Highlights
- •Expression and pharmacological rescue of G1244E-CFTR depend on cell background.
- •In heterologous models elexacaftor mainly acts on G1244E-CFTR as a co-potentiator.
- •In native cells, elexacaftor increases mature CFTR expression.
- •Co-potentiators are needed to improve channel activity of G1244E-CFTR.
- •Development of novel co-potentiating drugs will help rescue of G1244E-CFTR.
Abstract
Background
Cystic fibrosis is caused by mutations impairing expression, trafficking, stability
and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR)
chloride channel. The G1244E mutation causes a severe gating defect that it is not
completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator).
Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator.
Methods
By using molecular, biochemical and functional analyses we performed an in-depth characterization
of the G1244E-CFTR mutant in heterologous and native cell models.
Results
Our studies demonstrate that processing and function of the mutant protein, as well
as its pharmacological sensitivity, are markedly dependent on cell background. In
heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator,
thus ameliorating the gating defect. On the contrary, in the native nasal epithelial
cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR
expression possibly by improving mutant's defective stability at the plasma membrane.
Conclusions
Our study highlights the importance of the cell background in the evaluation of CFTR
modulator effects. Further, our results draw attention to the need for the development
of novel potentiators having different mechanisms with respect to ivacaftor to improve
channel activity for mutants with severe gating defect.
Keywords
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Article info
Publication history
Published online: December 19, 2022
Accepted:
December 13,
2022
Received in revised form:
November 23,
2022
Received:
September 8,
2022
Publication stage
In Press Corrected ProofIdentification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
