Altered chloride ion channel kinetics associated with the ΔF508 cystic fibrosis mutation
Abstract
Cystic fibrosis is associated with a defect in epithelial chloride ion transport which is caused by mutations in a membrane protein called CFTR (cystic fibrosis transmembrane conductance regulator). Heterologous expression of CFTR produces cyclicAMP-sensitive Cl(-)-channel activity. Deletion of phenylalanine at amino-acid position 508 in CFTR (delta F508 CFTR) is the most common mutation in cystic fibrosis. It has been proposed that this mutation prevents glycoprotein maturation and its transport to its normal cellular location. We have expressed both CFTR and delta F508 CFTR in Vero cells using recombinant vaccinia virus. Although far less delta F508 CFTR reached the plasma membrane than normal CFTR, sufficient delta F508 CFTR was expressed at the plasma membrane to permit functional analysis. delta F508 CFTR expression induced a reduced activity of the cAMP-activated Cl- channel, with conductance, anion selectivity and open-time kinetics similar to those of CFTR, but with much greater closed times, resulting in a large decrease of open probability. The delta F508 mutation thus seems to have two major consequences, an abnormal translocation of the CFTR protein which limits membrane insertion, and an abnormal function in mediating Cl- transport.
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Phe508del CFTR protein exhibits defective channel gating, which further limits anion transport.
“Phe508del CFTR protein also exhibits defective channel gating, which further limits anion transport.7”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [7]
The Phe508del CFTR mutation causes defective intracellular processing and trafficking and decreased stability, drastically reducing the quantity of CFTR protein at the apical surface of epithelial cells.
“The Phe508del CFTR mutation causes defective intracellular processing and trafficking and decreased stability, which drastically reduces the quantity of CFTR protein at the apical surface of epithelial cells.4,7,8”
From Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele (2019) · cites this paper as [7]
CFTR dysfunction caused by F508del is multifactorial, involving defective protein processing and trafficking to the cell surface, reduced channel gating, and high turnover once at the cell surface.
“CFTR dysfunction caused by F508del is multifactorial, with defective protein processing and trafficking to the cell surface, reduced channel gating, and high turnover once at the cell surface.2,9,10”
F508del leads to severely impaired processing, plasma membrane expression, and stability, as well as defective gating of F508del-CFTR.
“This leads to a combination of defects, consisting of severely impaired processing, plasma membrane (PM) expression, and stability, as well as defective gating of the F508del-CFTR (12–14).”
From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [12]
Cited by
Sorted by citations
Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele
Middleton, P. G., Mall, M. A., Dřevínek, P., Lands, L. C., McKone, E. F., Polineni, D., Ramsey, B. W., Taylor-Cousar, J. L., Tullis, E., Vermeulen, F., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908639 · Cited by 2,198 · see citing works
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis
Welsh, M. J., & Smith, A. E. (1993) · Cell · doi:10.1016/0092-8674(93)90353-r · Cited by 1,485 · see citing works
Heijerman, H. G. M., McKone, E. F., Downey, D. G., Van Braeckel, E., Rowe, S. M., Tullis, E., Mall, M. A., Welter, J. J., Ramsey, B. W., McKee, C. M., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32597-8 · Cited by 1,414 · see citing works
Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Van Goor, F., Hadida, S., Grootenhuis, P. D. J., Burton, B., Stack, J. H., Straley, K. S., Decker, C. J., Miller, M., McCartney, J., Olson, E. R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105787108 · Cited by 1,088 · see citing works
Veit, G., Roldan, A., Hancock, M. A., Da Fonte, D. F., Xu, H., Hussein, M., Frenkiel, S., Matouk, E., Velkov, T., & Lukacs, G. L. (2020) · JCI Insight · doi:10.1172/jci.insight.139983 · Cited by 250 · see citing works
Brown, M. B., Haack, K. K. V., Pollack, B. P., Millard-Stafford, M., & McCarty, N. A. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00660.2010 · Cited by 45 · see citing works
- Authors
- Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Jallat, S., Dott, K., Dreyer, D., Crystal, R. G., Pavirani, A., Lecocq, J.-P., & Lazdunski, M.
- Affiliations
- Transgene (France) (FR)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- National Institutes of Health (US)
- Venue
- Nature
- Published
- 1991-12-26
- Volume
- 354
- Issue
- 6354
- Pages
- 526-528
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2075257287
- Cited by
- 707
- References
- 0
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 16 · 2023: 13 · 2022: 19 · 2021: 17 · 2020: 27 · 2019: 35 · 2018: 26 · 2017: 18 · 2016: 24 · 2015: 25 · 2014: 21 · 2013: 30 · 2012: 22
- FWCI
- 40.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- cystic fibrosis, CFTR, F508del mutation, chloride channels, glycoprotein maturation, protein translocation, anion selectivity, plasma membrane expression
- MeSH terms
- Cyclic AMP, Cells, Cultured, Cystic Fibrosis, DNA, Humans, Ion Channels, Kinetics, Lung, Membrane Proteins, Probability, Promoter Regions, Genetic, RNA, Messenger, Vaccinia virus, Ion Channel Gating, Gene Expression, Chloride Channels, Cystic Fibrosis Transmembrane Conductance Regulator
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