Genistein improves regulatory interactions between G551D-cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel in Xenopus oocytes.
The cystic fibrosis transmembrane conductance regulator (CFTR) in addition to its well defined Cl(-) channel properties regulates other ion channels. CFTR inhibits epithelial Na(+) channel (ENaC) currents in many epithelial and non-epithelial cells, whereas the presence of ENaC increases CFTR functional expression. This interregulation is reproduced in Xenopus oocytes where both the open probability and surface expression of wild type CFTR Cl(-) channels are increased when CFTR is co-expressed with alphabetagamma-mouse ENaC (mENaC) and conversely when the activity of mENaC is inhibited after wild type CFTR activation. Using the Xenopus oocyte expression system, different functional regulatory interactions were observed between G551D-CFTR and alphabetagamma-mENaC. The co-expression of G551D-CFTR and alphabetagamma-mENaC resulted in a 5-fold increase in G551D-CFTR Cl(-) current compared with oocytes expressing G551D-CFTR alone. Oocytes co-injected with both G551D-CFTR and ENaC expressed an amiloride-sensitive whole cell current that was similar to that observed before and after G551D-CFTR activation with forskolin/isobutylmethylxanthine. Treatment with genistein both enhanced the functional expression of G551D-CFTR and improved regulatory interactions between G551D-CFTR and ENaC. These data suggest that genistein may be useful in patients with cystic fibrosis and the G551D-CFTR mutation.
Suaud
Laurence
L
Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Carattino
Marcelo
M
Kleyman
Thomas R
TR
Rubenstein
Ronald C
RC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019943:Amino Acid Substitution; D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053503:Epithelial Sodium Channels; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000502:physiology*; D011336:Probability; D020239:Receptor Cross-Talk / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014981:Xenopus
C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; D011994:Recombinant Proteins; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019833:Genistein; D015056:1-Methyl-3-isobutylxanthine