Ion channel regulators for the treatment of cystic fibrosis

Therapy ◽  
2011 ◽  
Vol 8 (6) ◽  
pp. 661-670 ◽  
Author(s):  
Christiane De Boeck ◽  
Harry Cuppens
Keyword(s):  
Cystic Fibrosis ◽  
Ion Channel

Glutathione permeability of CFTR

1998 ◽  
Vol 275 (1) ◽  
pp. C323-C326 ◽  
Author(s):  
Paul Linsdell ◽  
John W. Hanrahan
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Ion Channel ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Transmembrane Conductance ◽  
High Concentrations ◽  
Cystic Fibrosis Transmembrane ◽  
Glutathione Transport

The cystic fibrosis transmembrane conductance regulator (CFTR) forms an ion channel that is permeable both to Cl− and to larger organic anions. Here we show, using macroscopic current recording from excised membrane patches, that the anionic antioxidant tripeptide glutathione is permeant in the CFTR channel. This permeability may account for the high concentrations of glutathione that have been measured in the surface fluid that coats airway epithelial cells. Furthermore, loss of this pathway for glutathione transport may contribute to the reduced levels of glutathione observed in airway surface fluid of cystic fibrosis patients, which has been suggested to contribute to the oxidative stress observed in the lung in cystic fibrosis. We suggest that release of glutathione into airway surface fluid may be a novel function of CFTR.

Altered chloride ion channel kinetics associated with the ΔF508 cystic fibrosis mutation

Nature ◽  
1991 ◽  
Vol 354 (6354) ◽  
pp. 526-528 ◽  
Author(s):  
Wilfried Dalemans ◽  
Pascal Barbry ◽  
Guy Champigny ◽  
Sophie Jallat ◽  
Sophie Jallat ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ion Channel ◽  
Chloride Ion ◽  
Channel Kinetics ◽  
Cystic Fibrosis Mutation ◽  
Ion Channel Kinetics

scholarly journals Defective Ion Channel in Cystic Fibrosis: Current Development in Treatment of Cystic Fibrosis

2020 ◽  
pp. 28-34
Author(s):  
Ngoga Godfrey ◽  
M. M. Ganyam ◽  
G.O. Ibiang ◽  
C. A. Difa ◽  
Nelson Christian
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Ion Channel ◽  
Lung Disease ◽  
Defense Mechanisms ◽  
Respiratory Infections ◽  
The Body ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Airway Defense

Cystic fibrosis is an inherited disorder that causes severe damage to the lungs, digestive system and other organs in the body. Cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the production of mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with cystic fibrosis, a defective gene in CFTR causes the secretions to become sticky and thick. Instead of acting as a lubricant, the secretions plug up tubes, ducts and passage ways, especially in the lungs and pancreas. This mucus leads to the formation of bacterial microenvironments known as biofilms (a niche that harbors bacteria; Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa ) that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. CFTR, a Cl– selective ion channel, is a prototypic member of the ATP-binding cassette transporter super family that is expressed in several organs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases associated to it. Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport, disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. New therapies are currently in development that target the ion transport defects in CF with the intention of rehydrating airway surfaces.

scholarly journals Can two wrongs make a right? F508del-CFTR ion channel rescue by second-site mutations in its transmembrane domains

2021 ◽  
Author(s):  
Stella Prins ◽  
Valentina Corradi ◽  
David N. Sheppard ◽  
D. Peter Tieleman ◽  
Paola Vergani
Keyword(s):  
Cystic Fibrosis ◽  
Hydrogen Bonds ◽  
Ion Channel ◽  
Hydrophobic Interactions ◽  
Anion Channel ◽  
Transmembrane Helices ◽  
Aromatic Rings ◽  
Intracellular Loop ◽  
Dynamic Interface ◽  
Dynamics Simulations

AbstractDeletion of phenylalanine 508 (F508del), in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, is the most common cause of cystic fibrosis (CF). F508 is located on nucleotide-binding domain 1 (NBD1) in contact with cytosolic extensions of transmembrane helices, in particular intracellular loop 4 (ICL4). We carried out a mutagenesis scan of ICL4 by introducing five or six second-site mutations at eleven positions in cis with F508del, and quantifying changes in membrane proximity and ion-channel function of CFTR. The scan strongly validated the effectiveness of R1070W at rescuing F508del defects. Molecular dynamics simulations highlighted two features characterizing the ICL4/NBD1 interface of F508del/R1070W-CFTR: flexibility, with frequent transient formation of interdomain hydrogen bonds, and loosely stacked aromatic sidechains, (F1068, R1070W, and F1074, mimicking F1068, F508 and F1074 in wild-type CFTR). F508del-CFTR had a distorted aromatic stack, with F1068 displaced towards space vacated by F508. In F508del/R1070F-CFTR, which largely retained F508del defects, R1070F could not form hydrogen bonds, and the interface was less flexible. Other ICL4 second-site mutations which partially rescued F508del-CFTR are F1068M and F1074M. Methionine side chains allow hydrophobic interactions without the steric rigidity of aromatic rings, possibly conferring flexibility to accommodate the absence of F508 and retain a dynamic interface. Finally, two mutations identified in a yeast scan (A141S and R1097T, on adjacent transmembrane helices linked to ICL1 and ICL4) also partially rescued F508del-CFTR function. These studies highlight the importance of hydrophobic interactions and conformational flexibility at the ICL4/NBD1 interface, advancing understanding of the structural underpinning of F508del dysfunction.

scholarly journals Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity

2020 ◽  
Vol 295 (49) ◽  
pp. 16529-16544 ◽  
Author(s):  
Stella Prins ◽  
Emily Langron ◽  
Cato Hastings ◽  
Emily J. Hill ◽  
Andra C. Stefan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Ion Channel ◽  
Molecular Mechanisms ◽  
Anion Channel ◽  
Fluorescence Assay ◽  
Fluid Loss ◽  
Published Data ◽  
Channel Function ◽  
Drug Classes

The cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane anion channel that plays a key role in controlling transepithelial fluid movement. Excessive activation results in intestinal fluid loss during secretory diarrheas, whereas CFTR mutations underlie cystic fibrosis (CF). Anion permeability depends both on how well CFTR channels work (permeation/gating) and on how many are present at the membrane. Recently, treatments with two drug classes targeting CFTR—one boosting ion-channel function (potentiators) and the other increasing plasma membrane density (correctors)—have provided significant health benefits to CF patients. Here, we present an image-based fluorescence assay that can rapidly and simultaneously estimate both CFTR ion-channel function and the protein's proximity to the membrane. We monitor F508del-CFTR, the most common CF-causing variant, and confirm rescue by low temperature, CFTR-targeting drugs and second-site revertant mutation R1070W. In addition, we characterize a panel of 62 CF-causing mutations. Our measurements correlate well with published data (electrophysiology and biochemistry), further confirming validity of the assay. Finally, we profile effects of acute treatment with approved potentiator drug VX-770 on the rare-mutation panel. Mapping the potentiation profile on CFTR structures raises mechanistic hypotheses on drug action, suggesting that VX-770 might allow an open-channel conformation with an alternative arrangement of domain interfaces. The assay is a valuable tool for investigation of CFTR molecular mechanisms, allowing accurate inferences on gating/permeation. In addition, by providing a two-dimensional characterization of the CFTR protein, it could better inform development of single-drug and precision therapies addressing the root cause of CF disease.

The Molecular Physiology of Cystic Fibrosis

Physiology ◽  
1993 ◽  
Vol 8 (3) ◽  
pp. 117-120 ◽  
Author(s):  
RA Frizzell
Keyword(s):  
Cystic Fibrosis ◽  
Ion Channel ◽  
Disease Mechanism ◽  
Molecular Physiology ◽  
Channel Function ◽  
New Concepts

In the last 10 years, research into the causes of cystic fibrosis has brought forth many exciting discoveries and new concepts of ion channel function and disease mechanism. It has also provided a paradigm for productive collaborations between physiologists and molecular biologists.

scholarly journals Identification of an ion channel-forming motif in the primary structure of CFTR, the cystic fibrosis chloride channel.

1994 ◽  
Vol 91 (4) ◽  
pp. 1495-1499 ◽  
Author(s):  
M. Oblatt-Montal ◽  
G. L. Reddy ◽  
T. Iwamoto ◽  
J. M. Tomich ◽  
M. Montal
Keyword(s):  
Cystic Fibrosis ◽  
Ion Channel ◽  
Primary Structure ◽  
Chloride Channel

scholarly journals The role of cystic fibrosis transmembrane conductance regulator phenylalanine 508 side chain in ion channel gating

2006 ◽  
Vol 572 (2) ◽  
pp. 347-358 ◽  
Author(s):  
Liying Cui ◽  
Luba Aleksandrov ◽  
Yue-Xian Hou ◽  
Martina Gentzsch ◽  
Jey-Hsin Chen ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ion Channel ◽  
Channel Gating ◽  
Side Chain ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ion Channel Gating ◽  
Cystic Fibrosis Transmembrane
Sign in / Sign up

Export Citation Format

Share Document