ArticleAmerican journal of physiology. Lung cellular and molecular physiology2016
Positioning of extracellular loop 1 affects pore gating of the cystic fibrosis transmembrane conductance regulator.
Article in American journal of physiology. Lung cellular and molecular physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed.
- 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
- Article
- Tweaking the catalytic efficiency of the CFTR ion channel.The Journal of general physiology · 2023Article
- Optimization of CFTR gating through the evolution of its extracellular loops.The Journal of general physiology · 2023Article
- Permissive and nonpermissive channel closings in CFTR revealed by a factor graph inference algorithm.Biophysical reports · 2022Article
- The molecular evolution of function in the CFTR chloride channel.The Journal of general physiology · 2021Article
- Electrophysiological Approaches for the Study of Ion Channel Function.Methods in molecular biology (Clifton, N.J.) · 2021Article
- An Ancient CFTR Ortholog Informs Molecular Evolution in ABC Transporters.Developmental cell · 2019Article
- Ion channels of the lung and their role in disease pathogenesis.American journal of physiology. Lung cellular and molecular physiology · 2017Review
- Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae.American journal of physiology. Lung cellular and molecular physiology · 2017Review
- Altering intracellular pH reveals the kinetic basis of intraburst gating in the CFTR ClThe Journal of physiology · 2017Article
- Architecture and functional properties of the CFTR channel pore.Cellular and molecular life sciences : CMLS · 2017Review
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
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Authors and funding
4 authors.
Funding
Abstract
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a chloride ion channel, the dysfunction of which directly leads to the life-shortening disease CF. Extracellular loop 1 (ECL1) of CFTR contains several residues involved in stabilizing the open state of the channel; some, including D110, are sites of disease-associated gating mutations. Structures from related proteins suggest that the position of CFTR's extracellular loops may change considerably during gating. To better understand the roles of ECL1 in CFTR function, we utilized functional cysteine cross-linking to determine the effects of modulation of D110C-CFTR and of a double mutant of D110C with K892C in extracellular loop 4 (ECL4). The reducing agent DTT elicited a large potentiation of the macroscopic conductance of D110C/K892C-CFTR, likely due to breakage of a spontaneous disulfide bond between C110 and C892. DTT-reduced D110C/K892C-CFTR was rapidly inhibited by binding cadmium ions with high affinity, suggesting that these residues frequently come in close proximity in actively gating channels. Effects of DTT and cadmium on modulation of pore gating were demonstrated at the single-channel level. Finally, disulfided D110C/K892C-CFTR channels were found to be less sensitive than wild-type or DTT-treated D110C/K892C-CFTR channels to stimulation by IBMX, suggesting an impact of this conformational restriction on channel activation by phosphorylation. The results are best explained in the context of a model of CFTR gating wherein stable channel opening requires correct positioning of functional elements structurally influenced by ECL1.
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