Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells

Am J Physiol Lung Cell Mol Physiol. 2014 Jul 1;307(1):L48-61. doi: 10.1152/ajplung.00305.2013. Epub 2014 May 9.


Cystic fibrosis transmembrane conductance regulator (CFTR) carrying the F508del mutation is retained in endoplasmic reticulum and fails to traffic to the cell surface where it functions as a protein kinase A (PKA)-activated chloride channel. Pharmacological correctors that rescue the trafficking of F508del CFTR may overcome this defect; however, the rescued F508del CFTR still displays reduced chloride permeability. Therefore, a combined administration of correctors and potentiators of the gating defect is ideal. We recently found that 4,6,4'-trimethylangelicin (TMA), besides inhibiting the expression of the IL-8 gene in airway cells in which the inflammatory response was challenged with Pseudomonas aeruginosa, also potentiates the cAMP/PKA-dependent activation of wild-type CFTR or F508del CFTR that has been restored to the plasma membrane. Here, we demonstrate that long preincubation with nanomolar concentrations of TMA is able to effectively rescue both F508del CFTR-dependent chloride secretion and F508del CFTR cell surface expression in both primary or secondary airway cell monolayers homozygous for F508del mutation. The correction effect of TMA seems to be selective for CFTR and persisted for 24 h after washout. Altogether, the results suggest that TMA, besides its anti-inflammatory and potentiator activities, also displays corrector properties.

Keywords: F508del cystic fibrosis transmembrane conductance regulator corrector; F508del cystic fibrosis transmembrane conductance regulator rescue; chloride transport; cystic fibrosis.

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Chlorides / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Endoplasmic Reticulum / metabolism
  • Furocoumarins / pharmacology*
  • Furocoumarins / therapeutic use
  • HEK293 Cells
  • Humans
  • Lung / pathology
  • Protein Transport / genetics
  • Rats


  • CFTR protein, human
  • Chlorides
  • Furocoumarins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Cyclic AMP-Dependent Protein Kinases
  • 4,4',6-trimethylangelicin