Estradiol activates epithelial sodium channels in rat alveolar cells through the G protein-coupled estrogen receptor

Greenlee MM, Mitzelfelt JD, Yu L, Yue Q, Duke BJ, Harrell CS, Neigh GN, Eaton DC. Estradiol activates epithelial sodium channels in rat alveolar cells through the G protein-coupled estrogen receptor. Am J Physiol Lung Cell Mol Physiol 305: L878-L889, 2013. First published October 4, 2013; doi:10.1152/ajplung.00008.2013.-Female sex predisposes individuals to poorer outcomes during respiratory disorders like cystic fibrosis and influenza-associated pneumonia. A common link between these disorders is dysregulation of alveolar fluid clearance via disruption of epithelial sodium channel (ENaC) activity. Recent evidence suggests that female sex hormones directly regulate expression and activity of alveolar ENaC. In our study, we identified the mechanism by which estradiol (E2) or progesterone (P4) independently regulates alveolar ENaC. Using cell-attached patch clamp, we measured ENaC single-channel activity in a rat alveolar cell line (L2) in response to overnight exposure to either E2 or P4. In contrast to P4, E2 increased ENaC channel activity (NPo) through an increase in channel open probability (P-o) and an increased number of patches with observable channel activity. Apical plasma membrane abundance of the ENaC alpha-subunit (alpha ENaC) more than doubled in response to E2 as determined by cell surface biotinylation. alpha ENaC membrane abundance was approximately threefold greater in lungs from female rats in proestrus, when serum E2 is greatest, compared with diestrus, when it is lowest. Our results also revealed a significant role for the G protein-coupled estrogen receptor (Gper) to mediate E2's effects on ENaC. Overall, our results demonstrate that E2 signaling through Gper selectively activates alveolar ENaC through an effect on channel gating and channel density, the latter via greater trafficking of channels to the plasma membrane. The results presented herein implicate E2-mediated regulation of alveolar sodium channels in the sex differences observed in the pathogenesis of several pulmonary diseases.