title: Regulated transport of sulfate and oxalate by SLC26A2/DTDST.
abstract: Nephrolithiasis in the Slc26a6(-/-) mouse is accompanied by 50-75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO(4)(2-) transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [(14)C]oxalate uptake (K(1/2) of 0.65 +/- 0.08 mM) was cis-inhibited by external SO(4)(2-) (K(1/2) of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO(4)(2-) exchange exhibited extracellular SO(4)(2-) K(1/2) of 1.58 +/- 0.44 mM for exchange with intracellular [(14)C]oxalate, and extracellular oxalate K(1/2) of 0.14 +/- 0.11 mM for exchange with intracellular (35)SO(4)(2-). Influx rates and K(1/2) values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl(-) exchange and bidirectional SO(4)(2-)/Cl(-) exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl(-) dependence for efflux of intracellular [(14)C]oxalate, (35)SO(4)(2-), or (36)Cl(-). Rate constants for (36)Cl(-) efflux into extracellular Cl(-), SO(4)(2-), and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pH(o)) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pH(i)) selectively activated exchange of extracellular Cl(-) for intracellular (35)SO(4)(2-) but not for intracellular (36)Cl(-) or [(14)C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both (35)SO(4)(2-) and [(14)C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Heneghan
authors.forename: Arash
authors.initials: A
authors.lastname: Akhavein
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Salas
authors.forename: Boris E
authors.initials: BE
authors.lastname: Shmukler
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Karniski
authors.forename: David H
authors.initials: DH
authors.lastname: Vandorpe
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051379:Mice; D009154:Mutation; D009865:Oocytes; D019815:Oxalic Acid / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012965:Sodium Chloride / Q000378:metabolism; D000076988:Sulfate Transporters; D013431:Sulfates / Q000378:metabolism*; D014981:Xenopus
chemical_list: D027321:Anion Transport Proteins; D047428:Protein Kinase Inhibitors; C089651:SLC26A2 protein, human; C513264:Slc26a2 protein, mouse; D000076988:Sulfate Transporters; D013431:Sulfates; C012036:sodium sulfate; D012965:Sodium Chloride; D019815:Oxalic Acid; D011493:Protein Kinase C