Affinage

CFTR

Cystic fibrosis transmembrane conductance regulator · UniProt P13569

Length
1480 aa
Mass
168.1 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFTR is a PKA-phosphorylated, ATP-gated anion channel that provides the cAMP-regulated chloride conductance of epithelial apical membranes, and its loss causes salt/water hyperabsorption that impairs mucociliary clearance (PMID:9922383). Gating couples R-domain phosphorylation to ATP binding and hydrolysis at two nucleotide-binding domains, of which only the second is hydrolytic; phosphorylation licenses transduction of the nucleotide-binding allosteric signal to the gate, while hydrolysis clears the ligand-binding site to enable a new gating cycle rather than driving opening or closing transitions (PMID:17021796). The channel gate maps to TM6 residues 337–344 coincident with the selectivity filter, and the permeation pathway alternates access — inwardly facing when open, outwardly facing when closed — with the first membrane-spanning domain (TM1–6) setting anion selectivity and conductance (PMID:25675504, PMID:22303012, PMID:8810276). Beyond ATP-driven gating, CFTR is intrinsically mechanosensitive, activated by membrane stretch independent of cytosolic factors (PMID:20400957), and conducts bicarbonate under WNK1 control (PMID:31561038). Channel activity is pharmacologically potentiated by ivacaftor (VX-770) and GLPG1837, which raise open probability by binding the open state at a common site independent of NBD dimerization and hydrolysis, mechanistically paralleling potentiation by permeant anions such as nitrate (PMID:19846789, PMID:25512598, PMID:29079713). CFTR abundance and surface residency are set by a balance of trafficking and degradation regulators: COMMD1 protects it from ubiquitination (PMID:21483833), syntaxin 1A and WNK kinases suppress surface activity (PMID:17194447, PMID:11845306), and the disease-causing F508del mutant misfolds in the ER and is targeted for proteasomal and lysosomal degradation through Hsp70/DNAJA2/calnexin and the E3 ligase CHIP — the central molecular lesion in cystic fibrosis (PMID:9922380, PMID:15126691, PMID:31408507). CFTR functions in compartments and cell types beyond apical epithelia, acting as an endosomal Cl- channel (PMID:7508186), cooperating functionally with TMEM16A and Ca2+/cAMP signaling machinery (PMID:28963502, PMID:29331508), supporting neutrophil phagosomal HOCl production (PMID:27406994), and maintaining endothelial barrier integrity via a CFTR→WNK1→TRPV4 pathway (PMID:36475904).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 Medium

    Established that CFTR function is not confined to the plasma membrane but operates as a cAMP-regulated Cl- channel in endosomes, broadening its cellular role to organellar ion homeostasis.

    Evidence Quantitative endosomal pH/Cl- conductance fluorescence imaging in CFTR-expressing vs. mock fibroblasts

    PMID:7508186

    Open questions at the time
    • Functional consequence of endosomal Cl- conductance for trafficking/acidification not resolved
    • Whether endosomal pool is the same channel population as apical CFTR unaddressed
  2. 1996 High

    Mapped which structural region of CFTR encodes its permeation properties, localizing anion selectivity and conductance to the first membrane-spanning domain.

    Evidence Human-Xenopus chimeric CFTR with TM1-6/TM7-12 swaps and extracellular-loop mutagenesis, patch-clamp in HeLa cells

    PMID:8810276

    Open questions at the time
    • Did not resolve atomic pore architecture
    • Did not identify the gate position within the pathway
  3. 1999 High

    Defined CFTR as the cAMP-regulated chloride conductance whose loss drives the airway surface liquid defect, linking the molecular channel to cystic fibrosis pathophysiology.

    Evidence Electrophysiology and airway surface liquid measurements in CF vs. non-CF epithelia (review synthesis)

    PMID:9922383

    Open questions at the time
    • Does not address gating mechanism
    • Relative contribution of ENaC hyperabsorption vs. CFTR loss debated
  4. 1999 High

    Identified the molecular fate of the most common disease mutation, showing F508del-CFTR misfolds and is degraded rather than mistargeted, defining the ER quality-control lesion in CF.

    Evidence Pulse-chase labeling, proteasome inhibition, ubiquitination assays (review of biochemical processing)

    PMID:9922380

    Open questions at the time
    • Specific chaperones and E3 ligases not yet enumerated here
    • Lysosomal vs. proteasomal partition not distinguished
  5. 2001 Medium

    Established the kinase/phosphatase logic of CFTR regulation, identifying PKA as activator, PKC as enhancer, and a membrane PP2C that forms a stable complex to terminate signaling.

    Evidence Patch-clamp plus co-IP, chemical cross-linking, and pull-down assays

    PMID:11845311

    Open questions at the time
    • Single-lab biochemistry
    • Stoichiometry and structural basis of CFTR-PP2C complex unknown
  6. 2001 Medium

    Showed that trafficking partners gate CFTR surface availability, with syntaxin 1A binding CFTR and isoform-specifically reducing its plasma membrane delivery and currents.

    Evidence Patch-clamp, membrane capacitance, and cell-surface flag-epitope detection

    PMID:11845306

    Open questions at the time
    • Single lab
    • Whether interaction is direct vs. mediated unresolved
  7. 2006 High

    Resolved the energetics of CFTR gating, showing ATP hydrolysis at the single hydrolytic NBD is not required for opening/closing but resets the cycle, with R-domain phosphorylation licensing allosteric coupling.

    Evidence In vitro ATPase assays, patch-clamp, and NBD/R-domain mutagenesis

    PMID:17021796

    Open questions at the time
    • Does not pinpoint the physical gate
    • Conformational path from NBD to gate not structurally defined
  8. 2006 Medium

    Identified WNK kinases as negative regulators of CFTR acting through distinct mechanisms — WNK1 via kinase activity, WNK4 via reduced surface abundance.

    Evidence Immunofluorescence co-localization, Xenopus oocyte electrophysiology, surface biotinylation

    PMID:17194447

    Open questions at the time
    • Direct vs. indirect WNK1-CFTR interaction not shown here
    • Physiological context of inhibition unclear
  9. 2010 High

    Revealed an intrinsic mechanosensitive mode of CFTR, showing membrane stretch activates the channel independent of kinase signaling and cytosolic factors.

    Evidence Cell-attached single-channel patch-clamp with mechanical stimulation; Ussing chamber in Calu-3 and mouse intestine

    PMID:20400957

    Open questions at the time
    • Structural element sensing stretch unidentified
    • Physiological stimulus generating stretch in vivo not defined
  10. 2011 Medium

    Identified COMMD1 as a stabilizer that protects CFTR from ubiquitination and promotes surface expression, adding a positive arm to CFTR proteostasis.

    Evidence Endogenous co-IP, cell-surface biotinylation, genetic screen

    PMID:21483833

    Open questions at the time
    • Which ubiquitin ligase COMMD1 antagonizes not defined
    • Single lab
  11. 2012 High

    Demonstrated alternating-access conformational changes in the CFTR transmembrane pathway, with state-dependent probe access establishing an inward-facing open and outward-facing closed configuration.

    Evidence Cysteine-scanning with MTSES/Au(CN)2- probes and gating manipulation via NBD mutations

    PMID:22303012

    Open questions at the time
    • Limited to two reporter positions
    • Atomic-resolution conformational states not derived
  12. 2014 High

    Showed permeant anions modulate CFTR gating phosphorylation-independently in a manner mechanistically parallel to VX-770, implying a pore-based gating modulation distinct from the potentiator site.

    Evidence Single-channel/whole-cell patch-clamp with phosphorylation-independent and ΔNBD2 constructs, VX-770 comparison

    PMID:25512598

    Open questions at the time
    • Physical site of nitrate action not mapped
    • Physiological relevance of anion modulation unclear
  13. 2015 High

    Localized the CFTR gate to TM6 residues 337–344 coincident with the selectivity filter, unifying gating and permeation at a single structural locus.

    Evidence Cysteine-scanning mutagenesis with Au(CN)2- permeant probe, inside/outside-out patch-clamp

    PMID:25675504

    Open questions at the time
    • Coupling of NBD motions to this gate not structurally traced
    • Role of other TMs in gating not fully resolved
  14. 2015 High

    Established a functional dependence of CFTR-mediated secretion on TMEM16A, showing TMEM16A is required for CFTR activation and membrane expression via Ca2+/adenylyl cyclase signaling.

    Evidence Tissue-specific TMEM16A knockout mice, Ussing chamber and whole-cell electrophysiology, surface expression assays

    PMID:28963502

    Open questions at the time
    • Direct physical association vs. signaling crosstalk not distinguished
    • Tissue generality beyond gut/airway untested
  15. 2016 Medium

    Extended CFTR function to innate immunity, showing activated neutrophils mobilize CFTR to phagosomes to enable HOCl production, a step lost in F508del-CF neutrophils.

    Evidence Flow cytometry, confocal phagosomal imaging, HOCl assays in normal vs. CF neutrophils

    PMID:27406994

    Open questions at the time
    • Mechanism of CFTR redistribution to phagosomes unknown
    • Quantitative contribution to bacterial killing not established
  16. 2017 High

    Defined the pharmacological mechanism of CFTR potentiators, showing VX-770 and GLPG1837 share an open-state-preferring binding site acting independently of NBD dimerization and hydrolysis.

    Evidence Single-channel patch-clamp with competitive binding analysis, kinetic modeling, NBD mutagenesis

    PMID:29079713

    Open questions at the time
    • Structural identity of the potentiator site not resolved here
    • Synergy mechanism with ATP analogues not mapped to residues
  17. 2018 Medium

    Described compartmentalized CFTR signaling, showing GPCR-driven translocation of ADCY1 and EPAC1 into membrane domains containing CFTR and TMEM16A integrates Ca2+ and cAMP control.

    Evidence GPCR knockdown, co-localization, FRET cAMP biosensors, Golgi disruption, electrophysiology

    PMID:29331508

    Open questions at the time
    • Single lab
    • Scaffolding architecture of the signaling domain undefined
  18. 2019 High

    Identified WNK1 as a direct, [Cl-]i-sensitive regulator of CFTR bicarbonate permeability and linked pancreatitis CFTR mutations (R74Q, R75Q) to disrupted WNK1 association.

    Evidence Whole-cell/outside-out/inside-out patch-clamp, domain-deletion dissection, WNK1-CFTR co-IP

    PMID:31561038

    Open questions at the time
    • Structural basis of elbow-helix-1/WNK1 interface not resolved
    • How [Cl-]i is sensed mechanistically unclear
  19. 2019 Medium

    Dissected the chaperone-driven degradation of F508del-CFTR, distinguishing DNAJA2/Hsc70-CHIP ER proteasomal and Hsp70-driven lysosomal routes and showing Hsp70 inhibition rescues channel activity.

    Evidence Overexpression/knockdown, proteasome/lysosome inhibitors, ubiquitination assays, patch-clamp with VX-809

    PMID:31408507

    Open questions at the time
    • Single lab
    • Relative in vivo contribution of the two degradation routes unknown
  20. 2020 High

    Defined a co-translational mechanism of CFTR mRNA stabilization by amplifier compounds acting through direct PCBP1 binding to a consensus element in the CFTR ORF.

    Evidence Chemical proteomics, polysome profiling, mRNA stability assays, PCBP1 element mutagenesis

    PMID:32067958

    Open questions at the time
    • Endogenous (drug-free) role of PCBP1 in CFTR expression not established
    • Structural basis of amplifier-PCBP1-mRNA recognition unknown
  21. 2022 High

    Established a non-epithelial vascular role for CFTR, defining a CFTR→WNK1→TRPV4 pathway whose loss during infection causes endothelial barrier failure rescued by ivacaftor.

    Evidence Isolated perfused rat lungs, CFTR/WNK1 pharmacology, Trpv4-/- mice, ion measurements, in vivo S. pneumoniae model

    PMID:36475904

    Open questions at the time
    • Molecular trigger of CFTR loss during infection not identified
    • Generalizability to other infections/inflammatory states untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the NBD dimerization/ATP-hydrolysis cycle is mechanically transmitted to the TM6 gate, and how the potentiator and permeant-anion modulatory sites map onto channel structure, remains unresolved.
  • No atomic-resolution gating-cycle structure in the timeline
  • Physical location of the VX-770/GLPG1837 site not mapped to residues
  • Integration of mechanosensitive, anion, and ATP gating inputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140657 ATP-dependent activity 3 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 4 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 6 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3
Partners
COMMD1DNAJA2HSPA8PCBP1PP2CSTX1ATMEM16AWNK1

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 VX-770 (ivacaftor) increases CFTR channel open probability (Po) for both F508del and G551D mutant CFTR in recombinant cells, and increases Cl- secretion ~10-fold in cultured human CF bronchial epithelia carrying G551D/F508del, demonstrating pharmacological potentiation of CFTR channel gating. Patch-clamp electrophysiology in recombinant cells; Ussing chamber Cl- secretion measurements in primary human bronchial epithelial cultures Proceedings of the National Academy of Sciences of the United States of America High 19846789
1999 CFTR accounts for the cAMP-regulated chloride conductance of airway epithelial cells; deletion of CFTR causes hyperabsorption of sodium chloride and reduction in periciliary salt and water content, impairing mucociliary clearance. Electrophysiological studies and airway surface liquid measurements in CF vs. non-CF epithelia; review synthesizing loss-of-function data Physiological reviews High 9922383
1999 F508del-CFTR is synthesized but retained as a core-glycosylated intermediate in the ER due to misfolding; it is recognized by molecular chaperones and rapidly degraded by cytoplasmic proteasomes via multiubiquitination. Pulse-chase metabolic labeling, proteasome inhibitor experiments, ubiquitination assays; review of biochemical processing data Physiological reviews High 9922380
2006 CFTR is regulated by both phosphorylation of the R domain and ATP binding/hydrolysis at dual nucleotide-binding sites; only the second NBD is hydrolytic. R domain phosphorylation enables transduction of the nucleotide-binding allosteric signal to the channel gate, but ATP hydrolysis is not required for opening or closing transitions — it clears the ligand-binding site to enable a new gating cycle. In vitro ATPase assays, patch-clamp electrophysiology, mutagenesis of NBD residues and R domain phosphorylation sites Pflugers Archiv : European journal of physiology High 17021796
2001 CFTR chloride channels are regulated by protein kinase A (PKA) as an activator and protein kinase C (PKC) as an enhancer of PKA stimulation; CFTR is also regulated by a membrane-bound protein phosphatase-2C (PP2C) that forms a stable complex with CFTR as shown by co-immunoprecipitation, chemical cross-linking, and pull-down assays. Patch-clamp electrophysiology, co-immunoprecipitation, chemical cross-linking, pull-down assays Pflugers Archiv : European journal of physiology Medium 11845311
1998 CFTR Cl- channels and an associated ATP channel (5.2 pS) are distinct permeation pathways that share common gating machinery dependent on PKA phosphorylation and cytoplasmic ATP/NBD function; gating kinetics of the ATP channel are similarly affected by non-hydrolyzable ATP analogues and mutations in the CFTR R domain and NBDs, but the ATP conduction pathway is not obligatorily linked to CFTR expression. Single-channel patch-clamp recordings in excised inside-out patches from MDCK cells transiently expressing CFTR, with pharmacological and mutagenesis analysis The EMBO journal Medium 9463368
2010 CFTR is activated by membrane stretch (negative pressures as small as 5 mmHg), increasing both NPo and unitary conductance; this mechanosensitive activation is an intrinsic channel property independent of cytosolic factors and kinase signaling, and results in chloride transport in airway epithelial cells and intestinal tissue. Single-channel patch-clamp in cell-attached patches with mechanical stimulation; Ussing chamber measurements in Calu-3 cells and mouse intestinal tissue Nature cell biology High 20400957
2015 Tissue-specific knockout of TMEM16A in mouse intestine and airways abolishes not only Ca2+-activated Cl- currents but also CFTR-mediated Cl- secretion; TMEM16A is required for proper activation and membrane expression of CFTR, acting through ER Ca2+ store release engaging Ca2+-regulated adenylyl cyclases. Tissue-specific gene knockout in mice, Ussing chamber electrophysiology, whole-cell patch-clamp, surface expression assays Scientific reports High 28963502
2006 WNK1 co-localizes with CFTR in pulmonary epithelial cells; co-expression of WNK1 or WNK4 with CFTR in Xenopus oocytes suppresses chloride channel activity. WNK4 reduces CFTR protein abundance at the plasma membrane independently of its kinase activity, while WNK1 inhibition of CFTR requires intact kinase activity. Co-localization by immunofluorescence; Xenopus oocyte expression system with electrophysiology; cell surface biotinylation assays Biochemical and biophysical research communications Medium 17194447
2019 WNK1 kinase domain directly associates with CFTR and increases CFTR bicarbonate permeability (PHCO3/PCl) and conductance; this regulation is [Cl-]i-sensitive. Pancreatitis-causing CFTR mutations R74Q and R75Q in the elbow helix 1 of CFTR impair WNK1-CFTR physical association and reduce WNK1-mediated CFTR HCO3- channel regulation. Whole-cell, outside-out, and inside-out patch-clamp recordings; molecular dissection with domain deletion constructs; co-immunoprecipitation of WNK1 and CFTR Cellular and molecular gastroenterology and hepatology High 31561038
2011 COMMD1 interacts with CFTR endogenously, protects CFTR from ubiquitination, and promotes CFTR cell surface expression as measured by biotinylation experiments. Co-immunoprecipitation in cells expressing endogenous proteins; cell surface biotinylation; genetic screen PloS one Medium 21483833
2001 Syntaxin 1A (S1A) interacts with CFTR and reduces CFTR channel currents in a syntaxin-isoform-specific manner; S1A inhibits cAMP-regulated CFTR trafficking to the plasma membrane and decreases cell-surface CFTR detected by flag-epitope labeling. Patch-clamp electrophysiology; membrane capacitance measurements; cell-surface flag-epitope detection by immunofluorescence Pflugers Archiv : European journal of physiology Medium 11845306
2004 CFTR folding and biosynthetic processing involve molecular chaperones Hsp70/Hdj-1 and calnexin; F508del-CFTR is retained in the ER due to misfolding and degraded by proteasomes, while wild-type CFTR matures through the secretory pathway to the plasma membrane. Co-immunoprecipitation with chaperones; pulse-chase metabolic labeling; proteasome inhibition experiments; glycosylation analysis Journal of molecular neuroscience : MN Medium 15126691
2019 Hsp70 and co-chaperone DNAJA2 promote CFTR degradation: DNAJA2 overexpression enhances CFTR degradation at the ER via Hsc70/Hsp70 and the E3 ubiquitin ligase CHIP, while excess Hsp70 drives CFTR through lysosomal degradation requiring CHIP but not HOP/Hsp90. Hsp70 inhibitor MKT077 increases mature CFTR levels and enhances ΔF508-CFTR channel activity when combined with corrector VX-809. Protein overexpression/knockdown; proteasome and lysosome inhibitors; ubiquitination assays; patch-clamp channel activity measurements PloS one Medium 31408507
2015 CFTR's gate is located between amino acid residues 337 and 344 along TM6, coinciding with the predicted selectivity filter; cysteines cytoplasmic to this region (positions 344 in TM6, 1148 in TM12) are accessible from both open and closed states, while cysteines external to this region (334, 335, 337) are only accessible from the cytoplasmic side when the channel is open and accessible from the extracellular side when Po is reduced. Cysteine-scanning mutagenesis with Au(CN)2- as channel-permeant probe; patch-clamp electrophysiology in inside-out and outside-out configurations Proceedings of the National Academy of Sciences of the United States of America High 25675504
2012 CFTR transmembrane domains exhibit alternating access: in the open state the transmembrane pathway faces inwardly (cytoplasm-accessible), while in the closed state it faces outwardly (extracellular-accessible), as demonstrated by state-dependent access of cysteine-reactive probes from both sides of the membrane to introduced cysteines at Leu-102 (TM1) and Thr-338 (TM6). Cysteine-scanning mutagenesis; MTSES and Au(CN)2- probe access in patch-clamp with gating manipulations via NBD mutations The Journal of biological chemistry High 22303012
1996 The first membrane-spanning domain (TM1-6) of CFTR determines anion permeability sequence and single-channel conductance, as demonstrated by chimeric human-Xenopus CFTR proteins replacing either TM1-6 or TM7-12; the first extracellular loop within TM1-6 influences channel gating. Chimeric protein construction; whole-cell and single-channel patch-clamp in HeLa cells; site-directed mutagenesis of extracellular loop residues The Journal of biological chemistry High 8810276
2014 Permeant ions such as nitrate increase CFTR open probability by increasing opening rate and decreasing closing rate, independently of PKA-dependent phosphorylation and NBD dimerization; the effect of nitrate is remarkably similar to VX-770 on single-channel kinetics and deceleration of nonhydrolytic closing, suggesting a shared gating modulation mechanism acting through separate sites. Single-channel and whole-cell patch-clamp with phosphorylation-independent CFTR constructs and NBD2-deletion constructs; comparison with VX-770 pharmacology The Journal of general physiology High 25512598
2017 CFTR potentiators GLPG1837 and VX-770 share a common mechanism of action: they potentiate CFTR gating independently of NBD dimerization and ATP hydrolysis, compete for the same binding site (shown by combined application), and bind preferentially to the open-channel state (state-dependent binding). GLPG1837 and the ATP analogue dPATP act synergistically through distinct sites. Single-channel patch-clamp with competitive binding analysis, kinetic modeling, and mutagenesis of NBD residues The Journal of general physiology High 29079713
1994 Functional CFTR in endosomal compartments acts as a cAMP-regulated Cl- channel that modulates endosomal Cl- conductance; forskolin increased endosomal pH and dpH/dt (a measure of Cl- conductance) 1.6-fold in CFTR-expressing fibroblasts but not mock-transfected controls. Quantitative fluorescence image analysis of individual endosomes labeled with carboxyfluorescein-dextran; protonophore-induced pH dissipation assay for endosomal Cl- conductance The American journal of physiology Medium 7508186
2020 CFTR amplifiers stabilize CFTR mRNA co-translationally through a mechanism requiring the translated CFTR sequence and translational elongation; amplifiers bind directly to PCBP1 (poly(rC)-binding protein 1) and require a PCBP1 consensus element within the CFTR ORF; amplifiers enrich ER-associated CFTR mRNA and increase its polysome association. Chemical proteomics pulldown identifying PCBP1 as amplifier-binding protein; polysome profiling; mRNA stability assays; mutagenesis of PCBP1 consensus element in CFTR ORF Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society High 32067958
2018 In airway epithelial cells, CFTR compartmentalized signaling requires Ca2+-sensitive adenylyl cyclase type 1 (ADCY1) and exchange protein directly activated by cAMP (EPAC1); activation of Gq/11-coupled GPCRs translocates ADCY1 and EPAC1 to plasma membrane domains containing GPCRs, CFTR, and TMEM16A, enabling crosstalk between Ca2+- and cAMP-dependent signaling. CFTR biosynthesis and membrane trafficking require a functional Golgi apparatus. GPCR knockdown; co-localization imaging; FRET-based cAMP biosensors; Golgi disruption experiments; electrophysiology Cellular signalling Medium 29331508
2016 In activated human neutrophils, CFTR redistributes from intracellular compartments to the cell surface and to phagosomes; this mobilization correlates with secretory vesicle exocytosis. ΔF508-CF neutrophils fail to mobilize CFTR to phagosomes upon stimulation, resulting in deficient hypochlorous acid production. Flow cytometry with multiple anti-CFTR antibodies; confocal microscopy of phagosomal targeting; hypochlorous acid production assay in CF vs. normal neutrophils Journal of leukocyte biology Medium 27406994
2022 Endothelial CFTR loss during S. pneumoniae infection increases intracellular [Cl-], inhibits WNK1, and causes TRPV4-dependent Ca2+ influx leading to vascular barrier failure; ivacaftor prevents CFTR loss and lung edema in infected mice. Mechanistically, the CFTR→WNK1→TRPV4 pathway controls endothelial permeability. Isolated perfused rat lungs; CFTR inhibitor/activator pharmacology; WNK1 activator/inhibitor experiments; Trpv4-/- mice; intracellular Cl- and Ca2+ measurements; in vivo S. pneumoniae infection model Science translational medicine High 36475904

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proceedings of the National Academy of Sciences of the United States of America 1005 19846789
2008 CFTR function and prospects for therapy. Annual review of biochemistry 479 18304008
1999 Role of CFTR in airway disease. Physiological reviews 312 9922383
1999 Biosynthesis and degradation of CFTR. Physiological reviews 305 9922380
2003 The phenotypic consequences of CFTR mutations. Annals of human genetics 242 12940920
1992 CFTR! The American journal of physiology 217 1381146
2014 CFTR: cystic fibrosis and beyond. The European respiratory journal 207 24925916
2005 Molecular mechanisms of reduced glutathione transport: role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicology and applied pharmacology 182 15845416
2002 Isolation of CF cell lines corrected at DeltaF508-CFTR locus by SFHR-mediated targeting. Gene therapy 137 12032687
2004 CFTR and chaperones: processing and degradation. Journal of molecular neuroscience : MN 120 15126691
1999 Intracellular CFTR: localization and function. Physiological reviews 120 9922381
1994 CFTR and calcium-activated chloride currents in pancreatic duct cells of a transgenic CF mouse. The American journal of physiology 119 7508188
2008 Assessment of the CFTR and ENaC association. Molecular bioSystems 109 19156256
1998 CFTR Cl- channel and CFTR-associated ATP channel: distinct pores regulated by common gates. The EMBO journal 107 9463368
2017 Epithelial Chloride Transport by CFTR Requires TMEM16A. Scientific reports 106 28963502
2012 Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clinical biochemistry 106 22698459
1998 CFTR gene and male fertility. Molecular human reproduction 99 9542966
2018 Structural mechanisms of CFTR function and dysfunction. The Journal of general physiology 91 29581173
2004 CFTR mutations and polymorphisms in male infertility. International journal of andrology 88 15379964
2012 Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 87 22658665
2021 CFTR Protein: Not Just a Chloride Channel? Cells 86 34831067
2014 Genetics of cystic fibrosis: CFTR mutation classifications toward genotype-based CF therapies. The international journal of biochemistry & cell biology 86 24631642
1995 CFTR and differentiation markers expression in non-CF and delta F 508 homozygous CF nasal epithelium. The Journal of clinical investigation 86 7544810
2000 Permeation through the CFTR chloride channel. The Journal of experimental biology 83 10851114
2005 Oxidant stress suppresses CFTR expression. American journal of physiology. Cell physiology 82 16162662
1996 Gene targeting of CFTR DNA in CF epithelial cells. Gene therapy 80 8908499
2014 CFTR and lung homeostasis. American journal of physiology. Lung cellular and molecular physiology 77 25381027
1994 CFTR haplotype backgrounds on normal and mutant CFTR genes. Human molecular genetics 74 7520797
2013 CFTR: a hub for kinases and crosstalk of cAMP and Ca2+. The FEBS journal 69 23895508
2006 CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Archiv : European journal of physiology 68 17021796
2004 Severe osteopenia in CFTR-null mice. Bone 68 15336594
2013 CFTR activity and mitochondrial function. Redox biology 67 24024153
2005 CFTR: more than just a chloride channel. Pediatric pulmonology 65 15573386
2010 Mechanosensitive gating of CFTR. Nature cell biology 63 20400957
2015 CFTR, bicarbonate, and the pathophysiology of cystic fibrosis. Pediatric pulmonology 59 26335950
1992 Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Human genetics 58 1380943
2005 The CFTR gene and regulation of its expression. Pediatric pulmonology 57 15806593
2001 Regulation of the CFTR channel by phosphorylation. Pflugers Archiv : European journal of physiology 57 11845311
2007 Restoration of W1282X CFTR activity by enhanced expression. American journal of respiratory cell and molecular biology 55 17541014
1993 Close linkage between the Cf-2/Cf-5 and Mi resistance loci in tomato. Molecular plant-microbe interactions : MPMI 55 8100724
2015 Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors. Pediatric pulmonology 54 26097168
2000 Regulated trafficking of the CFTR chloride channel. European journal of cell biology 54 11001491
1994 Functional CFTR in endosomal compartment of CFTR-expressing fibroblasts and T84 cells. The American journal of physiology 54 7508186
1997 Cystic fibrosis transmembrane conductance regulator (CFTR) and renal function. Wiener klinische Wochenschrift 53 9261986
1998 Efficient expression of CFTR function with adeno-associated virus vectors that carry shortened CFTR genes. Proceedings of the National Academy of Sciences of the United States of America 52 9707617
2014 CFTR structure and cystic fibrosis. The international journal of biochemistry & cell biology 50 24534272
2017 A common mechanism for CFTR potentiators. The Journal of general physiology 49 29079713
2018 Compartmentalized crosstalk of CFTR and TMEM16A (ANO1) through EPAC1 and ADCY1. Cellular signalling 48 29331508
2013 Optimizing nasal potential difference analysis for CFTR modulator development: assessment of ivacaftor in CF subjects with the G551D-CFTR mutation. PloS one 48 23922647
2012 CFTR inhibitors for treating diarrheal disease. Clinical pharmacology and therapeutics 48 22850599
2006 WNK1 and WNK4 modulate CFTR activity. Biochemical and biophysical research communications 48 17194447
2016 The gating of the CFTR channel. Cellular and molecular life sciences : CMLS 47 27696113
2011 COMMD1-mediated ubiquitination regulates CFTR trafficking. PloS one 47 21483833
2001 Role of snare proteins in CFTR and ENaC trafficking. Pflugers Archiv : European journal of physiology 46 11845306
2013 Cystic fibrosis transmembrane conductance regulator (ABCC7) structure. Cold Spring Harbor perspectives in medicine 45 23378596
2018 The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 44 29685812
2021 Genetics of CFTR and male infertility. Translational andrology and urology 42 33850775
2022 ECFS standards of care on CFTR-related disorders: Diagnostic criteria of CFTR dysfunction. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 41 36207272
2021 Review of CFTR modulators 2020. Pediatric pulmonology 41 34407318
2019 The impact of CFTR modulator therapies on CF airway microbiology. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 41 31416774
2016 Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity. Frontiers in chemistry 40 26835446
2011 Curcumin and genistein additively potentiate G551D-CFTR. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 40 21441077
1996 Function of Xenopus cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels and use of human-Xenopus chimeras to investigate the pore properties of CFTR. The Journal of biological chemistry 40 8810276
2020 Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 39 32067958
2014 Modulation of CFTR gating by permeant ions. The Journal of general physiology 38 25512598
2016 Islet-intrinsic effects of CFTR mutation. Diabetologia 37 27033560
2015 Localizing a gate in CFTR. Proceedings of the National Academy of Sciences of the United States of America 37 25675504
1997 CFTR: domains, structure, and function. Journal of bioenergetics and biomembranes 37 9511929
2020 The bidirectional relationship between CFTR and lipids. Communications biology 36 32313074
2005 Correction of the CF defect by curcumin: hypes and disappointments. BioEssays : news and reviews in molecular, cellular and developmental biology 35 15612029
2007 Organelle redox of CF and CFTR-corrected airway epithelia. Free radical biology & medicine 34 17603939
2000 The cystic fibrosis transmembrane regulator (CFTR) in the kidney. Anais da Academia Brasileira de Ciencias 34 11028104
2017 Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatric pulmonology 33 28881097
2016 Genetic medicines for CF: Hype versus reality. Pediatric pulmonology 33 27662105
2022 A survey: Understanding the health and perspectives of people with CF not benefiting from CFTR modulators. Pediatric pulmonology 32 35170259
2021 Fertility, Pregnancy and Lactation Considerations for Women with CF in the CFTR Modulator Era. Journal of personalized medicine 32 34063507
2007 CFTR mutations in the Algerian population. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 30 17572159
2004 Antibodies for CFTR studies. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 30 15463931
2001 Increased functional cell surface expression of CFTR and DeltaF508-CFTR by the anthracycline doxorubicin. American journal of physiology. Cell physiology 30 11287314
2013 CFTR inhibitors. Current pharmaceutical design 29 23331030
2011 CFTR mutation analysis and haplotype associations in CF patients. Molecular genetics and metabolism 29 22137130
2008 Identification and characterization of CFTR gene mutations in Indian CF patients. Annals of human genetics 29 18782298
2021 Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene. JCI insight 28 33232302
2019 Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-Related Disorders. Cellular and molecular gastroenterology and hepatology 28 31561038
2016 CFTR pharmacology. Cellular and molecular life sciences : CMLS 28 27704174
2012 Alternating access to the transmembrane domain of the ATP-binding cassette protein cystic fibrosis transmembrane conductance regulator (ABCC7). The Journal of biological chemistry 28 22303012
2006 Atypical CF and CF related diseases. Paediatric respiratory reviews 28 16798544
2014 Delivery of genes into the CF airway. Thorax 27 25015239
2005 Frequency of large CFTR gene rearrangements in Italian CF patients. European journal of human genetics : EJHG 27 15741992
2011 Targeting CFTR: how to treat cystic fibrosis by CFTR-repairing therapies. Current drug targets 26 21039334
2004 NO pathway in CF and non-CF children. Pediatric pulmonology 26 15022131
2001 Cystic fibrosis and CFTR. Pflugers Archiv : European journal of physiology 26 11845294
2022 Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation. Science translational medicine 25 36475904
2019 Hsp70 and DNAJA2 limit CFTR levels through degradation. PloS one 25 31408507
2016 CFTR targeting during activation of human neutrophils. Journal of leukocyte biology 25 27406994
2013 The CF-modifying gene EHF promotes p.Phe508del-CFTR residual function by altering protein glycosylation and trafficking in epithelial cells. European journal of human genetics : EJHG 25 24105369
2011 CFTR Folding Consortium: methods available for studies of CFTR folding and correction. Methods in molecular biology (Clifton, N.J.) 25 21547742
2014 Cytoskeleton and CFTR. The international journal of biochemistry & cell biology 24 24685681
2013 CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders. Journal of medical genetics 24 23378603
2010 UMD-CFTR: a database dedicated to CF and CFTR-related disorders. Human mutation 24 20607857

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