ArticleThe Journal of biological chemistry2012
Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 151 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
151 citing papers in PubMed, 1 synthesis or guideline pooled it, 306 citations in OpenAlex.
- Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype.Clinical pharmacology and therapeutics · 2014Guideline
- Sweat rate analysis of ivacaftor potentiation of CFTR in non-CF adults.Scientific reports · 2018Trial
- Quantitative imaging of airway liquid absorption in cystic fibrosis.The European respiratory journal · 2014Trial
- Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study.Pediatric diabetes · 2013Trial
- Anti-inflammatory and phosphorylation effects of CFTR modulator triple therapy in cystic fibrosis.iScience · 2026Article
- Functional Rescue of CFTR-Dependent Transport in a Pancreatic Ductal Epithelial Cell Model: The Impact of Pharmacological Modulation and Inflammation.International journal of molecular sciences · 2026Article
- Targeting PI3Kγ anchoring enhances CFTR membrane localization and modulator efficacy via PKD1.JCI insight · 2026Article
- Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causingProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Effects of cAMP and CFTR modulation on apical fluid pH in human airway Calu-3 cells.Physiological reports · 2026Article
- In vivo conformational space and defects of misfolded CFTR variants by covalent protein painting.Nature communications · 2025Article
- Genetically engineered approaches to the treatment of cystic fibrosis.Biophysical reviews · 2025Review
- The potentiator ivacaftor is essential for pharmacological restoration of F508del-CFTR function and mucociliary clearance in cystic fibrosis.JCI insight · 2025Article
- Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators.Molecular and cellular pediatrics · 2025Review
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- Functional Characterization of Ion Channels in Planar Lipid Bilayers.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Rescue of Mutant CFTR Channel Activity by Investigational Co-Potentiator Therapy.Biomedicines · 2025Article
- Article
- Novel gain-of-function mutants identify a critical region within CFTR membrane-spanning domain 2 controlling cAMP-dependent and ATP-independent channel activation.Cellular and molecular life sciences : CMLS · 2024Article
- Association between biomarkers of tobacco smoke exposure and clinical efficacy of ivacaftor in the G551D observational trial (GOAL).Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2024Observational
- Cystic fibrosis.Nature reviews. Disease primers · 2024Review
91 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) acts as a channel on the apical membrane of epithelia. Disease-causing mutations in the cystic fibrosis gene can lead to CFTR protein misfolding as in the case of the F508del mutation and/or channel dysfunction. Recently, a small molecule, VX-770 (ivacaftor), has shown efficacy in restoring lung function in patients bearing the G551D mutation, and this has been linked to repair of its channel gating defect. However, these studies did not reveal the mechanism of action of VX-770 in detail. Normally, CFTR channel activity is regulated by phosphorylation, ATP binding, and hydrolysis. Hence, it has been hypothesized that VX-770 modifies one or more of these metabolic events. In this study, we examined VX-770 activity using a reconstitution system for purified CFTR protein, a system that enables control of known regulatory factors. We studied the consequences of VX-770 interaction with CFTR incorporated in planar lipid bilayers and in proteoliposomes, using a novel flux-based assay. We found that purified and phosphorylated CFTR was potentiated in the presence of Mg-ATP, suggesting that VX-770 bound directly to the CFTR protein, rather than associated kinases or phosphatases. Interestingly, we also found that VX-770 enhanced the channel activity of purified and mutant CFTR in the nominal absence of Mg-ATP. These findings suggest that VX-770 can cause CFTR channel opening through a nonconventional ATP-independent mechanism. This work sets the stage for future studies of the structural properties that mediate CFTR gating using VX-770 as a probe.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.