Genistein restores functional interactions between ΔF508-CFTR and ENaC in Xenopus oocytes

The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its Cl^- channel properties, has regulatory interactions with other epithelial ion channels including the epithelial Na⁺ channel (ENaC). Both the open probability and surface expression of wild type CFTR Cl^- channels are increased significantly when CFTR is co-expressed in Xenopus oocytes with αβγ-ENaC, and conversely, the activity of ENaC is inhibited following wild type CFTR activation. Using the Xenopus oocyte expression system, a lack of functional regulatory interactions between ΔF508-CFTR and ENaC was observed following activation of ΔF508-CFTR by forskolin and isobutylmethylxanthine (IBMX). Whole cell currents in oocytes expressing ENaC alone decreased in response to genistein but increased in response to a combination of forskolin and IBMX followed by genistein. In contrast, ENaC currents in oocytes coexpressing ENaC and ΔF508-CFTR remained stable following stimulation with forskolin/IBMX/genistein. Furthermore, co-expression of ΔF508-CFTR with ENaC enhanced the forskolin/IBMX/genistein-mediated activation of ΔF508-CFTR. Our data suggest that genistein restores regulatory interactions between ΔF508-CFTR and ENaC and that combinations of protein repair agents, such as 4-phenylbutyrate and genistein, may be necessary to restore ΔF508-CFTR function in vivo.