Cystic fibrosis transmembrane conductance regulator differentially regulates human and mouse epithelial sodium channels in Xenopus oocytes

Wusheng Yan, Frederick F. Samaha, Mohan Ramkumar, Thomas R. Kleyman, Ronald C. Rubenstein

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its well defined Cl- channel properties, regulates other ion channels. CFTR inhibits murine or rat epithelial Na+ channel (mENaC of rENaC) currents in many epithelial and non-epithelial cells, whereas murine or rat ENaC increases CFTR functional expression. These regulatory interactions are 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 αβγ mENaC, and conversely the activity of mENaC is inhibited after wild type CFTR activation. Using the Xenopus oocyte expression system, differences in functional regulatory interactions were observed when CFTR was co-expressed with either αβγ mENaC or αβγ human ENaC (hENaC). Co-expression of CFTR and αβγ mENaC or hENaC resulted in an ∼3-fold increase in CFTR Cl- current compared with oocytes expressing CFTR alone. Oocytes co-injected with both CFTR and mENaC of hENaC expressed an amiloride-sensitive whole cell current that was decreased compared with that observed with the injection of mENaC or hENaC alone before CFTR activation with forskolin/3-isobutyl-1-methylxanthine. CFTR activation resulted in a further 50% decrease in mENaC-mediated currents, an ∼20% decrease in α-T663-hENaC-mediated currents, and essentially no change in α-A663-hENaC-mediated currents. Changes in ENaC functional expression correlated with ENaC surface expression by oocyte surface biotinylation experiments. Assessment of regulatory interactions between CFTR and chimeric mouse/human ENaCs suggest that the 20 C-terminal amino acid residues of α ENaC confer species specificity regarding ENaC inhibition by activated CFTR.

Original languageEnglish
Pages (from-to)23183-23192
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number22
DOIs
StatePublished - May 28 2004

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