title: Extracellular Cl(-) regulates human SO4 (2-)/anion exchanger SLC26A1 by altering pH sensitivity of anion transport.
abstract: Genetic deficiency of the SLC26A1 anion exchanger in mice is known to be associated with hyposulfatemia and hyperoxaluria with nephrolithiasis, but many aspects of human SLC26A1 function remain to be explored. We report here the functional characterization of human SLC26A1, a 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid (DIDS)-sensitive, electroneutral sodium-independent anion exchanger transporting sulfate, oxalate, bicarbonate, thiosulfate, and (with divergent properties) chloride. Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs in its stimulation by alkaline pHo and inhibition by acidic pHo but not pHi and in its failure to transport glyoxylate. SLC26A1-mediated transport of sulfate and oxalate is highly dependent on allosteric activation by extracellular chloride or non-substrate anions. Extracellular chloride stimulates apparent V max of human SLC26A1-mediated sulfate uptake by conferring a 2-log decrease in sensitivity to inhibition by extracellular protons, without changing transporter affinity for extracellular sulfate. In contrast to SLC26A1-mediated sulfate transport, SLC26A1-associated chloride transport is activated by acid pHo, shows reduced sensitivity to DIDS, and exhibits cation dependence of its DIDS-insensitive component. Human SLC26A1 resembles SLC26 paralogs in its inhibition by phorbol ester activation of protein kinase C (PKC), which differs in its undiminished polypeptide abundance at or near the oocyte surface. Mutation of SLC26A1 residues corresponding to candidate anion binding site-associated residues in avian SLC26A5/prestin altered anion transport in patterns resembling those of prestin. However, rare SLC26A1 polymorphic variants from a patient with renal Fanconi Syndrome and from a patient with nephrolithiasis/calcinosis exhibited no loss-of-function phenotypes consistent with disease pathogenesis.
authors.affiliation: Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.|Division of Laboratory Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.|Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Heneghan
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Vandorpe
authors.affiliation: Department of Physiology, Faculty of Medicine, Universidad Nacional Autonoma de Mexico, Mexico, DF, 04510, Mexico.
authors.forename: Laura I
authors.initials: LI
authors.lastname: Escobar
authors.affiliation: Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.|Division of Laboratory Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. salper@bidmc.harvard.edu.|Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. salper@bidmc.harvard.edu.|Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. salper@bidmc.harvard.edu.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000838:Anions / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002712:Chlorides / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009865:Oocytes / Q000378:metabolism; D010070:Oxalates / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism; D013885:Thiosulfates / Q000378:metabolism; D014981:Xenopus / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D000838:Anions; D001639:Bicarbonates; D002712:Chlorides; D010070:Oxalates; C473560:SLC26A1 protein, human; D000076988:Sulfate Transporters; D013431:Sulfates; D013885:Thiosulfates; D011493:Protein Kinase C
keywords: Glyoxylate; Nephrocalcinosis; Oxalate transport; Protein kinase C; Renal Fanconi syndrome; Xenopus oocyte