometry; pharmacological inhibitors of Cl-/HCO3- exchange and carbonic anhydrase","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two KO models with functional pH measurement; pharmacological corroboration; establishes CAII functional interaction","pmids":["20150244"],"is_preprint":false},{"year":2011,"finding":"SLC26A6-dependent transcellular oxalate secretion in the duodenum is saturable and DIDS-sensitive, whereas absorptive oxalate flux occurs through the paracellular 'leak' pathway (passive, non-saturable, parallels mannitol). In Slc26a6-null mice, secretory flux of oxalate is equivalent to paracellular mannitol flux, confirming SLC26A6 as the transcellular secretory pathway.","method":"Slc26a6 knockout mice; simultaneous [14C]oxalate and [3H]mannitol flux measurements; DIDS inhibition; saturation analysis","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with dual-tracer quantitative flux assay; clearly dissects transcellular from paracellular pathways","pmids":["22021714"],"is_preprint":false},{"year":2012,"finding":"SLC26A3, SLC26A6, and SLC9A3R1 are expressed in mouse sperm midpiece and interact with each other and with CFTR, as demonstrated by RT-PCR, immunocytochemistry, Western blot, and immunoprecipitation. SLC26A3 and CFTR are involved in the Cl- increase induced by db-cAMP during capacitation.","method":"RT-PCR; immunocytochemistry; Western blot; co-immunoprecipitation from mouse sperm","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and localization data; SLC26A6 co-precipitates with CFTR and SLC9A3R1 but functional role of SLC26A6 specifically in capacitation is less definitively established","pmids":["21976599"],"is_preprint":false},{"year":2013,"finding":"The STAS domain of Slc26a6 physically interacts with the first intracellular loop of NaDC-1, and this interaction has functional consequences: NaDC-1 enhances Slc26a6 transport activity when co-expressed in Xenopus oocytes, while Slc26a6 inhibits NaDC-1 citrate transport in an activity-dependent manner. Slc26a6-null mice show increased NaDC-1-mediated succinate uptake, hyperoxaluria, and hypocitraturia.","method":"Co-expression in Xenopus oocytes; biochemical pulldown/co-IP; Slc26a6-null mice; in vitro succinate uptake assays; STAS domain mutagenesis","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction data plus functional assays in oocytes and null mice; domain mutagenesis; multiple orthogonal methods","pmids":["23833257"],"is_preprint":false},{"year":2013,"finding":"Cardiac Slc26a6 functions as an electrogenic Cl-/HCO3- and Cl-/oxalate exchanger in cardiomyocytes, as directly demonstrated by patch-clamp recordings. Four cardiac isoforms (C-a, C-b, C-c, C-d) are expressed in both atrial and ventricular myocytes at the plasma membrane.","method":"RT-PCR; immunofluorescence confocal microscopy; patch-clamp electrophysiology with fast solution exchange in cardiomyocytes","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct patch-clamp electrophysiology in native cardiomyocytes; multiple isoforms identified by RT-PCR","pmids":["23933580"],"is_preprint":false},{"year":2016,"finding":"N-glycosylation at two sites in the putative second extracellular loop of SLC26A6 is critically required for Cl--dependent oxalate transport activity. Glycosylation is not essential for cell-surface delivery but affects the efficacy of plasma membrane trafficking. Enzymatic deglycosylation of surface-expressed SLC26A6 strongly reduces oxalate transport.","method":"Enzymatic deglycosylation; N-glycosylation site mutagenesis; surface biotinylation; functional oxalate transport assays in transfected cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific glycosylation sites combined with functional transport assays and surface biotinylation; multiple orthogonal methods","pmids":["27681177"],"is_preprint":false},{"year":2017,"finding":"PAT1 (Slc26a6) contributes to sulfate efflux across the apical membrane of the distal ileum; PAT1-KO mice show increased urinary sulfate excretion 1.8-fold, indicating that PAT1-mediated secretion reduces net intestinal sulfate absorption.","method":"Slc26a6 and Slc26a3 knockout mice; 35SO4 and 36Cl- transepithelial flux measurements in Ussing chambers; urine and plasma sulfate measurements","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with isotopic flux measurements; single lab","pmids":["28526688"],"is_preprint":false},{"year":2018,"finding":"Slc26a6 localizes to the apical membrane of submandibular salivary gland acinar cells (not ducts) and mediates Cl-/oxalate exchange in these cells. Slc26a6-/- mice show significantly reduced Cl-/oxalate exchange and reduced oxalate secretion in submandibular saliva, but HCO3- secretion is unaffected.","method":"Slc26a6 knockout mice; RNA-seq and Western blot; immunolocalization; CHO-K1 cell transfection and functional assay; salivary oxalate and HCO3- measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with functional readout in vivo, heterologous expression for mechanistic confirmation, multiple orthogonal methods","pmids":["29530983"],"is_preprint":false},{"year":2019,"finding":"Slc26a6 localizes primarily to the apical membrane of pancreatic exocrine acinar cells and mediates the HCO3--dependent component of fluid secretion (~35% of total fluid secretion); Slc26a6-null mice show ~35% reduction in stimulated pancreatic juice volume and HCO3- secretion.","method":"Slc26a6 knockout mice; ex vivo pancreas secretion assay; immunolocalization","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with quantitative functional readout; single lab","pmids":["31532720"],"is_preprint":false},{"year":2019,"finding":"miR-125a-5p negatively regulates SLC26A6 (PAT-1) expression by binding to the 3'-UTR of PAT-1 mRNA; transfection of miR-125a-5p mimic in Caco-2 cells decreased both PAT-1 mRNA and protein levels.","method":"Dual luciferase reporter assay with 3'-UTR cloning; miRNA mimic transfection in intestinal epithelial cell lines; RT-PCR and Western blot","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with 3'-UTR plus miRNA mimic functional validation; single lab","pmids":["31042422"],"is_preprint":false},{"year":2020,"finding":"Slc26a6-mediated enteric oxalate secretion is critical for decreasing body burden of oxalate in chronic kidney disease (CKD): Slc26a6-null mice with CKD fail to increase fecal oxalate excretion and show elevated plasma oxalate. Intestinal Slc26a6 mRNA and protein are greatly increased in CKD mice, and this upregulation is driven by CKD-associated changes rather than elevated plasma oxalate per se.","method":"Slc26a6 knockout mice with CKD models (high oxalate diet or aristolochic acid); qPCR, immunohistochemistry, Western blot for intestinal Slc26a6; fecal and plasma oxalate measurements","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with two independent CKD models and quantitative oxalate measurements; multiple orthogonal expression analyses","pmids":["32660969"],"is_preprint":false},{"year":2020,"finding":"STAS domain mutations of SLC26A6 (homolog of D23H/D673N and R621G) abolish or reduce SLC26A6 expression and membrane trafficking and impair regulation of SLC13-mediated citrate transport; cotransfection experiments in vitro confirm dominant-negative effects of D673N on wild-type SLC26A6.","method":"In vitro expression of SLC26A6 STAS domain variants; surface expression assays; citrate transport functional assays with SLC13 co-expression","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mutagenesis with functional and expression readouts; single lab","pmids":["32317970"],"is_preprint":false},{"year":2021,"finding":"SLC26A6 (PAT1inh-B01) selective inhibitor (pyrazolo-pyrido-pyrimidinone, IC50 ~350 nM) fully inhibits PAT1-mediated anion exchange without inhibiting SLC26A3 (DRA). In vivo, PAT1inh-B01 inhibits fluid absorption by ~50% in midjejunal loops and >80% in ileal loops in mice, establishing PAT1 as the predominant anion exchanger for fluid absorption in the ileum.","method":"High-throughput small-molecule screen; halide-sensing fluorescent protein assay; in vivo intestinal loop experiments in mice; co-administration with DRA inhibitor","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1 / Strong — selective pharmacological inhibitor with defined IC50, confirmed in vivo with segment-specific functional readout; comparison with related transporter inhibitor","pmids":["34100381"],"is_preprint":false},{"year":2022,"finding":"A rare heterozygous missense mutation R507W in SLC26A6 causes dominant-negative reduction of Cl--dependent oxalate transport by reducing both transport activity and membrane surface expression. Co-transfection of R507W with wild-type SLC26A6 demonstrates strong dominant-negative suppression of wild-type protein, cosegregating with enteric hyperoxaluria and nephrolithiasis in the family.","method":"Cell culture transfection; Cl--dependent oxalate transport assay; surface expression analysis; cotransfection dominant-negative assay; whole-exome sequencing","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional characterization of human disease variant with dominant-negative assay; cosegregation with clinical phenotype; multiple orthogonal in vitro methods","pmids":["35115415"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of human SLC26A6 defines an inward-facing conformation. The ion-binding site is located in the center of a mobile unit of the membrane-inserted domain. Structure-function reconstitution in proteoliposomes establishes 1:1 stoichiometry, electroneutral Cl-/HCO3- exchange, and electrogenic Cl-/oxalate exchange. The remodeled ion-binding site (vs. SLC26A9) explains altered anion selectivity and coupling mechanism.","method":"Cryo-electron microscopy structure determination; reconstitution in proteoliposomes; functional transport assays; comparison with SLC26A9 structure","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with reconstitution and functional transport assay; establishes mechanism of coupled anion exchange with stoichiometry","pmids":["37351578"],"is_preprint":false},{"year":2024,"finding":"Loss of PAT1 (SLC26A6) in PKO mice disrupts gut microbiome composition, reduces butyrate and butyrate-producing microbes, decreases tight junction protein expression, and increases susceptibility to DSS-induced colitis. Co-housing WT with PKO mice transfers PKO-like tight junction signatures to WT mice, indicating that the gut barrier defect is linked to microbiome changes.","method":"PAT1 knockout mice; DSS colitis model; 16S rRNA sequencing; mass spectrometry metabolomics; Western blot and RT-PCR for tight junction proteins; co-housing experiment; cytokine measurements; H&E staining","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal methods; co-housing experiment establishes microbiome-mediated mechanism; comprehensive multi-omics","pmids":["38735402"],"is_preprint":false},{"year":2025,"finding":"Ablation of Slc26a6 protects the mouse heart from ischemia/reperfusion (I/R) injury: Slc26a6-null mice show lower troponin I, better systolic/diastolic function, reduced infarct size, and elevated intracellular pH (pHi) in the heart. Cardiomyocytes from the infarct zone of Slc26a6-null mice show better sarcomere shortening, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load.","method":"Slc26a6 knockout mice; I/R model; echocardiography; hemodynamic monitoring; fluorescence microscopy for pHi; histochemistry; cellular sarcomere shortening and Ca2+ transient measurements","journal":"Biomedicines","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with comprehensive multidisciplinary in vivo, in vitro, and ex vivo functional readouts in a defined I/R model","pmids":["41462888"],"is_preprint":false},{"year":2026,"finding":"CaSR activation promotes PKA-mediated phosphorylation of FOXO4, which transcriptionally upregulates SLC26A6 expression in renal tubular epithelial cells. FOXO4 directly regulates the SLC26A6 promoter, as confirmed by dual-luciferase reporter assay. Inhibition of CaSR, PKA, or FOXO4 reduces SLC26A6 expression and crystal formation in a rat calcium oxalate stone model.","method":"Rat calcium oxalate stone model; NRK-52E cell line with agonists/inhibitors; Western blot; immunohistochemistry; RT-qPCR; dual-luciferase reporter assay for SLC26A6 promoter","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo and in vitro approaches with reporter assay; single lab; preprint-level paper published ahead of print","pmids":["41938536"],"is_preprint":false}],"current_model":"SLC26A6 (PAT1/CFEX) is a multifunctional apical membrane anion exchanger whose cryo-EM structure reveals an inward-facing conformation with a central ion-binding site mediating electroneutral Cl-/HCO3- exchange and electrogenic Cl-/oxalate2- exchange (1:1 stoichiometry in proteoliposomes); it is the predominant secretory oxalate transporter in intestine (critical for preventing hyperoxaluria and nephrolithiasis), the major apical Cl-/HCO3- and Cl-/OH- exchanger in duodenal villi and the predominant Cl-/HCO3- exchanger in the heart, where it functions as an acid loader; its activity is negatively regulated by PKC-delta (causing plasma membrane internalization) and by alpha-adrenergic signaling, positively coupled to CFTR and NHE3, requires N-glycosylation at two extracellular loop sites for transport function, physically interacts with NaDC-1 (via its STAS domain) to regulate citrate homeostasis, and is transcriptionally regulated by IRF-1 (via IFN-gamma/ISRE), miR-125a-5p, and the CaSR-PKA-FOXO4 signaling axis."},"narrative":{"mechanistic_narrative":"SLC26A6 (PAT1/CFEX) is a multifunctional apical-membrane anion exchanger that couples chloride transport to bicarbonate, oxalate, sulfate, hydroxide, and formate movement across epithelial and cardiac plasma membranes [PMID:12444019, PMID:15498800, PMID:20501439]. Its cryo-EM structure adopts an inward-facing conformation with a central ion-binding site, and reconstitution in proteoliposomes establishes a 1:1 stoichiometry supporting electroneutral Cl-/HCO3- exchange and electrogenic Cl-/oxalate exchange [PMID:37351578]. In the intestine SLC26A6 is the predominant transcellular secretory pathway for oxalate, acting in exchange for Cl- to limit body oxalate burden and prevent hyperoxaluria; loss of this pathway reverses net oxalate transport from secretion to absorption and impairs enteric oxalate excretion, including the compensatory excretion required in chronic kidney disease [PMID:16373425, PMID:22021714, PMID:32660969]. In the kidney proximal tubule it mediates oxalate-stimulated NaCl absorption and the bulk of apical Cl-/base exchange [PMID:15574486], and across duodenal villi it is the major apical Cl-/HCO3- and SO4(2-)/HCO3- exchanger [PMID:17170027]. In the heart it serves as the predominant Cl-/HCO3- and Cl-/OH- exchanger acting as an acid loader, and its ablation protects against ischemia/reperfusion injury by raising intracellular pH [PMID:15498800, PMID:23933580, PMID:41462888]. Transport is functionally coupled to NHE3 in electroneutral NaCl absorption [PMID:17763866], to CFTR in secretagogue-specific HCO3- secretion [PMID:16472591, PMID:20969732], and to carbonic anhydrase II [PMID:20150244], while its STAS domain physically interacts with NaDC-1 to reciprocally regulate citrate handling [PMID:23833257]. Activity requires N-glycosylation at two extracellular-loop sites [PMID:27681177] and is negatively regulated by PKC-delta-driven membrane internalization and alpha-adrenergic signaling [PMID:15498800, PMID:17151144]. Human dominant-negative missense mutations (e.g. R507W) reduce oxalate transport and surface expression and cosegregate with enteric hyperoxaluria and nephrolithiasis [PMID:35115415].","teleology":[{"year":2000,"claim":"Established where SLC26A6 acts by placing the protein at the luminal surface of secretory epithelia, framing it as a candidate apical anion exchanger.","evidence":"Immunohistochemistry on pancreatic ductal cell lines","pmids":["11087667"],"confidence":"Medium","gaps":["No functional transport assay in the same study","Substrate specificity undefined"]},{"year":2002,"claim":"Demonstrated that SLC26A6 and its splice variants are functional anion transporters with intracellular N- and C-termini, and that the C-terminal TRL motif binds NHERF/E3KARP PDZ domains, linking the transporter to scaffolding machinery.","evidence":"Functional expression and topology mapping in Xenopus oocytes; in vitro PDZ binding with truncation mutagenesis","pmids":["12444019"],"confidence":"High","gaps":["In vivo consequence of PDZ interaction not characterized","PDZ binding shown in vitro only"]},{"year":2004,"claim":"Knockout mice defined SLC26A6's native physiological roles, identifying it as the mediator of oxalate-stimulated NaCl absorption and a major Cl-/base exchanger in proximal tubule and duodenum, and as the predominant cardiac Cl-/HCO3- and Cl-/OH- exchanger inhibited by alpha-adrenergic/PKC signaling.","evidence":"Slc26a6-null mice with proximal tubule microperfusion, duodenal Ussing chambers, and cardiac pHi measurements with pharmacological modulation","pmids":["15574486","15498800"],"confidence":"High","gaps":["Stoichiometry and electrogenicity not yet resolved","Mechanism of PKC inhibition not defined"]},{"year":2005,"claim":"Quantified SLC26A6's contribution to intestinal oxalate secretion, showing that its loss reverses net oxalate flux from secretion to absorption in the distal ileum.","evidence":"Ussing chamber radiotracer flux in Slc26a6-null mice with DIDS inhibition","pmids":["16373425"],"confidence":"High","gaps":["Relative contribution along the gut not yet mapped","Coupling counterion not fully defined"]},{"year":2006,"claim":"Defined the relative and directional roles of SLC26A6 in duodenal and pancreatic anion transport and resolved the PKC-delta downregulation mechanism, establishing distinct CFTR-dependent and -independent secretagogue pathways.","evidence":"Comparative KO panels (PAT-1, DRA, AE4, CFTR), Ussing chamber and BCECF readouts, surface biotinylation, and PKC-delta inhibition assays","pmids":["17170027","16472591","17151144","16901991"],"confidence":"High","gaps":["Molecular target of PKC-delta-induced internalization unknown","Direction of transport context-dependent"]},{"year":2007,"claim":"Established functional coupling between SLC26A6 and NHE3 in electroneutral NaCl absorption in jejunum and proximal tubule, showing loss of SLC26A6 reduces NHE3 activity without changing its abundance.","evidence":"Slc26a6-/- and NHE3-/- mice; isotopic flux measurements and proximal tubule microperfusion with pH measurements","pmids":["17763866","18046080"],"confidence":"Medium","gaps":["Mechanism of functional coupling to NHE3 not defined","Indirect coupling, single lab for tubule data"]},{"year":2008,"claim":"Revealed species-specific transport kinetics and electrogenicity governed by both transmembrane and cytoplasmic domains, and identified a hypofunctional human variant, opening the question of SLC26A6 contribution to human hyperoxaluria.","evidence":"Xenopus oocyte expression, electrophysiology, human-mouse chimeras, and variant transport assays","pmids":["18174209","18951670"],"confidence":"High","gaps":["V206M heterozygosity showed no clinical oxalate effect","Structural basis of electrogenicity difference unresolved"]},{"year":2008,"claim":"Identified transcriptional control of SLC26A6 by IFN-gamma via an IRF-1/ISRE element, connecting inflammatory signaling to anion transport capacity.","evidence":"Promoter-luciferase reporters, deletion and ISRE mutagenesis, and IFN-gamma treatment of Caco-2 cells","pmids":["18655181"],"confidence":"Medium","gaps":["In vivo relevance of IRF-1 regulation untested","Single lab"]},{"year":2009,"claim":"Confirmed in a human intestinal epithelial model that SLC26A6 mediates a major fraction of apical oxalate, Cl-, and HCO3- exchange, with vectorial transport driven by counterion gradients.","evidence":"siRNA knockdown in Caco-2BBe1 monolayers with radiotracer flux, Ussing chamber, and BCECF assays","pmids":["20501439"],"confidence":"High","gaps":["Regulatory inputs in human cells not addressed"]},{"year":2010,"claim":"Showed membrane-potential and CFTR-dependent modulation of SLC26A6 Cl-/HCO3- exchange and its functional interaction with carbonic anhydrase II during nutrient absorption, integrating it into epithelial pH homeostasis.","evidence":"Multiple KO models (Pat-1, DRA, CFTR, CAII), BCECF fluorometry, and Ussing chamber Isc measurements","pmids":["20969732","20150244"],"confidence":"High","gaps":["Molecular basis of CFTR-dependent voltage modulation unknown","Direct CAII binding not structurally defined"]},{"year":2011,"claim":"Cleanly separated transcellular SLC26A6-mediated secretory oxalate flux from paracellular absorptive flux, defining SLC26A6 as the saturable transcellular secretory route.","evidence":"Dual-tracer oxalate/mannitol flux in Slc26a6-null mice with DIDS and saturation analysis","pmids":["22021714"],"confidence":"High","gaps":["Regulation of the secretory route in disease not addressed here"]},{"year":2013,"claim":"Identified the STAS domain-NaDC-1 interaction as a node linking SLC26A6 to citrate homeostasis, and confirmed cardiac SLC26A6 as an electrogenic Cl-/HCO3- and Cl-/oxalate exchanger by direct electrophysiology.","evidence":"Oocyte co-expression, reciprocal pulldown, STAS mutagenesis, null mice, and patch-clamp in cardiomyocytes","pmids":["23833257","23933580"],"confidence":"High","gaps":["Structural basis of STAS-NaDC-1 interaction unresolved","Physiological balance of citrate regulation in humans untested"]},{"year":2016,"claim":"Established that N-glycosylation at two extracellular-loop sites is required for transport activity and influences trafficking efficiency, defining a post-translational determinant of function.","evidence":"Glycosylation-site mutagenesis, enzymatic deglycosylation, surface biotinylation, and oxalate transport assays","pmids":["27681177"],"confidence":"High","gaps":["Mechanism by which glycans enable transport not defined"]},{"year":2017,"claim":"Extended SLC26A6's substrate repertoire to intestinal sulfate efflux, showing it limits net sulfate absorption.","evidence":"35SO4 and 36Cl- flux in Slc26a6 and Slc26a3 KO mice with urinary sulfate measurements","pmids":["28526688"],"confidence":"Medium","gaps":["Single lab","Physiological importance of sulfate handling unclear"]},{"year":2018,"claim":"Showed tissue-specific substrate selectivity, with salivary acinar SLC26A6 mediating Cl-/oxalate but not HCO3- secretion.","evidence":"Slc26a6 KO mice, immunolocalization, heterologous expression, and salivary oxalate/HCO3- measurements","pmids":["29530983"],"confidence":"High","gaps":["Basis of tissue-specific substrate preference unexplained"]},{"year":2019,"claim":"Defined SLC26A6's contribution to pancreatic acinar fluid/HCO3- secretion and identified miR-125a-5p as a post-transcriptional repressor, adding a non-coding regulatory layer.","evidence":"Slc26a6 KO pancreas secretion assays; 3'-UTR luciferase reporter and miRNA mimic in Caco-2 cells","pmids":["31532720","31042422"],"confidence":"Medium","gaps":["In vivo role of miR-125a-5p regulation untested","Single lab for each finding"]},{"year":2020,"claim":"Established the physiological importance of enteric SLC26A6 secretion in chronic kidney disease and the dominant-negative impact of STAS-domain disease variants on trafficking and citrate regulation.","evidence":"Slc26a6 KO in two CKD models with fecal/plasma oxalate; STAS-variant surface expression and SLC13 co-transport assays","pmids":["32660969","32317970"],"confidence":"High","gaps":["Driver of CKD-associated SLC26A6 upregulation not identified","STAS variant disease relevance based on in vitro homolog modeling"]},{"year":2021,"claim":"Provided a selective small-molecule inhibitor that confirmed SLC26A6 as the predominant anion exchanger driving fluid absorption in the ileum, separable from DRA.","evidence":"High-throughput screen yielding PAT1inh-B01; halide-sensing assay; in vivo intestinal loop experiments","pmids":["34100381"],"confidence":"High","gaps":["Therapeutic context not yet validated"]},{"year":2022,"claim":"Provided direct human genetic evidence linking SLC26A6 to disease, with a dominant-negative R507W mutation cosegregating with enteric hyperoxaluria and nephrolithiasis.","evidence":"Whole-exome sequencing with family cosegregation; transport, surface expression, and co-transfection dominant-negative assays","pmids":["35115415"],"confidence":"High","gaps":["Penetrance and broader allelic spectrum not defined"]},{"year":2023,"claim":"Resolved the molecular mechanism of anion exchange by solving the inward-facing cryo-EM structure and reconstituting transport, establishing 1:1 stoichiometry and the structural basis of altered anion selectivity versus SLC26A9.","evidence":"Cryo-EM structure determination, proteoliposome reconstitution, and functional transport assays","pmids":["37351578"],"confidence":"High","gaps":["Outward-facing and substrate-bound states not captured","Regulatory STAS-domain interactions not resolved structurally"]},{"year":2024,"claim":"Revealed a microbiome-dependent role for SLC26A6 in maintaining the gut barrier, with its loss reducing butyrate-producing microbes and increasing colitis susceptibility transferable by co-housing.","evidence":"PAT1 KO mice, DSS colitis, 16S sequencing, metabolomics, tight-junction analysis, and co-housing experiment","pmids":["38735402"],"confidence":"High","gaps":["Mechanistic link between anion transport and microbiome composition undefined"]},{"year":2025,"claim":"Showed that cardiac SLC26A6 ablation protects against ischemia/reperfusion injury by raising intracellular pH and improving contractile and Ca2+ handling, identifying it as a detrimental acid loader in the ischemic heart.","evidence":"Slc26a6 KO mice in an I/R model with echocardiography, hemodynamics, pHi imaging, and cardiomyocyte sarcomere/Ca2+ measurements","pmids":["41462888"],"confidence":"High","gaps":["Translational relevance to human cardiac ischemia untested"]},{"year":2026,"claim":"Identified a CaSR-PKA-FOXO4 axis that transcriptionally upregulates SLC26A6 and promotes calcium oxalate crystal formation, connecting calcium-sensing signaling to stone risk.","evidence":"Rat calcium oxalate stone model and NRK-52E cells with agonists/inhibitors; SLC26A6 promoter dual-luciferase reporter assay","pmids":["41938536"],"confidence":"Medium","gaps":["Single lab","Human relevance of the CaSR-FOXO4 axis untested"]},{"year":null,"claim":"How SLC26A6 conformational dynamics, STAS-domain regulation, post-translational control, and partner interactions integrate to tune anion selectivity and trafficking across diverse tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No outward-facing or substrate-bound structural states","Mechanism coupling PKC-delta signaling to internalization undefined","Structural basis of NHE3/CFTR/CAII functional coupling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,5,13,16,22,32]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,16,22,23,25,26]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,11,16,19,30,32]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,24,28]}],"complexes":[],"partners":["NHE3","CFTR","NHERF1","NADC-1","CAII"],"other_free_text":[]}},"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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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31042422","citation_count":11,"is_preprint":false},{"pmid":"32317970","id":"PMC_32317970","title":"Novel Human Polymorphisms Define a Key Role for the SLC26A6-STAS Domain in Protection From Ca2+-Oxalate Lithogenesis.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32317970","citation_count":11,"is_preprint":false},{"pmid":"27346053","id":"PMC_27346053","title":"Involvement of Cl(-)/HCO3(-) exchanger SLC26A3 and SLC26A6 in preimplantation embryo cleavage.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27346053","citation_count":11,"is_preprint":false},{"pmid":"35500753","id":"PMC_35500753","title":"Estrogen treatment reduced oxalate transporting activity and enhanced migration through the involvement of SLC26A6 in lung cancer cells.","date":"2022","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/35500753","citation_count":10,"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":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":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":"26372434","id":"PMC_26372434","title":"Genetic analysis of the bicarbonate secreting anion exchanger SLC26A6 in chronic pancreatitis.","date":"2015","source":"Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/26372434","citation_count":9,"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":"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":"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":"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":2,"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":39115,"output_tokens":9286,"usd":0.128318,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19153,"output_tokens":6336,"usd":0.127082,"stage2_stop_reason":"end_turn"},"total_usd":0.2554,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","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, as determined by immunohistochemistry, suggesting a role as a luminal anion exchanger.\",\n      \"method\": \"Immunohistochemistry on pancreatic ductal cell lines (Capan-1 and Capan-2)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunolocalization without functional transport assay in the same study; replicated in subsequent work\",\n      \"pmids\": [\"11087667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SLC26A6 and its splice variants SLC26A6c and SLC26A6d function as anion transporters mediating Cl- and SO4(2-) transport when expressed in Xenopus oocytes; transport is inhibited by DIDS and HCO3-. The NH2- and COOH-terminal tails are intracellular, consistent with an even number of transmembrane domains.\",\n      \"method\": \"Functional expression in Xenopus oocytes; immunofluorescence for topology\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — heterologous expression assay with pharmacological inhibition; replicated across multiple subsequent studies\",\n      \"pmids\": [\"12444019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The COOH-terminus of SLC26A6 binds to the first and second PDZ domains of E3KARP (NHE3 kinase A regulatory protein) and NHERF proteins in vitro; truncation of the last three amino acids (TRL) abolishes this interaction without affecting transport function.\",\n      \"method\": \"In vitro PDZ domain binding assay; truncation mutagenesis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with mutagenesis in single study; functional consequence of PDZ interaction not fully characterized in vivo\",\n      \"pmids\": [\"12444019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Slc26a6-null mice show abolished oxalate-stimulated NaCl absorption in kidney proximal tubules and a 58% decrease in apical membrane Cl-/base exchange activity, establishing Slc26a6 as the mediator of oxalate-stimulated NaCl transport and a major contributor to proximal tubule Cl-/base exchange.\",\n      \"method\": \"Gene knockout mice; in vitro microperfusion of proximal tubules; pH-sensitive dye BCPCF\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple defined physiological readouts; replicated by subsequent studies\",\n      \"pmids\": [\"15574486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Slc26a6 deletion reduces baseline HCO3- secretion (~30%) in the duodenum, as measured in Ussing chambers, but does not affect forskolin-stimulated HCO3- secretion.\",\n      \"method\": \"Slc26a6 knockout mice; Ussing chamber HCO3- secretion measurements\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with quantitative functional readout; replicated in subsequent duodenal studies\",\n      \"pmids\": [\"15574486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Slc26a6 (SLC26A6) functions as a Cl-/HCO3- exchanger and Cl-/OH- exchanger in the heart; it is the predominant Cl-/HCO3- and Cl-/OH- exchanger in mouse ventricular myocytes. Alpha-adrenergic receptor activation (via PKC) inhibits SLC26A6 Cl-/HCO3- exchange activity.\",\n      \"method\": \"Quantitative RT-PCR; immunohistochemistry; intracellular pH fluorescence measurements (BCECF) in HEK293 cells transfected with SLC26A6; pharmacological stimulation with alpha-adrenergic agonists\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (expression profiling, heterologous functional assay, pharmacological modulation); replicated in later cardiac studies\",\n      \"pmids\": [\"15498800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PAT1 (Slc26a6) mediates a significant fraction of oxalate efflux (secretion) across the apical membrane of the distal ileum in exchange for Cl-, as demonstrated by the reversal of net oxalate transport from secretion to absorption in Slc26a6-null mice and DIDS sensitivity.\",\n      \"method\": \"Slc26a6 knockout mice; Ussing chamber radiotracer flux measurements; pharmacological inhibition with DIDS\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with quantitative unidirectional flux measurements; multiple orthogonal approaches; replicated across labs\",\n      \"pmids\": [\"16373425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PAT-1 (Slc26a6) is the predominant contributor (65-80%) to basal Cl-/HCO3- exchange and the sole mediator of SO4(2-)/HCO3- exchange across the apical membrane of the upper villous epithelium of the murine duodenum.\",\n      \"method\": \"Gene-targeted deletion mice (PAT-1-, DRA-, AE4-); pH-sensitive dye BCECF fluorescence in intact duodenal mucosa\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comparative KO strategy with three exchangers, quantitative functional readout, multiple deletion lines\",\n      \"pmids\": [\"17170027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SLC26A6-mediated PGE2-stimulated duodenal HCO3- secretion is CFTR-independent, whereas forskolin-stimulated HCO3- secretion is completely SLC26A6-independent and CFTR-dependent, establishing distinct transport pathways for different secretagogues.\",\n      \"method\": \"SLC26A6-/- and CFTR-/- mouse duodenal mucosa in Ussing chambers; pharmacological stimulation with PGE2, forskolin, and carbachol\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double KO epistasis with quantitative functional readout; clearly dissects two mechanistic pathways\",\n      \"pmids\": [\"16472591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PKC-delta activation inhibits multiple modes of Slc26a6-mediated anion exchange (Cl/formate, Cl/oxalate, Cl/Cl) and causes redistribution of Slc26a6 from the plasma membrane to an intracellular compartment, reducing surface-biotinylation-accessible protein.\",\n      \"method\": \"Functional expression in Xenopus oocytes; surface biotinylation; immunofluorescence microscopy; PKC-delta-selective inhibitor rottlerin; PMA stimulation; mouse duodenal oxalate secretion assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (oocyte functional assay, surface biotinylation, immunofluorescence, in vivo secretion assay) in single study\",\n      \"pmids\": [\"17151144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Slc26a6 deletion in pancreatic ducts shows HCO3- efflux is mediated by Slc26a6 (HCO3-efflux mode decreased in null mice), while HCO3-influx mode is upregulated in null mice. Compensatory >5-fold upregulation of Slc26a3 (DRA) expression occurs in Slc26a6 knockout pancreas.\",\n      \"method\": \"Slc26a6 knockout mice; pH-sensitive dye BCECF in microperfused interlobular pancreatic ducts; semiquantitative RT-PCR\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with directional transport measurements in native tissue; demonstrates unidirectionality of Slc26a6-mediated HCO3- transport\",\n      \"pmids\": [\"16901991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Slc26a6 acts in concert with NHE3 in electroneutral NaCl absorption in the small intestinal jejunum; net Cl- and Na+ fluxes are significantly reduced in Slc26a6-/- animals, and Slc26a6 also mediates Cl- absorption during glucose-driven salt absorption.\",\n      \"method\": \"Slc26a6-/- and NHE3-/- knockout mice; Ussing chambers with 36Cl- and 22Na+ flux measurements; NHE3 immunofluorescence and immunoblot\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO comparison with isotopic flux measurements establishes functional coupling between SLC26A6 and NHE3\",\n      \"pmids\": [\"17763866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Slc26a6 deletion reduces apical Na+/H+ exchanger (NHE3) activity in the straight segment (S3) of the kidney proximal tubule, decreasing intracellular pH and blunting formate-induced alkalinization, without affecting NHE3 protein abundance or distribution.\",\n      \"method\": \"In vitro microperfusion of proximal tubule S3 segments; BCPCF-AM pH measurements; immunoblotting and immunofluorescence for NHE3\",\n      \"journal\": \"American journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with functional readout in native tissue; indirect functional coupling to NHE3 activity, single lab\",\n      \"pmids\": [\"18046080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human SLC26A6 mediates oxalate/Cl- exchange with different kinetics than mouse Slc26a6: human SLC26A6 has a K1/2 for extracellular Cl- of ~62 mM (vs. 8 mM for mouse), and human SLC26A6-mediated oxalate transport appears electroneutral whereas mouse Slc26a6 mediates electrogenic oxalate/Cl- exchange. These differences are determined by both transmembrane and C-terminal cytoplasmic domains.\",\n      \"method\": \"Heterologous expression in Xenopus oocytes; isotopic flux assays; electrophysiology; human-mouse chimera studies\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Xenopus oocytes with domain-swap chimeras and electrophysiology; multiple orthogonal methods establishing mechanistic species differences\",\n      \"pmids\": [\"18174209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SLC26A6 variant V206M (p.Val206Met) shows ~30% reduction in oxalate transport activity when expressed in Xenopus oocytes, though heterozygosity for this variant does not measurably affect plasma or urine oxalate in hyperoxaluria patients.\",\n      \"method\": \"Functional expression of SLC26A6 variants in Xenopus laevis oocytes; oxalate transport assay\",\n      \"journal\": \"American journal of kidney diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — heterologous functional expression with defined variant; single lab, limited clinical correlation\",\n      \"pmids\": [\"18951670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SLC26A6 promoter region -214/-44 harbors cis-acting elements required for maximal promoter activity; IFN-gamma decreases SLC26A6 mRNA, function, and promoter activity via an IRF-1 binding site (ISRE) located at -318/-300 bp, and mutation of this ISRE abrogates IFN-gamma inhibition.\",\n      \"method\": \"Promoter-luciferase reporter assays; deletion analysis; site-directed mutagenesis of ISRE; IFN-gamma treatment of Caco-2 cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with mutagenesis identifies regulatory element; 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-2BBe1 cells mediates oxalate, Cl-, and HCO3- exchange; siRNA knockdown reduces PAT-1 protein >60% and decreases unidirectional oxalate fluxes ~50%, Cl- fluxes ~35%, and Cl-/HCO3- exchange ~50%. PAT-1-mediated oxalate exchange is inhibited by mucosal DIDS (EC50 ~5 µM) and by mucosal Cl- (EC50 <20 mM). Vectorial oxalate transport depends principally on counterion gradients.\",\n      \"method\": \"siRNA knockdown in Caco-2BBe1 monolayers; radiotracer flux measurements; Ussing chambers; BCECF fluorometry\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA KD with multiple quantitative functional readouts in a native epithelial model; multiple orthogonal methods\",\n      \"pmids\": [\"20501439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pat-1 (Slc26a6) contributes to Cl-/HCO3- exchange in the lower villus epithelium; its activity is masked during glucose absorption due to membrane depolarization, but is active during electroneutral mannose absorption. Pat-1-dependent Cl-/HCO3- exchange activity is inhibited by membrane depolarization only when CFTR is co-expressed.\",\n      \"method\": \"Pat-1 KO, DRA KO, CFTR KO, and DRA/CFTR double-KO mice; BCECF fluorometry; Ussing chamber Isc measurements\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO comparisons with quantitative functional readout; establishes CFTR-dependent modulation of Pat-1 activity\",\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 in villous epithelium during H+-dipeptide absorption via Pept1. This involves interaction with carbonic anhydrase II (CAII), and both Pat-1 and CAII are required for increased Cl-(OUT)/HCO3-(IN) exchange during glycyl-sarcosine exposure.\",\n      \"method\": \"Pat-1 KO and CAII KO mice; Ussing chambers; BCECF microfluorometry; pharmacological inhibitors of Cl-/HCO3- exchange and carbonic anhydrase\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two KO models with functional pH measurement; pharmacological corroboration; establishes CAII functional interaction\",\n      \"pmids\": [\"20150244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLC26A6-dependent transcellular oxalate secretion in the duodenum is saturable and DIDS-sensitive, whereas absorptive oxalate flux occurs through the paracellular 'leak' pathway (passive, non-saturable, parallels mannitol). In Slc26a6-null mice, secretory flux of oxalate is equivalent to paracellular mannitol flux, confirming SLC26A6 as the transcellular secretory pathway.\",\n      \"method\": \"Slc26a6 knockout mice; simultaneous [14C]oxalate and [3H]mannitol flux measurements; DIDS inhibition; saturation analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with dual-tracer quantitative flux assay; clearly dissects transcellular from paracellular pathways\",\n      \"pmids\": [\"22021714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SLC26A3, SLC26A6, and SLC9A3R1 are expressed in mouse sperm midpiece and interact with each other and with CFTR, as demonstrated by RT-PCR, immunocytochemistry, Western blot, and immunoprecipitation. SLC26A3 and CFTR are involved in the Cl- increase induced by db-cAMP during capacitation.\",\n      \"method\": \"RT-PCR; immunocytochemistry; Western blot; co-immunoprecipitation from mouse sperm\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and localization data; SLC26A6 co-precipitates with CFTR and SLC9A3R1 but functional role of SLC26A6 specifically in capacitation is less definitively established\",\n      \"pmids\": [\"21976599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The STAS domain of Slc26a6 physically interacts with the first intracellular loop of NaDC-1, and this interaction has functional consequences: NaDC-1 enhances Slc26a6 transport activity when co-expressed in Xenopus oocytes, while Slc26a6 inhibits NaDC-1 citrate transport in an activity-dependent manner. Slc26a6-null mice show increased NaDC-1-mediated succinate uptake, hyperoxaluria, and hypocitraturia.\",\n      \"method\": \"Co-expression in Xenopus oocytes; biochemical pulldown/co-IP; Slc26a6-null mice; in vitro succinate uptake assays; STAS domain mutagenesis\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction data plus functional assays in oocytes and null mice; domain mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"23833257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cardiac Slc26a6 functions as an electrogenic Cl-/HCO3- and Cl-/oxalate exchanger in cardiomyocytes, as directly demonstrated by patch-clamp recordings. Four cardiac isoforms (C-a, C-b, C-c, C-d) are expressed in both atrial and ventricular myocytes at the plasma membrane.\",\n      \"method\": \"RT-PCR; immunofluorescence confocal microscopy; patch-clamp electrophysiology with fast solution exchange in cardiomyocytes\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct patch-clamp electrophysiology in native cardiomyocytes; multiple isoforms identified by RT-PCR\",\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 required for Cl--dependent oxalate transport activity. Glycosylation is not essential for cell-surface delivery but affects the efficacy of plasma membrane trafficking. Enzymatic deglycosylation of surface-expressed SLC26A6 strongly reduces oxalate transport.\",\n      \"method\": \"Enzymatic deglycosylation; N-glycosylation site mutagenesis; 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 / Strong — mutagenesis of specific glycosylation sites combined with functional transport assays and surface biotinylation; multiple orthogonal methods\",\n      \"pmids\": [\"27681177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PAT1 (Slc26a6) contributes to sulfate efflux across the apical membrane of the distal ileum; PAT1-KO mice show increased urinary sulfate excretion 1.8-fold, indicating that PAT1-mediated secretion reduces net intestinal sulfate absorption.\",\n      \"method\": \"Slc26a6 and Slc26a3 knockout mice; 35SO4 and 36Cl- transepithelial flux measurements in Ussing chambers; urine and plasma sulfate measurements\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with isotopic flux measurements; single lab\",\n      \"pmids\": [\"28526688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Slc26a6 localizes to the apical membrane of submandibular salivary gland acinar cells (not ducts) and mediates Cl-/oxalate exchange in these cells. Slc26a6-/- mice show significantly reduced Cl-/oxalate exchange and reduced oxalate secretion in submandibular saliva, but HCO3- secretion is unaffected.\",\n      \"method\": \"Slc26a6 knockout mice; RNA-seq and Western blot; immunolocalization; CHO-K1 cell transfection and functional assay; salivary oxalate and HCO3- measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with functional readout in vivo, heterologous expression for mechanistic confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"29530983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Slc26a6 localizes primarily to the apical membrane of pancreatic exocrine acinar cells and mediates the HCO3--dependent component of fluid secretion (~35% of total fluid secretion); Slc26a6-null mice show ~35% reduction in stimulated pancreatic juice volume and HCO3- secretion.\",\n      \"method\": \"Slc26a6 knockout mice; ex vivo pancreas secretion assay; immunolocalization\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with quantitative functional readout; single lab\",\n      \"pmids\": [\"31532720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-125a-5p negatively regulates SLC26A6 (PAT-1) expression by binding to the 3'-UTR of PAT-1 mRNA; transfection of miR-125a-5p mimic in Caco-2 cells decreased both PAT-1 mRNA and protein levels.\",\n      \"method\": \"Dual luciferase reporter assay with 3'-UTR cloning; miRNA mimic transfection in intestinal epithelial cell lines; RT-PCR and Western blot\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with 3'-UTR plus miRNA mimic functional validation; single lab\",\n      \"pmids\": [\"31042422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Slc26a6-mediated enteric oxalate secretion is critical for decreasing body burden of oxalate in chronic kidney disease (CKD): Slc26a6-null mice with CKD fail to increase fecal oxalate excretion and show elevated plasma oxalate. Intestinal Slc26a6 mRNA and protein are greatly increased in CKD mice, and this upregulation is driven by CKD-associated changes rather than elevated plasma oxalate per se.\",\n      \"method\": \"Slc26a6 knockout mice with CKD models (high oxalate diet or aristolochic acid); qPCR, immunohistochemistry, Western blot for intestinal Slc26a6; fecal and plasma oxalate measurements\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with two independent CKD models and quantitative oxalate measurements; multiple orthogonal expression analyses\",\n      \"pmids\": [\"32660969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STAS domain mutations of SLC26A6 (homolog of D23H/D673N and R621G) abolish or reduce SLC26A6 expression and membrane trafficking and impair regulation of SLC13-mediated citrate transport; cotransfection experiments in vitro confirm dominant-negative effects of D673N on wild-type SLC26A6.\",\n      \"method\": \"In vitro expression of SLC26A6 STAS domain variants; surface expression assays; citrate transport functional assays with SLC13 co-expression\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mutagenesis with functional and expression readouts; single lab\",\n      \"pmids\": [\"32317970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLC26A6 (PAT1inh-B01) selective inhibitor (pyrazolo-pyrido-pyrimidinone, IC50 ~350 nM) fully inhibits PAT1-mediated anion exchange without inhibiting SLC26A3 (DRA). In vivo, PAT1inh-B01 inhibits fluid absorption by ~50% in midjejunal loops and >80% in ileal loops in mice, establishing PAT1 as the predominant anion exchanger for fluid absorption in the ileum.\",\n      \"method\": \"High-throughput small-molecule screen; halide-sensing fluorescent protein assay; in vivo intestinal loop experiments in mice; co-administration with DRA inhibitor\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — selective pharmacological inhibitor with defined IC50, confirmed in vivo with segment-specific functional readout; comparison with related transporter inhibitor\",\n      \"pmids\": [\"34100381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A rare heterozygous missense mutation R507W in SLC26A6 causes dominant-negative reduction of Cl--dependent oxalate transport by reducing both transport activity and membrane surface expression. Co-transfection of R507W with wild-type SLC26A6 demonstrates strong dominant-negative suppression of wild-type protein, cosegregating with enteric hyperoxaluria and nephrolithiasis in the family.\",\n      \"method\": \"Cell culture transfection; Cl--dependent oxalate transport assay; surface expression analysis; cotransfection dominant-negative assay; whole-exome sequencing\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional characterization of human disease variant with dominant-negative assay; cosegregation with clinical phenotype; multiple orthogonal in vitro methods\",\n      \"pmids\": [\"35115415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of human SLC26A6 defines an inward-facing conformation. The ion-binding site is located in the center of a mobile unit of the membrane-inserted domain. Structure-function reconstitution in proteoliposomes establishes 1:1 stoichiometry, electroneutral Cl-/HCO3- exchange, and electrogenic Cl-/oxalate exchange. The remodeled ion-binding site (vs. SLC26A9) explains altered anion selectivity and coupling mechanism.\",\n      \"method\": \"Cryo-electron microscopy structure determination; reconstitution in proteoliposomes; functional transport assays; comparison with SLC26A9 structure\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with reconstitution and functional transport assay; establishes mechanism of coupled anion exchange with stoichiometry\",\n      \"pmids\": [\"37351578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of PAT1 (SLC26A6) in PKO mice disrupts gut microbiome composition, reduces butyrate and butyrate-producing microbes, decreases tight junction protein expression, and increases susceptibility to DSS-induced colitis. Co-housing WT with PKO mice transfers PKO-like tight junction signatures to WT mice, indicating that the gut barrier defect is linked to microbiome changes.\",\n      \"method\": \"PAT1 knockout mice; DSS colitis model; 16S rRNA sequencing; mass spectrometry metabolomics; Western blot and RT-PCR for tight junction proteins; co-housing experiment; cytokine measurements; H&E staining\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal methods; co-housing experiment establishes microbiome-mediated mechanism; comprehensive multi-omics\",\n      \"pmids\": [\"38735402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ablation of Slc26a6 protects the mouse heart from ischemia/reperfusion (I/R) injury: Slc26a6-null mice show lower troponin I, better systolic/diastolic function, reduced infarct size, and elevated intracellular pH (pHi) in the heart. Cardiomyocytes from the infarct zone of Slc26a6-null mice show better sarcomere shortening, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load.\",\n      \"method\": \"Slc26a6 knockout mice; I/R model; echocardiography; hemodynamic monitoring; fluorescence microscopy for pHi; histochemistry; cellular sarcomere shortening and Ca2+ transient measurements\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with comprehensive multidisciplinary in vivo, in vitro, and ex vivo functional readouts in a defined I/R model\",\n      \"pmids\": [\"41462888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CaSR activation promotes PKA-mediated phosphorylation of FOXO4, which transcriptionally upregulates SLC26A6 expression in renal tubular epithelial cells. FOXO4 directly regulates the SLC26A6 promoter, as confirmed by dual-luciferase reporter assay. Inhibition of CaSR, PKA, or FOXO4 reduces SLC26A6 expression and crystal formation in a rat calcium oxalate stone model.\",\n      \"method\": \"Rat calcium oxalate stone model; NRK-52E cell line with agonists/inhibitors; Western blot; immunohistochemistry; RT-qPCR; dual-luciferase reporter assay for SLC26A6 promoter\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo and in vitro approaches with reporter assay; single lab; preprint-level paper published ahead of print\",\n      \"pmids\": [\"41938536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC26A6 (PAT1/CFEX) is a multifunctional apical membrane anion exchanger whose cryo-EM structure reveals an inward-facing conformation with a central ion-binding site mediating electroneutral Cl-/HCO3- exchange and electrogenic Cl-/oxalate2- exchange (1:1 stoichiometry in proteoliposomes); it is the predominant secretory oxalate transporter in intestine (critical for preventing hyperoxaluria and nephrolithiasis), the major apical Cl-/HCO3- and Cl-/OH- exchanger in duodenal villi and the predominant Cl-/HCO3- exchanger in the heart, where it functions as an acid loader; its activity is negatively regulated by PKC-delta (causing plasma membrane internalization) and by alpha-adrenergic signaling, positively coupled to CFTR and NHE3, requires N-glycosylation at two extracellular loop sites for transport function, physically interacts with NaDC-1 (via its STAS domain) to regulate citrate homeostasis, and is transcriptionally regulated by IRF-1 (via IFN-gamma/ISRE), miR-125a-5p, and the CaSR-PKA-FOXO4 signaling axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC26A6 (PAT1/CFEX) is a multifunctional apical-membrane anion exchanger that couples chloride transport to bicarbonate, oxalate, sulfate, hydroxide, and formate movement across epithelial and cardiac plasma membranes [#1, #5, #16]. Its cryo-EM structure adopts an inward-facing conformation with a central ion-binding site, and reconstitution in proteoliposomes establishes a 1:1 stoichiometry supporting electroneutral Cl-/HCO3- exchange and electrogenic Cl-/oxalate exchange [#32]. In the intestine SLC26A6 is the predominant transcellular secretory pathway for oxalate, acting in exchange for Cl- to limit body oxalate burden and prevent hyperoxaluria; loss of this pathway reverses net oxalate transport from secretion to absorption and impairs enteric oxalate excretion, including the compensatory excretion required in chronic kidney disease [#6, #19, #28]. In the kidney proximal tubule it mediates oxalate-stimulated NaCl absorption and the bulk of apical Cl-/base exchange [#3], and across duodenal villi it is the major apical Cl-/HCO3- and SO4(2-)/HCO3- exchanger [#7]. In the heart it serves as the predominant Cl-/HCO3- and Cl-/OH- exchanger acting as an acid loader, and its ablation protects against ischemia/reperfusion injury by raising intracellular pH [#5, #22, #34]. Transport is functionally coupled to NHE3 in electroneutral NaCl absorption [#11], to CFTR in secretagogue-specific HCO3- secretion [#8, #17], and to carbonic anhydrase II [#18], while its STAS domain physically interacts with NaDC-1 to reciprocally regulate citrate handling [#21]. Activity requires N-glycosylation at two extracellular-loop sites [#23] and is negatively regulated by PKC-delta-driven membrane internalization and alpha-adrenergic signaling [#5, #9]. Human dominant-negative missense mutations (e.g. R507W) reduce oxalate transport and surface expression and cosegregate with enteric hyperoxaluria and nephrolithiasis [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established where SLC26A6 acts by placing the protein at the luminal surface of secretory epithelia, framing it as a candidate apical anion exchanger.\",\n      \"evidence\": \"Immunohistochemistry on pancreatic ductal cell lines\",\n      \"pmids\": [\"11087667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional transport assay in the same study\", \"Substrate specificity undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that SLC26A6 and its splice variants are functional anion transporters with intracellular N- and C-termini, and that the C-terminal TRL motif binds NHERF/E3KARP PDZ domains, linking the transporter to scaffolding machinery.\",\n      \"evidence\": \"Functional expression and topology mapping in Xenopus oocytes; in vitro PDZ binding with truncation mutagenesis\",\n      \"pmids\": [\"12444019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of PDZ interaction not characterized\", \"PDZ binding shown in vitro only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Knockout mice defined SLC26A6's native physiological roles, identifying it as the mediator of oxalate-stimulated NaCl absorption and a major Cl-/base exchanger in proximal tubule and duodenum, and as the predominant cardiac Cl-/HCO3- and Cl-/OH- exchanger inhibited by alpha-adrenergic/PKC signaling.\",\n      \"evidence\": \"Slc26a6-null mice with proximal tubule microperfusion, duodenal Ussing chambers, and cardiac pHi measurements with pharmacological modulation\",\n      \"pmids\": [\"15574486\", \"15498800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and electrogenicity not yet resolved\", \"Mechanism of PKC inhibition not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Quantified SLC26A6's contribution to intestinal oxalate secretion, showing that its loss reverses net oxalate flux from secretion to absorption in the distal ileum.\",\n      \"evidence\": \"Ussing chamber radiotracer flux in Slc26a6-null mice with DIDS inhibition\",\n      \"pmids\": [\"16373425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution along the gut not yet mapped\", \"Coupling counterion not fully defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the relative and directional roles of SLC26A6 in duodenal and pancreatic anion transport and resolved the PKC-delta downregulation mechanism, establishing distinct CFTR-dependent and -independent secretagogue pathways.\",\n      \"evidence\": \"Comparative KO panels (PAT-1, DRA, AE4, CFTR), Ussing chamber and BCECF readouts, surface biotinylation, and PKC-delta inhibition assays\",\n      \"pmids\": [\"17170027\", \"16472591\", \"17151144\", \"16901991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of PKC-delta-induced internalization unknown\", \"Direction of transport context-dependent\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established functional coupling between SLC26A6 and NHE3 in electroneutral NaCl absorption in jejunum and proximal tubule, showing loss of SLC26A6 reduces NHE3 activity without changing its abundance.\",\n      \"evidence\": \"Slc26a6-/- and NHE3-/- mice; isotopic flux measurements and proximal tubule microperfusion with pH measurements\",\n      \"pmids\": [\"17763866\", \"18046080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of functional coupling to NHE3 not defined\", \"Indirect coupling, single lab for tubule data\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed species-specific transport kinetics and electrogenicity governed by both transmembrane and cytoplasmic domains, and identified a hypofunctional human variant, opening the question of SLC26A6 contribution to human hyperoxaluria.\",\n      \"evidence\": \"Xenopus oocyte expression, electrophysiology, human-mouse chimeras, and variant transport assays\",\n      \"pmids\": [\"18174209\", \"18951670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"V206M heterozygosity showed no clinical oxalate effect\", \"Structural basis of electrogenicity difference unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified transcriptional control of SLC26A6 by IFN-gamma via an IRF-1/ISRE element, connecting inflammatory signaling to anion transport capacity.\",\n      \"evidence\": \"Promoter-luciferase reporters, deletion and ISRE mutagenesis, and IFN-gamma treatment of Caco-2 cells\",\n      \"pmids\": [\"18655181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of IRF-1 regulation untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed in a human intestinal epithelial model that SLC26A6 mediates a major fraction of apical oxalate, Cl-, and HCO3- exchange, with vectorial transport driven by counterion gradients.\",\n      \"evidence\": \"siRNA knockdown in Caco-2BBe1 monolayers with radiotracer flux, Ussing chamber, and BCECF assays\",\n      \"pmids\": [\"20501439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory inputs in human cells not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed membrane-potential and CFTR-dependent modulation of SLC26A6 Cl-/HCO3- exchange and its functional interaction with carbonic anhydrase II during nutrient absorption, integrating it into epithelial pH homeostasis.\",\n      \"evidence\": \"Multiple KO models (Pat-1, DRA, CFTR, CAII), BCECF fluorometry, and Ussing chamber Isc measurements\",\n      \"pmids\": [\"20969732\", \"20150244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CFTR-dependent voltage modulation unknown\", \"Direct CAII binding not structurally defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cleanly separated transcellular SLC26A6-mediated secretory oxalate flux from paracellular absorptive flux, defining SLC26A6 as the saturable transcellular secretory route.\",\n      \"evidence\": \"Dual-tracer oxalate/mannitol flux in Slc26a6-null mice with DIDS and saturation analysis\",\n      \"pmids\": [\"22021714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of the secretory route in disease not addressed here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the STAS domain-NaDC-1 interaction as a node linking SLC26A6 to citrate homeostasis, and confirmed cardiac SLC26A6 as an electrogenic Cl-/HCO3- and Cl-/oxalate exchanger by direct electrophysiology.\",\n      \"evidence\": \"Oocyte co-expression, reciprocal pulldown, STAS mutagenesis, null mice, and patch-clamp in cardiomyocytes\",\n      \"pmids\": [\"23833257\", \"23933580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAS-NaDC-1 interaction unresolved\", \"Physiological balance of citrate regulation in humans untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that N-glycosylation at two extracellular-loop sites is required for transport activity and influences trafficking efficiency, defining a post-translational determinant of function.\",\n      \"evidence\": \"Glycosylation-site mutagenesis, enzymatic deglycosylation, surface biotinylation, and oxalate transport assays\",\n      \"pmids\": [\"27681177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which glycans enable transport not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SLC26A6's substrate repertoire to intestinal sulfate efflux, showing it limits net sulfate absorption.\",\n      \"evidence\": \"35SO4 and 36Cl- flux in Slc26a6 and Slc26a3 KO mice with urinary sulfate measurements\",\n      \"pmids\": [\"28526688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological importance of sulfate handling unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed tissue-specific substrate selectivity, with salivary acinar SLC26A6 mediating Cl-/oxalate but not HCO3- secretion.\",\n      \"evidence\": \"Slc26a6 KO mice, immunolocalization, heterologous expression, and salivary oxalate/HCO3- measurements\",\n      \"pmids\": [\"29530983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of tissue-specific substrate preference unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SLC26A6's contribution to pancreatic acinar fluid/HCO3- secretion and identified miR-125a-5p as a post-transcriptional repressor, adding a non-coding regulatory layer.\",\n      \"evidence\": \"Slc26a6 KO pancreas secretion assays; 3'-UTR luciferase reporter and miRNA mimic in Caco-2 cells\",\n      \"pmids\": [\"31532720\", \"31042422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo role of miR-125a-5p regulation untested\", \"Single lab for each finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the physiological importance of enteric SLC26A6 secretion in chronic kidney disease and the dominant-negative impact of STAS-domain disease variants on trafficking and citrate regulation.\",\n      \"evidence\": \"Slc26a6 KO in two CKD models with fecal/plasma oxalate; STAS-variant surface expression and SLC13 co-transport assays\",\n      \"pmids\": [\"32660969\", \"32317970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Driver of CKD-associated SLC26A6 upregulation not identified\", \"STAS variant disease relevance based on in vitro homolog modeling\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a selective small-molecule inhibitor that confirmed SLC26A6 as the predominant anion exchanger driving fluid absorption in the ileum, separable from DRA.\",\n      \"evidence\": \"High-throughput screen yielding PAT1inh-B01; halide-sensing assay; in vivo intestinal loop experiments\",\n      \"pmids\": [\"34100381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic context not yet validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided direct human genetic evidence linking SLC26A6 to disease, with a dominant-negative R507W mutation cosegregating with enteric hyperoxaluria and nephrolithiasis.\",\n      \"evidence\": \"Whole-exome sequencing with family cosegregation; transport, surface expression, and co-transfection dominant-negative assays\",\n      \"pmids\": [\"35115415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Penetrance and broader allelic spectrum not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the molecular mechanism of anion exchange by solving the inward-facing cryo-EM structure and reconstituting transport, establishing 1:1 stoichiometry and the structural basis of altered anion selectivity versus SLC26A9.\",\n      \"evidence\": \"Cryo-EM structure determination, proteoliposome reconstitution, and functional transport assays\",\n      \"pmids\": [\"37351578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Outward-facing and substrate-bound states not captured\", \"Regulatory STAS-domain interactions not resolved structurally\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a microbiome-dependent role for SLC26A6 in maintaining the gut barrier, with its loss reducing butyrate-producing microbes and increasing colitis susceptibility transferable by co-housing.\",\n      \"evidence\": \"PAT1 KO mice, DSS colitis, 16S sequencing, metabolomics, tight-junction analysis, and co-housing experiment\",\n      \"pmids\": [\"38735402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between anion transport and microbiome composition undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that cardiac SLC26A6 ablation protects against ischemia/reperfusion injury by raising intracellular pH and improving contractile and Ca2+ handling, identifying it as a detrimental acid loader in the ischemic heart.\",\n      \"evidence\": \"Slc26a6 KO mice in an I/R model with echocardiography, hemodynamics, pHi imaging, and cardiomyocyte sarcomere/Ca2+ measurements\",\n      \"pmids\": [\"41462888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Translational relevance to human cardiac ischemia untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a CaSR-PKA-FOXO4 axis that transcriptionally upregulates SLC26A6 and promotes calcium oxalate crystal formation, connecting calcium-sensing signaling to stone risk.\",\n      \"evidence\": \"Rat calcium oxalate stone model and NRK-52E cells with agonists/inhibitors; SLC26A6 promoter dual-luciferase reporter assay\",\n      \"pmids\": [\"41938536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Human relevance of the CaSR-FOXO4 axis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC26A6 conformational dynamics, STAS-domain regulation, post-translational control, and partner interactions integrate to tune anion selectivity and trafficking across diverse tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No outward-facing or substrate-bound structural states\", \"Mechanism coupling PKC-delta signaling to internalization undefined\", \"Structural basis of NHE3/CFTR/CAII functional coupling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 5, 13, 16, 22, 32]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 16, 22, 23, 25, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 11, 16, 19, 30, 32]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 24, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NHE3\",\n      \"CFTR\",\n      \"NHERF1\",\n      \"NaDC-1\",\n      \"CAII\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}