The mammalian FXYD family maintains Na+ and K+ gradients between the intracellular and extracellular milieus of cells in processes such as renal Na+-reabsorption, muscle contraction and neuronal excitability. FXYDs are single-span membrane proteins that share a 35 amino acid signature domain, beginning with the sequence PFXYD and containing seven invariant and six conserved amino acids. Members of the FXYD family include FXYD1 (PLM, phospholemman), FXYD2 (the g subunit of the Na+/K+-ATPase), FXYD3 (Mat8, mammary tumor protein), FXYD4 (CHIF) and FXYD5 (RIC). FXYD6 is expressed in various epithelial cells bordering the endolymph space and in the auditory neurons. FXYD6 co-localizes with Na+/K+-ATPase in the stria vascularis and can be co-immunoprecipitated with Na+/K+-ATPase. After expression, FXYD6 associates with Na+/K+-ATPase alpha1-beta1 and alpha1-beta2 isozymes, which are preferentially expressed in different regions of the inner ear and also with gastric and non-gastric H+/K+-ATPase.