ArticleThe Journal of physiology2003
Phosphorylation of protein kinase C sites in NBD1 and the R domain control CFTR channel activation by PKA.
Article in The Journal of physiology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 94 citations in OpenAlex.
- The Challenges of Detecting Neutrophil CFTR.Journal of innate immunity · 2026Review
- Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.Cellular & molecular biology letters · 2025Review
- Exploring the Mechanism of Activation of CFTR by Curcuminoids: An Ensemble Docking Study.International journal of molecular sciences · 2023Article
- Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins.International journal of molecular sciences · 2023Review
- PKC regulation of ion channels: The involvement of PIPThe Journal of biological chemistry · 2022Review
- Revisiting CFTR Interactions: Old Partners and New Players.International journal of molecular sciences · 2021Review
- CyFi-MAP: an interactive pathway-based resource for cystic fibrosis.Scientific reports · 2021Article
- Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation.Frontiers in physiology · 2021Review
- Pharmacological Modulation of Ion Channels for the Treatment of Cystic Fibrosis.Journal of experimental pharmacology · 2021Review
- Changes in the R-region interactions depend on phosphorylation and contribute to PKA and PKC regulation of the cystic fibrosis transmembrane conductance regulator chloride channel.FASEB bioAdvances · 2020Article
- Increases in cytosolic CaCellular and molecular life sciences : CMLS · 2019Article
- CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine.Frontiers in pharmacology · 2019Review
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- Sites associated with Kalydeco binding on human Cystic Fibrosis Transmembrane Conductance Regulator revealed by Hydrogen/Deuterium Exchange.Scientific reports · 2018Article
- Peripheral Protein Quality Control as a Novel Drug Target for CFTR Stabilizer.Frontiers in pharmacology · 2018Review
- The gating of the CFTR channel.Cellular and molecular life sciences : CMLS · 2017Review
- Trafficking and function of the cystic fibrosis transmembrane conductance regulator: a complex network of posttranslational modifications.American journal of physiology. Lung cellular and molecular physiology · 2016Review
- CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis.Frontiers in pharmacology · 2016Review
- Potential sites of CFTR activation by tyrosine kinases.Channels (Austin, Tex.) · 2016Article
- Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) channel by protein kinase A (PKA) is enhanced by protein kinase C (PKC). However, the mechanism of modulation is not known and it remains uncertain whether PKC acts directly on CFTR or through phosphorylation of an ancillary protein. Using excised patches that had been pre-treated with phosphatases, we found that PKC exposure results in much larger PKA-activated currents and shifts the PKA concentration dependence. To examine if these effects are mediated by direct PKC phosphorylation of CFTR, a mutant was constructed in which serines or threonines at nine PKC consensus sequences on CFTR were replaced by alanines (i.e. the '9CA' mutant T582A/T604A/S641A/T682A/S686A/S707A/S790A/T791A/S809A). In excised patches, 9CA channels had greatly reduced responses to PKA (i.e. 5-10 % that of wild-type), which were not enhanced by PKC pre-treatment, although the mutant channels were still functional according to iodide efflux assays. Stimulation of iodide efflux by chlorophenylthio-cAMP (cpt-cAMP) was delayed in cells expressing 9CA channels, and a similar delay was observed when cells expressing wild-type CFTR were treated with the PKC inhibitor chelerythrine. This suggests that weak activation by PKA in excised patches and slow stimulation of iodide efflux from intact cells are specifically due to the loss of PKC phosphorylation. Finally, PKC caused a slight activation of wild-type channels when added to excised patches after phosphatase pre-treatment but had no effect on the mutant. We conclude that direct phosphorylation of CFTR at one or more of the nine sites mutated in 9CA is required for both the partial activation by PKC and for its modulation of CFTR responses to PKA.
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