Potentiation of the cystic fibrosis transmembrane conductance regulator Cl- channel by ivacaftor is temperature-independent

Caroline Wang, Zhiwei Cai, Martin Gosling, David Sheppard

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
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Ivacaftor is the first drug to target directly defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which cause cystic fibrosis (CF). To understand better how ivacaftor potentiates CFTR channel gating, here we investigated the effects of temperature on its action. As a control, we studied the benzimidazolone UCCF-853, which potentiates CFTR by a different mechanism. Using the patch-clamp technique and cells expressing recombinant CFTR, we studied the single-channel behavior of wild-type and F508del-CFTR, the most 37 common CF mutation. Raising the temperature of the intracellular solution from 23 to 37 °C increased the frequency, but reduced the duration of wild-type and F508del-CFTR channel openings. While the open probability (Po) of wild-type CFTR increased progressively as temperature was elevated, the relationship between Po and temperature for F508del-CFTR was bell-shaped with a maximum Po at ~30 °C. For wild-type CFTR and, to a greatly reduced extent, F508del-CFTR, the temperature-dependence of channel gating was asymmetric with the opening rate demonstrating greater temperature sensitivity than the closing rate. At all
temperatures tested, ivacaftor and UCCF-853 potentiated wild-type and F508del-CFTR. Strikingly, ivacaftor, but not UCCF-853, abolished the asymmetric temperature-dependence of CFTR channel gating. At all temperatures tested, Po values of wild-type CFTR in the presence of ivacaftor were approximately double those of F508del-CFTR, which were equivalent to or greater than those of wild-type CFTR at 37 °C in the absence of the drug. We conclude that the principal effect of ivacaftor is to promote channel opening to abolish the temperature-dependence of CFTR channel gating.
Original languageEnglish
Pages (from-to)846-857
Number of pages12
JournalAJP - Lung Cellular and Molecular Physiology
Issue number5
Early online date23 Aug 2018
Publication statusPublished - 7 Nov 2018


  • CFTR chloride ion channel
  • cystic fibrosis
  • F508del-CFTR
  • CFTR potentiation
  • ivacaftor (VX-770)

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