SLC26A9 is a Cl channel regulated by the WNK kinases


  • M. R. Dorwart and N. Shcheynikov contributed equally to this work.

Corresponding author S. Muallem: Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9040, USA. Email:


SLC26A9 is a member of the SLC26 family of anion transporters, which is expressed at high levels in airway and gastric surface epithelial cells. The transport properties and regulation of SLC26A9, and thus its physiological function, are not known. Here we report that SLC26A9 is a highly selective Cl channel with minimal OH/HCO3 permeability that is regulated by the WNK kinases. Expression in Xenopus oocytes and simultaneous measurement of membrane potential or current, intracellular pH (pHi) and intracellular Cl (Cli) revealed that expression of SLC26A9 resulted in a large Cl current. SLC26A9 displays a selectivity sequence of I > Br > NO3 > Cl > Glu, but it conducts Br > Cl > I > NO3 > Glu, with NO3 and I inhibiting the Cl conductance. Similarly, expression of SLC26A9 in HEK cells resulted in a large Cl current. Although detectable, OH and HCO3 fluxes in oocytes expressing SLC26A9 were very small. Moreover, HCO3 had no discernable effect on the Cl current, the reversal potential in the presence or absence of Clo and, importantly, HCO3 had no effect on Cl fluxes. These findings indicate that SLC26A9 is a Cl channel with minimal OH/HCO3 permeability. Co-expression of SLC26A9 with the WNK kinases WNK1, WNK3 or WNK4 inhibited SLC26A9 activity, and the inhibition was independent of WNK kinase activity. Immunolocalization in oocytes and cell surface biotinylation in HEK cells indicated that the WNK-mediated inhibition of SLC26A9 activity is caused by reduced SLC26A9 surface expression. Expression of SLC26A9 in the airway and the response of the WNKs to homeostatic stress raise the possibility that SLC26A9 serves to mediate the response of the airway to stress.