ArticlePloS one2016
Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- Triple potentiator combinations increase the functional correction of several CFTR gating mutants.npj drug discovery · 2026Article
- Protocol for generating iPSC-derived intestinal organoids through dissection to model cystic fibrosis therapies.STAR protocols · 2026Article
- Barriers to the Pharmacologic Rescue of W1282X CFTR.Biochemistry · 2026Article
- ACE-tRNAs are a platform technology for suppressing nonsense mutations that cause cystic fibrosis.Nucleic acids research · 2025Article
- A W1282X cystic fibrosis mouse allows the study of pharmacological and gene-editing therapeutics to restore CFTR function.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2025Article
- Ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- 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
- Ribosomal Frameshifting Selectively Modulates the Assembly, Function, and Pharmacological Rescue of a Misfolded CFTR Variant.bioRxiv : the preprint server for biology · 2024Article
- Adjunctive nano-curcumin therapy improves inflammatory and clinical indices in children with cystic fibrosis: A randomized clinical trial.Food science & nutrition · 2023Article
- Antisense Oligonucleotide Therapeutics for Cystic Fibrosis: Recent Developments and Perspectives.Molecules and cells · 2023Review
- Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing.International journal of molecular sciences · 2022Article
- Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough.The Journal of clinical investigation · 2022Article
- Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy.Nature communications · 2022Article
- A medium composition containing normal resting glucose that supports differentiation of primary human airway cells.Scientific reports · 2022Article
- Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Exon-skipping antisense oligonucleotides for cystic fibrosis therapy.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Epigenome editing of the CFTR-locus for treatment of cystic fibrosis.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2022Article
- Article
- Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity.The Journal of biological chemistry · 2020Article
- G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations.American journal of physiology. Lung cellular and molecular physiology · 2020Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3-5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein.
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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.