Cl− transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC

摘要

Epithelial Na+ channels (ENaCs) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is activated by protein kinase A. Since cAMP-dependent activation of CFTR Cl− conductance is defective in cystic fibrosis (CF), ENaC currents are not inhibited by CFTR. This could explain the enhanced Na+ conductance found in CF. In the present study, we examined possible mechanisms of interaction between CFTR and ENaC co-expressed in Xenopus oocytes.The magnitude of CFTR Cl− currents activated by 3-isobutyl-1-methylxanthine (IBMX) in oocytes co-expressing either wild-type or mutant CFTR and ENaC determined the degree of downregulation of ENaC currents.The ability of CFTR to inhibit ENaC currents was significantly reduced either when extracellular Cl− was replaced by poorly conductive anions, e.g. SCN− or gluconate, or when CFTR was inhibited by diphenylamine-carboxylate (DPC, 1 mmol l−1).Downregulation of ENaC was more pronounced at positive when compared with negative clamp voltages. This suggests that outward currents, i.e. influx of Cl− through activated CFTR most effectively downregulated ENaC.Activation of endogenous Ca2+-activated Cl− currents by 1 μmol l−1 ionomycin did not inhibit ENaC current. This suggests that inhibition of ENaC mediated by Cl− currents may be specific to CFTR.The present findings indicate that downregulation of ENaC by CFTR is correlated to the ability of CFTR to conduct Cl−. The data have implications for how epithelia switch from NaCl absorption to NaCl secretion when CFTR is activated by secretagogues.