Amiloride-sensitive Na⁺ transport by lung epithelia plays a critical role in maintaining alveolar Na⁺ and water balance. It has been generally assumed that Na⁺ transport is mediated by the amiloride-sensitive epithelial Na⁺ channel (ENaC) because molecular biology studies have confirmed the presence of ENaC subunits , , and  in lung epithelia. However, the predominant Na⁺-transporting channel reported from electrophysiological studies by most laboratories is a nonselective, high-conductance channel that is very different from the highly selective, low-conductance ENaC reported in other tissues. In our laboratory, single-channel recordings from apical membrane patches from rat alveolar type II (ATII) cells in primary culture reveal a nonselective cation channel with a conductance of 20.6 ± 1.1 pS and an Na⁺-to-K⁺ selectivity of 0.97 ± 0.07. This channel is inhibited by submicromolar concentrations of amiloride. Thus there is some question about the relationship between the gene product observed with single-channel methods and the cloned ENaC subunits. We have employed antisense oligonucleotide methods to block the synthesis of individual ENaC subunit proteins (, , and ) and determined the effect of a reduction in the subunit expression on the density of the nonselective cation channel observed in apical membrane patches on ATII cells. Treatment of ATII cells with antisense oligonucleotides inhibited the production of each subunit protein; however, single-channel recordings showed that only the antisense oligonucleotide targeting the -subunit resulted in a significant decrease in the density of nonselective cation channels. Inhibition of the - and -subunit proteins alone or together did not cause any changes in the observed channel density. There were no changes in open probability or other channel characteristics. These results support the hypothesis that the -subunit of ENaC alone or in combination with some protein other than the - or -subunit protein is the major component of lung alveolar epithelial cation channels.

alveolar type II cells; epithelial sodium channel; single-channel recording

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