Related Experiment Video
Updated: Jan 10, 2026
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
12.6K
CFTR correctors potentiate gating mutants causing cystic fibrosis
Solène Castanier1, Ahmad Elbahnsi2, Benoit Chevalier1
1Université Paris Cité, INSERM U1151, CNRS UMR8253, Institut Necker Enfants Malades F-75015 Paris, France.
Summary
The CFTR modulator VX-445 (Elexacaftor) enhances channel activity in cystic fibrosis gating mutants. Its potentiator effect depends on the binding site integrity, but other correctors also show this capability.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators like VX-445 (Elexacaftor) are crucial for cystic fibrosis (CF) treatment.
- VX-445 exhibits both corrector and potentiator activities by binding to the CFTR protein.
- Previous studies linked VX-445 corrector activity to mutations in MSD1 and NBD1.
Purpose of the Study:
- To investigate whether mutations affecting VX-445's corrector activity also impact its potentiator function.
- To determine the relationship between VX-445 binding site integrity and its potentiator effects on CFTR gating mutants.
Main Methods:
- HEK293 cells were transfected with CFTR mutants.
- Halide-sensitive fluorescent assays measured responses to varying VX-445 concentrations.
- Mutations within and outside the VX-445 binding site were analyzed.
Main Results:
- VX-445 potentiated gating mutants in NBDs (G551D, G1349D) and ICLs (G178R, G970R).
- Mutations in the VX-445 binding site reduced potentiation of G551D.
- Mutations outside the binding site affected corrector activity, with M212A and F224A inducing CFTR gain-of-function.
- VX-809 and VX-121 also potentiated G551D.
Conclusions:
- VX-445 promotes channel activity in CFTR gating mutants, contingent on its binding site's structural integrity.
- CFTR correctors, including VX-809 and VX-121, can generally enhance channel activity of gating mutants.
Related Concept Videos
01:23Cystic Fibrosis: Pathogenesis
687
Cystic fibrosis (CF), an autosomal recessive disorder, significantly affects the function of exocrine glands. This genetically inherited disease is characterized by the production of thick and sticky mucus, which can severely affect various organs and systems in the body.
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
687
01:24Cystic Fibrosis: Management
456
Cystic fibrosis (CF) is an autosomal recessive disorder that predominantly affects individuals of Northern European descent, occurring at a rate of 1 in 3500. It is caused by a genetic mutation in a gene on chromosome 7, most commonly the ΔF508 mutation, that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This results in thicker mucus secretions and obstruction pathologies in multiple organs, including the lungs and sinuses.
Sinus disease and chronic...
Sinus disease and chronic...
456
01:09GPCRs Regulate Adenylyl Cylase Activity
7.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.3K
02:46Genome Copying Errors
5.0K
DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their survival. Therefore, the copying errors are checked and repaired at three levels.
5.0K
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
3.7K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
3.7K
01:39Mutations
94.3K
Overview
94.3K