The epithelial Na+ Channel (ENaC) mediates Na+ reabsorption in a varie
ty of epithelial tissues. ENaC is composed of three homologous subunit
s, termed alpha, beta, and gamma, All three subunits participate in ch
annel formation as the absence of any one subunit results in a signifi
cant reduction or complete abrogation of Na+ current expression in Xen
opus oocytes. To determine the subunit stoichiometry, a biophysical as
say was employed utilizing mutant subunits that display significant di
fferences in sensitivity to channel blockers from the wild type channe
l. Our results indicate that ENaC is a tetrameric channel with an alph
a(2) beta gamma stoichiometry, similar to that reported for other cati
on selective channels, such as K-v, K-ir, as well as voltage-gated Na and Ca2+ channels that have 4-fold internal symmetry.