Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia
Abstract In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK‐1. In addition,...
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| Language: | English |
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Springer Nature
2017-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606690 |
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| author | Niels Decher Beatriz Ortiz‐Bonnin Corinna Friedrich Marcus Schewe Aytug K Kiper Susanne Rinné Gunnar Seemann Rémi Peyronnet Sven Zumhagen Daniel Bustos Jens Kockskämper Peter Kohl Steffen Just Wendy González Thomas Baukrowitz Birgit Stallmeyer Eric Schulze‐Bahr |
| author_facet | Niels Decher Beatriz Ortiz‐Bonnin Corinna Friedrich Marcus Schewe Aytug K Kiper Susanne Rinné Gunnar Seemann Rémi Peyronnet Sven Zumhagen Daniel Bustos Jens Kockskämper Peter Kohl Steffen Just Wendy González Thomas Baukrowitz Birgit Stallmeyer Eric Schulze‐Bahr |
| author_sort | Niels Decher |
| collection | DOAJ |
| description | Abstract In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK‐1. In addition, mutant channels exhibit a hypersensitivity to stretch‐activation, suggesting that the selectivity filter is directly involved in stretch‐induced activation and desensitization. Increased sodium permeability and stretch‐sensitivity of mutant TREK‐1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK‐1 pore. Our findings provide important insights for future studies of K2P channel stretch‐activation and the role of TREK‐1 in mechano‐electrical feedback in the heart. |
| format | Article |
| id | doaj-art-9640f01ff7df45b1a9d350a18cebee9f |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9640f01ff7df45b1a9d350a18cebee9f2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-02-019440341410.15252/emmm.201606690Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardiaNiels Decher0Beatriz Ortiz‐Bonnin1Corinna Friedrich2Marcus Schewe3Aytug K Kiper4Susanne Rinné5Gunnar Seemann6Rémi Peyronnet7Sven Zumhagen8Daniel Bustos9Jens Kockskämper10Peter Kohl11Steffen Just12Wendy González13Thomas Baukrowitz14Birgit Stallmeyer15Eric Schulze‐Bahr16Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps‐University of MarburgInstitute of Physiology and Pathophysiology, Vegetative Physiology, Philipps‐University of MarburgDepartment of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital MünsterInstitute of Physiology, Christian‐Albrechts‐University of KielInstitute of Physiology and Pathophysiology, Vegetative Physiology, Philipps‐University of MarburgInstitute of Physiology and Pathophysiology, Vegetative Physiology, Philipps‐University of MarburgInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg – Bad Krozingen, Medical Center – University of FreiburgInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg – Bad Krozingen, Medical Center – University of FreiburgDepartment of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital MünsterCenter for Bioinformatics and Molecular Simulation, University of TalcaInstitute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC), Philipps‐University of MarburgInstitute for Experimental Cardiovascular Medicine, University Heart Center Freiburg – Bad Krozingen, Medical Center – University of FreiburgMolecular Cardiology, University Hospital UlmCenter for Bioinformatics and Molecular Simulation, University of TalcaInstitute of Physiology, Christian‐Albrechts‐University of KielDepartment of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital MünsterDepartment of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital MünsterAbstract In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK‐1. In addition, mutant channels exhibit a hypersensitivity to stretch‐activation, suggesting that the selectivity filter is directly involved in stretch‐induced activation and desensitization. Increased sodium permeability and stretch‐sensitivity of mutant TREK‐1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT. We present a pharmacological strategy to rescue the selectivity defect of the TREK‐1 pore. Our findings provide important insights for future studies of K2P channel stretch‐activation and the role of TREK‐1 in mechano‐electrical feedback in the heart.https://doi.org/10.15252/emmm.201606690arrhythmiaK2PRVOTTREK‐1two‐pore domain K+ channel |
| spellingShingle | Niels Decher Beatriz Ortiz‐Bonnin Corinna Friedrich Marcus Schewe Aytug K Kiper Susanne Rinné Gunnar Seemann Rémi Peyronnet Sven Zumhagen Daniel Bustos Jens Kockskämper Peter Kohl Steffen Just Wendy González Thomas Baukrowitz Birgit Stallmeyer Eric Schulze‐Bahr Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia EMBO Molecular Medicine arrhythmia K2P RVOT TREK‐1 two‐pore domain K+ channel |
| title | Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia |
| title_full | Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia |
| title_fullStr | Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia |
| title_full_unstemmed | Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia |
| title_short | Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia |
| title_sort | sodium permeable and hypersensitive trek 1 channels cause ventricular tachycardia |
| topic | arrhythmia K2P RVOT TREK‐1 two‐pore domain K+ channel |
| url | https://doi.org/10.15252/emmm.201606690 |
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