Regulated transport of sulfate and oxalate by SLC26A2/DTDST

Heneghan JF, Akhavein A, Salas MJ, Shmukler BE, Karniski LP, Vandorpe DH, Alper SL. Regulated transport of sulfate and oxalate by SLC26A2/DTDST. Am J Physiol Cell Physiol 298: C1363-C1375, 2010. First Published March 10, 2010; doi:10.1152/ajpcell.00004.2010.-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 SO42- 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 [C-14]oxalate uptake (K-1/2 of 0.65 +/- 0.08 mM) was cis-inhibited by external SO42- (K-1/2 of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO42- exchange exhibited extracellular SO42- K-1/2 of 1.58 +/- 0.44 mM for exchange with intracellular [C-14]oxalate, and extracellular oxalate K-1/2 of 0.14 +/- 0.11 mM for exchange with intracellular 35SO(4)(2-). Influx rates and K-1/2 values for mSlc26a2 were similar. hSLC26A2- mediated oxalate/Cl- exchange and bidirectional SO42-/Cl- exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl- dependence for efflux of intracellular [C-14]oxalate, (SO42-)-S-35, or Cl-36(-). Rate constants for Cl-36(-) efflux into extracellular Cl-, SO42-, 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 (SO42-)-S-35 but not for intracellular Cl-36(-) or [C-14]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 35SO(4)(2-) and [C-14]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.