Solute Carrier family 26 member a 2 ( Slc 26 a 2 ) functions as an electroneutral SO 4 = / OH - / Cl - exchanger regulated by extracellular

Slc26a2 is a ubiquitously expressed SO4 transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO4 and the ion gradients that mediate SO4 uptake are poorly understood. We report here that Slc26a2 functions as a SO4/2OH, SO4/2Cl and SO4/OH/Cl exchanger, depending on the Cl and OH gradients. At inward Cl and outward pH gradients (high Clout, low pHout) Slc26a2 functions primarily as SO4out/2OHin exchanger. At low Clout, high pHout Slc26a2 functions increasingly as SO4out/2Clin exchanger. The reverse is observed for SO4in/2OH out and SO4in/2Clout exchange. Slc26a2 also exchanges Cl for I, Br and NO3 and Clo competes with SO4 on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO4in/2OHout exchange. Slc26a2 can transport oxalate in exchange for OH and/or Cl with properties similar to SO4 transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP371 between TMD7 and TMD8 close to the conserved E417 in the permeation pathway. Mutation of E417 eliminated transport by Slc26a2, whereas mutation of F368 increased the affinity for SO4out 8 fold while reducing the affinity for Clo 2 fold, but without affecting regulation by Cl o. These findings clarify the mechanism of net SO4 transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia.