Abstract
Epithelial sodium channels (ENaC) play a crucial role in Na (+) reabsorption in mammals. To date, four subunits have been identified-α, β, γ, and δ-believed to form different heteromeric complexes. Currently, only the structure of the αβγ complex is known. To understand how these channels form with varying subunit compositions and define the contribution of each subunit to distinct properties, we co-expressed human δ, β, and γ. Using single-particle cryo-electron microscopy, we observed three distinct ENaC complexes. The structures unveil a pattern in which β and γ positions are conserved among the different complexes while the α position in αβγ trimer is occupied by either δ or another β. The presence of δ induces structural rearrangements in the γ subunit explaining the differences in channel activity observed between αβγ and δβγ channels. These structures define the mechanism by which ENaC subunit composition tunes ENaC function.