ArticleThe Journal of general physiology2002
Probing an open CFTR pore with organic anion blockers.
Article in The Journal of general physiology, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 65 citations in OpenAlex.
- Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.Nature communications · 2024Article
- Structural identification of a selectivity filter in CFTR.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Sharing genetic variants with the NGS pipeline is essential for effective genomic data sharing and reproducibility in health information exchange.Scientific reports · 2021Article
- Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.FEBS letters · 2020Review
- Structure of Transmembrane Helix 8 and Possible Membrane Defects in CFTR.Biophysical journal · 2018Article
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- CFTR pharmacology.Cellular and molecular life sciences : CMLS · 2017Review
- Spatial positioning of CFTR's pore-lining residues affirms an asymmetrical contribution of transmembrane segments to the anion permeation pathway.The Journal of general physiology · 2016Article
- The Fifth Transmembrane Segment of Cystic Fibrosis Transmembrane Conductance Regulator Contributes to Its Anion Permeation Pathway.Biochemistry · 2015Article
- Relative contribution of different transmembrane segments to the CFTR chloride channel pore.Pflugers Archiv : European journal of physiology · 2014Article
- Cystic fibrosis transmembrane conductance regulator chloride channel blockers: Pharmacological, biophysical and physiological relevance.World journal of biological chemistry · 2014Review
- Loop diuretics are open-channel blockers of the cystic fibrosis transmembrane conductance regulator with distinct kinetics.British journal of pharmacology · 2014Article
- The CFTR ion channel: gating, regulation, and anion permeation.Cold Spring Harbor perspectives in medicine · 2013Article
- Locating a plausible binding site for an open-channel blocker, GlyH-101, in the pore of the cystic fibrosis transmembrane conductance regulator.Molecular pharmacology · 2012Article
- Differential contribution of TM6 and TM12 to the pore of CFTR identified by three sulfonylurea-based blockers.Pflugers Archiv : European journal of physiology · 2012Article
- Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101.American journal of physiology. Cell physiology · 2012Article
- Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7).The Journal of general physiology · 2011Article
- ATP hydrolysis-dependent asymmetry of the conformation of CFTR channel pore.The journal of physiological sciences : JPS · 2011Article
- Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants.Methods in molecular biology (Clifton, N.J.) · 2011Article
- On the mechanism of CFTR inhibition by a thiazolidinone derivative.The Journal of general physiology · 2010Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts Cl- current. We explored the CFTR pore by studying voltage-dependent blockade of the channel by two organic anions: glibenclamide and isethionate. To simplify the kinetic analysis, a CFTR mutant, K1250A-CFTR, was used because this mutant channel, once opened, can remain open for minutes. Dose-response relationships of both blockers follow a simple Michaelis-Menten function with K(d) values that differ by three orders of magnitude. Glibenclamide blocks CFTR from the intracellular side of the membrane with slow kinetics. Both the on and off rates of glibenclamide block are voltage dependent. Removing external Cl- increases affinity of glibenclamide due to a decrease of the off rate and an increase of the on rate, suggesting the presence of a Cl- binding site external to the glibenclamide binding site. Isethionate blocks the channel from the cytoplasmic side with fast kinetics, but has no measurable effect when applied extracellularly. Increasing the internal Cl- concentration reduces isethionate block without affecting its voltage dependence, suggesting that Cl- and isethionate compete for a binding site in the pore. The voltage dependence and external Cl- concentration dependence of isethionate block are nearly identical to those of glibenclamide block, suggesting that these two blockers may bind to a common binding site, an idea further supported by kinetic studies of blocking with glibenclamide/isethionate mixtures. By comparing the physical and chemical natures of these two blockers, we propose that CFTR channel has an asymmetric pore with a wide internal entrance and a deeply embedded blocker binding site where local charges as well as hydrophobic components determine the affinity of the blockers.
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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.