Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SO ₄ ^2-/OH ^-/Cl ^- exchanger regulated by extracellular Cl ^-

Slc26a2 is a ubiquitously expressed SO ₄ ^2- transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO ₄ ^2- and the ion gradients that mediate SO ₄ ^2- uptake are poorly understood. We report here that Slc26a2 functions as an SO ₄ ^2-/2OH ^-, SO ₄ ^2-/2Cl ^-, and SO ₄ ^2-/OH ^-/Cl ^- exchanger, depending on the Cl ^- and OH ^- gradients. At inward Cl ^- and outward pH gradients (high Cl ^- _o and low pH _o) Slc26a2 functions primarily as an SO ₄ ^2- _o/2OH ^- _i exchanger. At low Cl ^- _o and high pH _o Slc26a2 functions increasingly as an SO ₄ ^2- _o/2Cl ^- _i exchanger. The reverse is observed for SO ₄ ^2- _i/2OH ^- _o and SO ₄ ^2- _i/2Cl ^- _o exchange. Slc26a2 also exchanges Cl ^- for I ^-, Br ^-, and NO ₃ ^- and Cl ^- _o competes with SO ₄ ^2- on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO ₄ ^2- _i/2OH ^- _o exchange. Slc26a2 can transport oxalate in exchange for OH ^- and/or Cl ^- with properties similar to SO ₄ ^2- transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence ³⁶⁷GFXXP ³⁷¹between TMD7 and TMD8 close to the conserved Glu ⁴¹⁷ in the permeation pathway. Mutation of Glu ⁴¹⁷ eliminated transport by Slc26a2, whereas mutation of Phe ³⁶⁸ increased the affinity for SO ₄ ^2- _o 8-fold while reducing the affinity for Cl ^- _o 2 fold, but without affecting regulation by Cl ^- _o. These findings clarify the mechanism of net SO ₄ ^2- 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.