Regulation of epithelial sodium channels by the cystic fibrosis transmembrane conductance regulator

Cystic fibrosis airway epithelia exhibit enhanced Na⁺ reabsorption in parallel with diminished Cl^- secretion. We tested the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) directly affects epithelial Na⁺ channel activity by co-incorporating into planar lipid bilayers immunopurified bovine tracheal CFTR and either heterologously expressed rat epithelial Na⁺ channel (α,β,γ-rENaC) or an immunopurified bovine renal Na⁺ channel protein complex. The single channel open probability (P(o)) of rENaC was decreased by 24% in the presence of CFTR. Protein kinase A (PKA) plus ATP activated CFTR, but did not have any effect on rENaC. CFTR also decreased the extent of elevation of the renal Na⁺ channel P(o) following PKA-mediated phosphorylation. Moreover, the presence of CFTR prohibited the inward rectification of the gating of this renal Na⁺ channel normally induced by PKA-mediated phosphorylation, thus down- regulating inward Na⁺ current. This interaction between CFTR and Na⁺ channels occurs independently of whether or not wild-type CFTR is conducting anions. However, the nonconductive CFTR mutant, G551D CFTR, cannot substitute for the wild-type molecule. Our results indicate that CFTR can directly down- regulate single Na⁺ channel activity, thus accounting, at least in part, for the observed differences in Na⁺ transport between normal and cystic fibrosis-affected airway epithelia.