SLC26A6 (putative anion transporter 1, PAT1; CFEX) is an SLC26A/SulP-family, STAS-domain anion exchanger of the apical (brush-border) membrane of small intestine, pancreatic duct and renal proximal tubule epithelia. It operates in several exchange modes, principally chloride/bicarbonate and chloride/oxalate, and also oxalate/formate, chloride/formate and, at low rates in the human protein, sulfate exchange. Its C-terminal PDZ-binding motif links it to NHERF scaffolds, and its bicarbonate transport is regulated by CFTR, cAMP, protein kinase C and carbonic anhydrase II binding. SLC26A6 mediates intestinal oxalate secretion, which limits net absorption of dietary oxalate; Slc26a6-null mice develop hyperoxaluria and calcium oxalate stones, and a heterozygous dominant-negative human variant (p.R507W) causes enteric hyperoxaluria with calcium oxalate nephrolithiasis. It also contributes to duodenal and pancreatic bicarbonate secretion and intracellular pH regulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005452 solute:inorganic anion antiporter activity | IDA PMID:15548529 Functional comparison of mouse slc26a6 anion exchanger with ... | ACCEPT | Summary: SLC26A6 is a DIDS-sensitive anion exchanger operating in chloride/bicarbonate, chloride/oxalate, oxalate/formate and related exchange modes; solute:inorganic anion antiporter activity correctly describes this. Reason: Human SLC26A6 anion exchange is shown in oocytes and in Caco-2 cells by knockdown (PMID:15548529, PMID:20501439, PMID:27681177). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0005452 solute:inorganic anion antiporter activity | IDA PMID:27681177 N-glycosylation critically regulates function of oxalate tra... | ACCEPT | Summary: SLC26A6 is a DIDS-sensitive anion exchanger operating in chloride/bicarbonate, chloride/oxalate, oxalate/formate and related exchange modes; solute:inorganic anion antiporter activity correctly describes this. Reason: Human SLC26A6 anion exchange is shown in oocytes and in Caco-2 cells by knockdown (PMID:15548529, PMID:20501439, PMID:27681177). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0005452 solute:inorganic anion antiporter activity | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: SLC26A6 is a DIDS-sensitive anion exchanger operating in chloride/bicarbonate, chloride/oxalate, oxalate/formate and related exchange modes; solute:inorganic anion antiporter activity correctly describes this. Reason: Human SLC26A6 anion exchange is shown in oocytes and in Caco-2 cells by knockdown (PMID:15548529, PMID:20501439, PMID:27681177). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0005452 solute:inorganic anion antiporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: SLC26A6 is a DIDS-sensitive anion exchanger operating in chloride/bicarbonate, chloride/oxalate, oxalate/formate and related exchange modes; solute:inorganic anion antiporter activity correctly describes this. Reason: Human SLC26A6 anion exchange is shown in oocytes and in Caco-2 cells by knockdown (PMID:15548529, PMID:20501439, PMID:27681177). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0005452 solute:inorganic anion antiporter activity | TAS Reactome:R-HSA-427666 | ACCEPT | Summary: SLC26A6 is a DIDS-sensitive anion exchanger operating in chloride/bicarbonate, chloride/oxalate, oxalate/formate and related exchange modes; solute:inorganic anion antiporter activity correctly describes this. Reason: Human SLC26A6 anion exchange is shown in oocytes and in Caco-2 cells by knockdown (PMID:15548529, PMID:20501439, PMID:27681177). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0005886 plasma membrane | EXP PMID:11247665 Cloning and characterization of SLC26A6, a novel member of t... | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | EXP PMID:12444019 Isoforms of SLC26A6 mediate anion transport and have functio... | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | EXP PMID:15990874 Metabolon disruption: a mechanism that regulates bicarbonate... | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | IDA PMID:27681177 N-glycosylation critically regulates function of oxalate tra... | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-427666 | ACCEPT | Summary: SLC26A6 is a plasma membrane transporter, apical in polarized epithelia. Reason: Experimental localization of human SLC26A6 to the cell membrane in several studies. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial PMID:20501439 PAT-1 was functionally targeted to the apical membrane |
| GO:0006821 chloride transport | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: Chloride is the principal counter-ion of SLC26A6-mediated bicarbonate and oxalate exchange; knockdown in Caco-2 cells reduced chloride flux. Reason: Supported by knockdown data in a human intestinal cell line (PMID:20501439), though the human protein moves 36Cl at lower rates than mouse (PMID:15548529). Supporting Evidence: PMID:20501439 the unidirectional fluxes in A6KD were reduced 50, 35, and 15%, respectively PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog |
| GO:0008271 secondary active sulfate transmembrane transporter activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Sulfate transport by human SLC26A6 is detectable but low compared with the mouse orthologue. Reason: Sulfate is a minor substrate for the human protein (PMID:15548529); core substrates are chloride, bicarbonate and oxalate. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:0012506 vesicle membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Slc26a6 has an intracellular vesicular pool that recycles to the apical membrane; the human annotation is by sequence similarity. Reason: A trafficking compartment rather than the functional site, which is the apical plasma membrane. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0015116 sulfate transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sulfate transport is a real but minor activity of human SLC26A6. Reason: Human SLC26A6 transports sulfate at low rates (PMID:15548529); retained as non-core. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:0015499 formate transmembrane transporter activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In mouse kidney proximal tubule, Slc26a6 mediates chloride/formate exchange and formate efflux; transferred to human by similarity. Reason: Plausible orthologous activity, mainly characterized in mouse; not the best-established human function. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0015562 efflux transmembrane transporter activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: "Efflux transmembrane transporter activity" adds no information about this anion exchanger, which moves substrates bidirectionally depending on counter-ion gradients. Reason: SLC26A6 exchange is symmetric and gradient-driven (PMID:20501439); the specific exchange activities are already annotated. Supporting Evidence: PMID:20501439 The overall symmetry of PAT-1-mediated oxalate exchange suggests that vectorial oxalate transport observed in vivo is principally dependent on the magnitude and direction of counterion gradients. |
| GO:0015701 bicarbonate transport | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: SLC26A6 mediates chloride-dependent bicarbonate transport (Cl-/HCO3- exchange) in intestine, pancreatic duct and proximal tubule. Reason: Knockdown of SLC26A6 in Caco-2 cells halves Cl-dependent HCO3- efflux (PMID:20501439). Supporting Evidence: PMID:20501439 Cl(-)-dependent HCO(3)(-) efflux from A6KD was reduced 50% compared with Con. PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. |
| GO:0015724 formate transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In mouse kidney proximal tubule, Slc26a6 mediates chloride/formate exchange and formate efflux; transferred to human by similarity. Reason: Plausible orthologous activity, mainly characterized in mouse; not the best-established human function. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt chloride-bicarbonate, chloride-oxalate, oxalate-formate, oxalate- |
| GO:0015797 mannitol transmembrane transport | ISS GO_REF:0000024 | REMOVE | Summary: Mannitol is a neutral polyol, not a plausible substrate of an SLC26 anion exchanger; no human evidence supports this similarity-based transfer. Reason: No evidence that SLC26A6 transports mannitol; likely an indirect phenotype (e.g. paracellular marker flux) in the source mouse study rather than a transporter function. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0016020 membrane | IDA PMID:11087667 Mapping of five new putative anion transporter genes in huma... | KEEP AS NON CORE | Summary: Generic membrane localization; true but uninformative. Reason: Plasma and apical membrane annotations capture the localization more precisely. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane localization; true but uninformative. Reason: Plasma and apical membrane annotations capture the localization more precisely. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0016020 membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Generic membrane localization; true but uninformative. Reason: Plasma and apical membrane annotations capture the localization more precisely. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0016323 basolateral plasma membrane | IDA PMID:11087667 Mapping of five new putative anion transporter genes in huma... | KEEP AS NON CORE | Summary: Basolateral localization is not the main site of SLC26A6, which is apical in intestine, pancreatic duct and proximal tubule; the experimental annotation is deferred to the curator who read the full text. Reason: Abstract of PMID:11087667 reports apical pancreatic duct staining; basolateral signal may reflect a specific tissue or cell type in the full text, which is not cached. Supporting Evidence: PMID:11087667 immunohistochemistry localizes SLC26A6 protein to the apical surface of |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Basolateral localization is not the main site of SLC26A6, which is apical in intestine, pancreatic duct and proximal tubule; the experimental annotation is deferred to the curator who read the full text. Reason: Abstract of PMID:11087667 reports apical pancreatic duct staining; basolateral signal may reflect a specific tissue or cell type in the full text, which is not cached. Supporting Evidence: PMID:11087667 immunohistochemistry localizes SLC26A6 protein to the apical surface of |
| GO:0016324 apical plasma membrane | IDA PMID:11087667 Mapping of five new putative anion transporter genes in huma... | ACCEPT | Summary: SLC26A6 is the apical (luminal) anion exchanger of intestinal, pancreatic duct and renal proximal tubule epithelia. Reason: Experimental apical localization in human tissue and Caco-2 cells (PMID:11087667, PMID:20501439). Supporting Evidence: PMID:20501439 PAT-1 was functionally targeted to the apical membrane PMID:11087667 immunohistochemistry localizes SLC26A6 protein to the apical surface of |
| GO:0016324 apical plasma membrane | IDA PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: SLC26A6 is the apical (luminal) anion exchanger of intestinal, pancreatic duct and renal proximal tubule epithelia. Reason: Experimental apical localization in human tissue and Caco-2 cells (PMID:11087667, PMID:20501439). Supporting Evidence: PMID:20501439 PAT-1 was functionally targeted to the apical membrane PMID:11087667 immunohistochemistry localizes SLC26A6 protein to the apical surface of |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: SLC26A6 is the apical (luminal) anion exchanger of intestinal, pancreatic duct and renal proximal tubule epithelia. Reason: Experimental apical localization in human tissue and Caco-2 cells (PMID:11087667, PMID:20501439). Supporting Evidence: PMID:20501439 PAT-1 was functionally targeted to the apical membrane PMID:11087667 immunohistochemistry localizes SLC26A6 protein to the apical surface of |
| GO:0019531 oxalate transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Oxalate transport, mainly chloride/oxalate exchange, is a core activity of SLC26A6 and underlies intestinal oxalate secretion. Reason: Human SLC26A6 transports oxalate in oocytes and in human intestinal cells (PMID:15548529, PMID:27681177, PMID:40356774, PMID:20501439); loss in mouse and a human dominant-negative variant cause hyperoxaluria (PMID:16532010, PMID:35115415). Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:40356774 Known human oxalate transporters (SLC26A6, SLC26A2/DTDST) and dPrestin were tested for oxalate uptake PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0019531 oxalate transmembrane transporter activity | IDA PMID:40356774 Ex vivo quantification of intracellular pH in Drosophila Mal... | ACCEPT | Summary: Oxalate transport, mainly chloride/oxalate exchange, is a core activity of SLC26A6 and underlies intestinal oxalate secretion. Reason: Human SLC26A6 transports oxalate in oocytes and in human intestinal cells (PMID:15548529, PMID:27681177, PMID:40356774, PMID:20501439); loss in mouse and a human dominant-negative variant cause hyperoxaluria (PMID:16532010, PMID:35115415). Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:40356774 Known human oxalate transporters (SLC26A6, SLC26A2/DTDST) and dPrestin were tested for oxalate uptake PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0019532 oxalate transport | IDA PMID:40356774 Ex vivo quantification of intracellular pH in Drosophila Mal... | ACCEPT | Summary: Oxalate transport, mainly chloride/oxalate exchange, is a core activity of SLC26A6 and underlies intestinal oxalate secretion. Reason: Human SLC26A6 transports oxalate in oocytes and in human intestinal cells (PMID:15548529, PMID:27681177, PMID:40356774, PMID:20501439); loss in mouse and a human dominant-negative variant cause hyperoxaluria (PMID:16532010, PMID:35115415). Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:40356774 Known human oxalate transporters (SLC26A6, SLC26A2/DTDST) and dPrestin were tested for oxalate uptake PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0019532 oxalate transport | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: Oxalate transport, mainly chloride/oxalate exchange, is a core activity of SLC26A6 and underlies intestinal oxalate secretion. Reason: Human SLC26A6 transports oxalate in oocytes and in human intestinal cells (PMID:15548529, PMID:27681177, PMID:40356774, PMID:20501439); loss in mouse and a human dominant-negative variant cause hyperoxaluria (PMID:16532010, PMID:35115415). Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:40356774 Known human oxalate transporters (SLC26A6, SLC26A2/DTDST) and dPrestin were tested for oxalate uptake PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0019532 oxalate transport | ISS GO_REF:0000024 | ACCEPT | Summary: Oxalate transport, mainly chloride/oxalate exchange, is a core activity of SLC26A6 and underlies intestinal oxalate secretion. Reason: Human SLC26A6 transports oxalate in oocytes and in human intestinal cells (PMID:15548529, PMID:27681177, PMID:40356774, PMID:20501439); loss in mouse and a human dominant-negative variant cause hyperoxaluria (PMID:16532010, PMID:35115415). Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:40356774 Known human oxalate transporters (SLC26A6, SLC26A2/DTDST) and dPrestin were tested for oxalate uptake PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0030165 PDZ domain binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The C-terminal TRL motif of SLC26A6 binds PDZ domains of NHERF-family scaffolds, linking it to apical transport microdomains. Reason: Shown for the human protein in vitro (PMID:12444019); the truncation did not affect transport, so this is a regulatory/scaffolding interaction. Supporting Evidence: PMID:12444019 the COOH terminus of SLC26A6 binds to the first and second PDZ domains |
| GO:0030321 transepithelial chloride transport | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | KEEP AS NON CORE | Summary: Apical Cl-/HCO3- and Cl-/oxalate exchange contribute to transepithelial chloride absorption in intestine. Reason: A physiological consequence of the exchange activity; chloride absorption is shared with SLC26A3 and NHE3 and is not the distinguishing role. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0030321 transepithelial chloride transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Apical Cl-/HCO3- and Cl-/oxalate exchange contribute to transepithelial chloride absorption in intestine. Reason: A physiological consequence of the exchange activity; chloride absorption is shared with SLC26A3 and NHE3 and is not the distinguishing role. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mouse Slc26a6 has an intracellular vesicular pool that recycles to the apical membrane; the human annotation is by sequence similarity. Reason: A trafficking compartment rather than the functional site, which is the apical plasma membrane. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0030659 cytoplasmic vesicle membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Slc26a6 has an intracellular vesicular pool that recycles to the apical membrane; the human annotation is by sequence similarity. Reason: A trafficking compartment rather than the functional site, which is the apical plasma membrane. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0031526 brush border membrane | IDA PMID:11087667 Mapping of five new putative anion transporter genes in huma... | ACCEPT | Summary: SLC26A6 is located in the brush border membrane of intestinal and proximal tubule epithelium. Reason: Consistent with apical brush-border function described for the human and mouse protein. Supporting Evidence: PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate |
| GO:0031982 vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Slc26a6 has an intracellular vesicular pool that recycles to the apical membrane; the human annotation is by sequence similarity. Reason: A trafficking compartment rather than the functional site, which is the apical plasma membrane. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0042045 epithelial fluid transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In mouse pancreatic duct, Slc26a6 supports bicarbonate-rich fluid secretion. Reason: Tissue physiology downstream of Cl-/HCO3- exchange, established in mouse. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0044849 estrous cycle | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Estrous-cycle involvement is an electronic ortholog transfer with no human or mechanistic support. Reason: No evidence that SLC26A6 participates in the estrous cycle; at most expression varies with it. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0046724 oxalic acid secretion | ISS GO_REF:0000024 | ACCEPT | Summary: SLC26A6 mediates intestinal oxalate secretion; loss in mouse abolishes secretion and causes enteric hyperoxaluria, and a human dominant-negative variant causes enteric hyperoxaluria. Reason: Core physiological process (PMID:16532010, PMID:27681177, PMID:35115415). Supporting Evidence: PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate PMID:27681177 The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate PMID:35115415 SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. |
| GO:0048240 sperm capacitation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Slc26a6 is present in sperm (midpiece) and contributes to capacitation-associated alkalinization; transferred by similarity. Reason: Mouse-derived, tissue-specific role; not a core human function. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Plays a role in sperm capacitation |
| GO:0050892 intestinal absorption | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Apical chloride absorption and oxalate secretion by SLC26A6 contribute to intestinal electrolyte handling. Reason: Broad process; SLC26A6 contributes chloride absorption, but its distinctive role is oxalate secretion. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0051453 regulation of intracellular pH | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | KEEP AS NON CORE | Summary: Cl-/HCO3- exchange by SLC26A6 contributes to intracellular pH regulation. Reason: Supported by knockdown in Caco-2 cells (PMID:20501439); a consequence of the bicarbonate exchange activity. Supporting Evidence: PMID:20501439 Cl(-)-dependent HCO(3)(-) efflux from A6KD was reduced 50% compared with Con. |
| GO:0051454 intracellular pH elevation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In mouse duodenal villus and sperm, Slc26a6 bicarbonate import raises intracellular pH. Reason: Context-specific consequence of the exchange activity, characterized in mouse. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt contributes to intracellular pH regulation in the duodenal upper |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: Very general process term. Reason: The specific transport processes are oxalate and chloride/bicarbonate transport. Proposed replacements: oxalate transport Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-9958790 | MODIFY | Summary: Very general process term. Reason: The specific transport processes are oxalate and chloride/bicarbonate transport. Proposed replacements: oxalate transport Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0070633 transepithelial transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transepithelial transport is a generic description of SLC26A6 apical exchange in polarized epithelia. Reason: Correct but general; oxalic acid secretion captures the specific transepithelial role. Supporting Evidence: PMID:16532010 mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate |
| GO:0071320 cellular response to cAMP | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cl-/HCO3- exchange by SLC26A6 is stimulated by cAMP, at least partly through CFTR. Reason: Regulatory response, shown for both human and mouse proteins in oocytes (PMID:15548529). Supporting Evidence: PMID:15548529 Cl(-)/HCO(3)(-) exchange by both orthologs was cAMP-sensitive |
| GO:0071332 cellular response to fructose stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Response to fructose is an indirect physiological observation transferred from mouse. Reason: No mechanistic evidence that SLC26A6 participates in a cellular response to fructose. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Apical membrane anion-exchanger with wide epithelial |
| GO:0071346 cellular response to type II interferon | IDA PMID:18655181 Characterization of the 5'-flanking region and regulation of... | MARK AS OVER ANNOTATED | Summary: IFN-gamma downregulates SLC26A6 expression and promoter activity in Caco-2 cells. That is regulation of the gene by the cytokine, not participation of the transporter in the interferon response. Reason: SLC26A6 is a target of IFN-gamma signalling (PMID:18655181), not an effector of the cellular response. Supporting Evidence: PMID:18655181 IFNgamma decreased both SLC26A6 mRNA and function and repressed SLC26A6 promoter activity. |
| GO:0097225 sperm midpiece | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Slc26a6 is present in sperm (midpiece) and contributes to capacitation-associated alkalinization; transferred by similarity. Reason: Mouse-derived, tissue-specific role; not a core human function. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt Plays a role in sperm capacitation |
| GO:0140900 chloride:bicarbonate antiporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Chloride/bicarbonate exchange is a core activity of SLC26A6 in intestine, pancreatic duct and proximal tubule. Reason: Human SLC26A6 mediates electroneutral Cl-/HCO3- exchange in oocytes and Cl-dependent HCO3- efflux in Caco-2 cells (PMID:15548529, PMID:20501439). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. PMID:20501439 Cl(-)-dependent HCO(3)(-) efflux from A6KD was reduced 50% compared with Con. |
| GO:0140900 chloride:bicarbonate antiporter activity | IDA PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | ACCEPT | Summary: Chloride/bicarbonate exchange is a core activity of SLC26A6 in intestine, pancreatic duct and proximal tubule. Reason: Human SLC26A6 mediates electroneutral Cl-/HCO3- exchange in oocytes and Cl-dependent HCO3- efflux in Caco-2 cells (PMID:15548529, PMID:20501439). Supporting Evidence: PMID:15548529 Mouse slc26a6 and human SLC26A6 each mediated electroneutral Cl(-)/HCO(3)(-) and Cl(-)/OH(-) exchange. PMID:20501439 Cl(-)-dependent HCO(3)(-) efflux from A6KD was reduced 50% compared with Con. |
| GO:1902358 sulfate transmembrane transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sulfate transport is a real but minor activity of human SLC26A6. Reason: Human SLC26A6 transports sulfate at low rates (PMID:15548529); retained as non-core. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:1902358 sulfate transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Sulfate transport is a real but minor activity of human SLC26A6. Reason: Human SLC26A6 transports sulfate at low rates (PMID:15548529); retained as non-core. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:1902358 sulfate transmembrane transport | IMP PMID:20501439 Parsing apical oxalate exchange in Caco-2BBe1 monolayers: si... | KEEP AS NON CORE | Summary: Sulfate transport is a real but minor activity of human SLC26A6. Reason: Human SLC26A6 transports sulfate at low rates (PMID:15548529); retained as non-core. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:1902358 sulfate transmembrane transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sulfate transport is a real but minor activity of human SLC26A6. Reason: Human SLC26A6 transports sulfate at low rates (PMID:15548529); retained as non-core. Supporting Evidence: PMID:15548529 the very low rates of (36)Cl(-) and [(35)S]sulfate transport by all active human SLC26A6 isoforms contrasted with the high rates of the mouse ortholog PMID:12444019 Functional expression of the three proteins in Xenopus oocytes demonstrated Cl(-) and SO(4)(2-) transport activity. |
| GO:1902476 chloride transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Chloride crosses the apical membrane as the counter-ion of SLC26A6 exchange. Reason: Consistent with chloride-coupled bicarbonate and oxalate exchange (PMID:20501439). Supporting Evidence: PMID:20501439 the unidirectional fluxes in A6KD were reduced 50, 35, and 15%, respectively |
| GO:2001150 positive regulation of dipeptide transmembrane transport | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: In mouse duodenum, Slc26a6 supports intracellular pH during proton-coupled dipeptide absorption by PepT1. Reason: Indirect, mouse-derived regulatory role. Supporting Evidence: file:human/SLC26A6/SLC26A6-uniprot.txt during proton-coupled peptide absorption |
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Download this section (compressed HTML)Q: How often do rare SLC26A6 loss-of-function or dominant-negative variants underlie enteric hyperoxaluria and calcium oxalate stones beyond the single reported p.R507W family?
Q: Is the human SLC26A6 chloride/oxalate exchange electroneutral in vivo, and how does its stoichiometry differ from the electrogenic mouse orthologue?
Experiment: Measure intestinal oxalate secretion (e.g. in human enteroids) carrying SLC26A6 p.R507W or loss-of-function alleles, with and without wild-type co-expression.
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