Ouabain mimics low temperature rescue of f508del-CFTR in cystic fibrosis epithelial cells

Donglei Zhang*, Fabiana Ciciriello, Suzana M. Anjos, Annamaria Carissimo, Jie Liao, Graeme W. Carlile, Haouaria Balghi, Renaud Robert, Alberto Luini, John W. Hanrahan, David Y. Thomas

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Most cases of cystic fibrosis (CF) are caused by the deletion of a single phenylalanine residue at position 508 of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutant F508del-CFTR is retained in the endoplasmic reticulum and degraded, but can be induced by low temperature incubation (29°C) to traffic to the plasma membrane where it functions as a chloride channel. Here we show that, cardiac glycosides, at nanomolar concentrations, can partially correct the trafficking of F508del-CFTR in human CF bronchial epithelial cells (CFBE41o-) and in an F508del-CFTR mouse model. Comparison of the tran-scriptional profiles obtained with polarized CFBE41o-cells after treatment with ouabain and by lowtemperature has revealed a striking similarity between the two corrector treatments that is not shared with other correctors. In summary, our study shows a novel function of ouabain and its analogs in the regulation of F508del-CFTR trafficking and suggests that com-pounds that mimic this low temperature correction of trafficking will provide new avenues for the development of therapeutics for CF.

Original languageEnglish (US)
Article numberArticle 176
JournalFrontiers in Pharmacology
Volume3 OCT
DOIs
StatePublished - 2012

Keywords

  • CFBE cells
  • Cftr
  • Connectivity map
  • Cystic fibrosis
  • Hierarchical clustering
  • Microarray
  • Quabain
  • Trafficking

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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