ArticleAmerican journal of physiology. Lung cellular and molecular physiology2011
Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators.
Article in American journal of physiology. Lung cellular and molecular physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Article
- Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies.Advances in respiratory medicine · 2024Review
- Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants.ACS pharmacology & translational science · 2024Review
- Therapeutic Targets and Precision Medicine in COPD: Inflammation, Ion Channels, Both, or Neither?International journal of molecular sciences · 2023Review
- Nicotine aerosols diminish airway CFTR function and mucociliary clearance.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR.British journal of pharmacology · 2022Article
- Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation.Frontiers in physiology · 2021Review
- Evaluation of secondhand smoke effects on CFTR function in vivo.Respiratory research · 2020Article
- Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine.Frontiers in pharmacology · 2019Review
- Article
- Potentiation of ΔF508- and G551D-CFTR-Mediated Cl- Current by Novel Hydroxypyrazolines.PloS one · 2016Article
- Resveratrol ameliorates abnormalities of fluid and electrolyte secretion in a hypoxia-Induced model of acquired CFTR deficiency.The Laryngoscope · 2015Article
- CFTR and lung homeostasis.American journal of physiology. Lung cellular and molecular physiology · 2014Review
- S-palmitoylation regulates biogenesis of core glycosylated wild-type and F508del CFTR in a post-ER compartment.The Biochemical journal · 2014Article
- Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor.American journal of respiratory cell and molecular biology · 2014Article
- Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis.American journal of respiratory cell and molecular biology · 2014Article
- Impact of heterozygote CFTR mutations in COPD patients with chronic bronchitis.Respiratory research · 2014Article
- Comparison of cystic fibrosis transmembrane conductance regulator (CFTR) and ciliary beat frequency activation by the CFTR Modulators Genistein, VRT-532, and UCCF-152 in primary sinonasal epithelial cultures.JAMA otolaryngology-- head & neck surgery · 2013Article
- Cystic fibrosis transmembrane regulator correctors and potentiators.Cold Spring Harbor perspectives in medicine · 2013Review
- Purification of CFTR for mass spectrometry analysis: identification of palmitoylation and other post-translational modifications.Protein engineering, design & selection : PEDS · 2012Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
Modulator compounds intended to overcome disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) show significant promise in clinical testing for cystic fibrosis. However, the mechanism(s) of action underlying these compounds are not fully understood. Activation of CFTR ion transport requires PKA-regulated phosphorylation of the regulatory domain (R-D) and dimerization of the nucleotide binding domains. Using a newly developed assay, we evaluated nine compounds including both CFTR potentatiators and activators discovered via various high-throughput screening strategies to acutely augment CFTR activity. We found considerable differences in the effects on R-D phosphorylation. Some (including UC(CF)-152) stimulated robust phosphorylation, and others had little effect (e.g., VRT-532 and VX-770). We then compared CFTR activation by UC(CF)-152 and VRT-532 in Ussing chamber studies using two epithelial models, CFBE41o(-) and Fischer rat thyroid cells, expressing various CFTR forms. UC(CF)-152 activated wild-type-, G551D-, and rescued F508del-CFTR currents but did not potentiate cAMP-mediated CFTR activation. In contrast, VRT-532 moderately activated CFTR short-circuit current and strongly potentiated forskolin-mediated current. Combined with the result that UC(CF)-152, but not VRT-532 or VX-770, acts by increasing CFTR R-D phosphorylation, these findings indicate that potentiation of endogenous cAMP-mediated activation of mutant CFTR is not due to a pathway involving augmented R-D phosphorylation. This study presents an assay useful to distinguish preclinical compounds by a crucial mechanism underlying CFTR activation, delineates two types of compound able to acutely augment CFTR activity (e.g., activators and potentiators), and demonstrates that a number of different mechanisms can be successfully employed to activate mutant CFTR.
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Registered trials
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