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The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family
Open accessAbstract
OBJECTIVE: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 alpha-subunits assemble with KCNE1 beta-subunits forming a channel complex constituting the delayed rectifier current I(Ks). In epithelia, KCNQ1 channels participate in controlling body electrolyte homeostasis. Several regulatory mechanisms of the KCNQ1 channel complexes have been reported, including protein kinase A (PKA)-phosphorylation and beta-subunit interactions. However, the mechanisms controlling the membrane density of KCNQ1 channels have attracted less attention. METHODS AND RESULTS: Here we demonstrate that KCNQ1 proteins expressed in HEK293 cells are down-regulated by Nedd4/Nedd4-like ubiquitin-protein ligases. KCNQ1 and KCNQ1/KCNE1 currents were reduced upon co-expression of Nedd4-2, the isoform among the nine members of the Nedd4/Nedd4-like family displaying the highest expression level in human heart. In vivo expression of a catalytically inactive form of Nedd4-2, able to antagonize endogenous Nedd4-2 in guinea-pig cardiomyocytes, increased I(Ks) significantly, but did not modify I(K1). Concomitant with the reduction in current induced by Nedd4-2, an increased ubiquitylation as well as a decreased total level of KCNQ1 proteins were observed in HEK293 cells. Pull-down and co-immunoprecipitation experiments showed that Nedd4-2 interacts with the C-terminal part of KCNQ1. The Nedd4/Nedd4-like-mediated regulation of the KCNQ1 channel complexes is strictly dependent on a PY motif located in the distal part of the C-terminal domain. When this motif was mutated, the current and ubiquitylation levels were unaffected by Nedd4-2, and Nedd4-2 proteins were neither pulled-down nor co-immunoprecipitated. CONCLUSIONS: These results suggest that KCNQ1 internalization and stability is physiologically regulated by its Nedd4/Nedd4-like-dependent ubiquitylation. This mechanism may thereby be important in regulating the surface density of the KCNQ1 channels in cardiomyocytes and other cell types.
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“The voltage-dependent K+ channels such as Kv7.1 and KATP-sensitive (KATP) undergo CME and are involved in tissue formation and insulin secretion, respectively [80,85].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [85]
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Insights of Endocytosis Signaling in Health and Disease
Pathak, C., Vaidya, F. U., Waghela, B. N., Jaiswara, P. K., Gupta, V. K., Kumar, A., Rajendran, B. K., & Ranjan, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032971 · Cited by 59
“1 and KATP-sensitive (KATP) undergo CME and are involved in tissue formation and insulin secretion, respectively [80,85].”
BackgroundAndersen, M. N., Krzystanek, K., Petersen, F., Bomholtz, S. H., Olesen, S.-P., Abriel, H., Jespersen, T., & Rasmussen, H. B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.525931 · Cited by 30
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Metadata
- Authors
- JESPERSEN, T., MEMBREZ, M., NICOLAS, C., PITARD, B., STAUB, O., OLESEN, S., BARO, I., & ABRIEL, H.
- Affiliations
- University of Lausanne (CH)
- Inserm (FR)
- University of Copenhagen (DK)
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- ABRIEL, H
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-01
- Volume
- 74
- Issue
- 1
- Pages
- 64-74
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2010009765
- Cited by
- 138
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 10 · 2019: 6 · 2018: 4 · 2017: 8 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 10 · 2012: 14
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- reroDoc Digital Library (submittedVersion)
- IRIS (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Science Foundation
- National Research Foundation
- Institut National de la Santé et de la Recherche Médicale
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (66149)
- Danmarks Grundforskningsfond
- Centre National de la Recherche Scientifique
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Nedd4-2, ubiquitination, KCNE1, delayed rectifier potassium current, IKs, channel internalization, protein stability, PY motif, cardiomyocytes
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Animals, Cell Line, Guinea Pigs, Humans, RNA, Messenger, Transfection, Down-Regulation, Gene Expression, Patch-Clamp Techniques, Reverse Transcriptase Polymerase Chain Reaction, Potassium Channels, Voltage-Gated, Ubiquitin, Myocytes, Cardiac, Ubiquitin-Protein Ligases, KCNQ1 Potassium Channel, Endosomal Sorting Complexes Required for Transport
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