We found that a mutation in the extra- cellular domain of alphaENaC causes Liddle syndrome by increasing intrinsic channel activity. This mecha- nism differs from that of the beta -and gamma -mutations, which result in an incr ease in channel density at the cell surface. This mutation may explain other cases of pati ents with resistant hypertension and also provides novel insight into ENaC activation, which is relevant for kidney sodium reabsorption and salt-sensitive hypertension.