FXYD3 facilitates Na⁺ and liquid absorption across human airway epithelia by increasing the transport capacity of the Na/K ATPase.

Na/K ATPase activity is essential for ion transport across epithelia. FXYD3, a γ subunit of the Na/K ATPase, is expressed in the airway, but its function remains undetermined. Single-cell RNA sequencing and immunohistochemistry revealed that FXYD3 localizes within the basolateral membrane of all airway epithelial cells. To study FXYD3 function, we reduced <i>FXYD3</i> expression using siRNA. After permeabilizing the apical membrane with nystatin, epithelia pretreated with <i>FXYD3</i>-targeting siRNA had lower ouabain-sensitive short-circuit currents than control epithelia. <i>FXYD3</i>-targeting siRNA also reduced amiloride-sensitive short-circuit currents and liquid absorption across intact epithelia. These data are consistent with FXYD3 facilitating Na⁺ and liquid absorption. FXYD3 may be needed to maintain the high rates of Na⁺ and fluid absorption observed for airway and other FXYD3-expressing epithelia.