Frontiers in Pharmacology (Oct 2012)

Ouabain mimics low temperature rescue of F508del-CFTR in cystic fibrosis epithelial cells

  • Donglei eZhang,
  • Fabiana eCiciriello,
  • Suzana eAnjos,
  • Annamaria eCarissimo,
  • Jie eLiao,
  • Graeme eCarlile,
  • Haouaria eBalghi,
  • Renaud eRobert,
  • Alberto eLuini,
  • John eHanrahan,
  • David eThomas

DOI
https://doi.org/10.3389/fphar.2012.00176
Journal volume & issue
Vol. 3

Abstract

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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 transcriptional profiles obtained with polarized CFBE41o- cells after treatment with ouabain and by low temperature 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 analogues in the regulation of F508del-CFTR trafficking and suggests that compounds that mimic this low temperature correction of trafficking will provide new avenues for the development of therapeutics for CF.

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