Cystic fibrosis transmembrane conductance regulator inhibits epithelial Na+ channels carrying Liddle's syndrome mutations
- PMID: 10318798
- DOI: 10.1074/jbc.274.20.13894
Cystic fibrosis transmembrane conductance regulator inhibits epithelial Na+ channels carrying Liddle's syndrome mutations
Abstract
Epithelial Na+ channels (ENaC) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) upon activation by protein kinase A. It is, however, still unclear how CFTR regulates the activity of ENaC. In the present study we examined whether CFTR interacts with ENaC by interfering with the Nedd4- and ubiquitin-mediated endocytosis of ENaC. Various C-terminal mutations were introduced into the three alpha-, beta-, and gamma-subunits of the rat epithelial Na+ channel, thereby eliminating PY motifs, which are important binding domains for the ubiquitin ligase Nedd4. When expressed in Xenopus oocytes, most of the ENaC stop (alpha-H647X, beta-P565X, gamma-S608X) or point (alpha-P671A, beta-Y618A, gamma-P(624-626)A) mutations induced enhanced Na+ currents when compared with wild type alpha,beta,gamma-rENaC. However, ENaC currents formed by either of the mutant alpha-, beta-, or gamma-subunits were inhibited during activation of CFTR by forskolin (10 micromol/l) and 3-isobutyl-1-methylxanthine (1 mmol/l). Antibodies to dynamin or ubiquitin enhanced alpha,beta,gamma-rENaC whole cell Na+ conductance but did not interfere with inhibition of ENaC by CFTR. Another mutant, beta-T592M,T593A-ENaC, also showed enhanced Na+ currents, which were down-regulated by CFTR. Moreover, activation of ENaC by extracellular proteases and xCAP1 does not disturb CFTR-dependent inhibition of ENaC. We conclude that regulation of ENaC by CFTR is distal to other regulatory limbs and does not involve Nedd4-dependent ubiquitination.
Similar articles
-
Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome.J Clin Invest. 1999 Mar;103(5):667-73. doi: 10.1172/JCI5713. J Clin Invest. 1999. PMID: 10074483 Free PMC article.
-
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.J Physiol. 1998 May 1;508 ( Pt 3)(Pt 3):825-36. doi: 10.1111/j.1469-7793.1998.825bp.x. J Physiol. 1998. PMID: 9518736 Free PMC article.
-
Inhibition of the epithelial Na+ channel by interaction of Nedd4 with a PY motif deleted in Liddle's syndrome.J Biol Chem. 1998 Nov 6;273(45):30012-7. doi: 10.1074/jbc.273.45.30012. J Biol Chem. 1998. PMID: 9792722
-
Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.Kidney Int. 2000 Mar;57(3):809-15. doi: 10.1046/j.1523-1755.2000.00919.x. Kidney Int. 2000. PMID: 10720933 Review.
-
Patch-clamp studies on epithelial sodium channels in salivary duct cells.Cell Biochem Biophys. 2002;36(2-3):105-13. doi: 10.1385/cbb:36:2-3:105. Cell Biochem Biophys. 2002. PMID: 12139396 Review.
Cited by
-
Proteases, cystic fibrosis and the epithelial sodium channel (ENaC).Cell Tissue Res. 2013 Feb;351(2):309-23. doi: 10.1007/s00441-012-1439-z. Epub 2012 May 22. Cell Tissue Res. 2013. PMID: 22729487 Free PMC article. Review.
-
Vasopressin-stimulated CFTR Cl- currents are increased in the renal collecting duct cells of a mouse model of Liddle's syndrome.J Physiol. 2005 Jan 1;562(Pt 1):271-84. doi: 10.1113/jphysiol.2004.077933. Epub 2004 Oct 28. J Physiol. 2005. PMID: 15513933 Free PMC article.
-
Regulation of endogenous ENaC functional expression by CFTR and ΔF508-CFTR in airway epithelial cells.Am J Physiol Lung Cell Mol Physiol. 2011 Jan;300(1):L88-L101. doi: 10.1152/ajplung.00142.2010. Epub 2010 Oct 8. Am J Physiol Lung Cell Mol Physiol. 2011. PMID: 20935229 Free PMC article.
-
Targeted therapy for cystic fibrosis: cystic fibrosis transmembrane conductance regulator mutation-specific pharmacologic strategies.Mol Diagn Ther. 2006;10(5):293-301. doi: 10.1007/BF03256204. Mol Diagn Ther. 2006. PMID: 17022692 Review.
-
Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaENaC-overexpressing mice.J Biol Chem. 2010 Aug 27;285(35):26945-26955. doi: 10.1074/jbc.M110.151803. Epub 2010 Jun 21. J Biol Chem. 2010. PMID: 20566636 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical