Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context
Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized c...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423000245 |
| _version_ | 1797924709045633024 |
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| author | Irene Hiniesto-Iñigo Laura M. Castro-Gonzalez Valentina Corradi Mark A. Skarsfeldt Samira Yazdi Siri Lundholm Johan Nikesjö Sergei Yu Noskov Bo Hjorth Bentzen D. Peter Tieleman Sara I. Liin |
| author_facet | Irene Hiniesto-Iñigo Laura M. Castro-Gonzalez Valentina Corradi Mark A. Skarsfeldt Samira Yazdi Siri Lundholm Johan Nikesjö Sergei Yu Noskov Bo Hjorth Bentzen D. Peter Tieleman Sara I. Liin |
| author_sort | Irene Hiniesto-Iñigo |
| collection | DOAJ |
| description | Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS. Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts. Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. Interpretation: We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts. Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing. |
| first_indexed | 2024-04-10T15:05:19Z |
| format | Article |
| id | doaj.art-68cc94b6c4f549b4b603e7aeba51442e |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-10T15:05:19Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-68cc94b6c4f549b4b603e7aeba51442e2023-02-15T04:28:29ZengElsevierEBioMedicine2352-39642023-03-0189104459Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in contextIrene Hiniesto-Iñigo0Laura M. Castro-Gonzalez1Valentina Corradi2Mark A. Skarsfeldt3Samira Yazdi4Siri Lundholm5Johan Nikesjö6Sergei Yu Noskov7Bo Hjorth Bentzen8D. Peter Tieleman9Sara I. Liin10Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenCentre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, CanadaCentre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, CanadaDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenCentre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, CanadaDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, DenmarkCentre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, CanadaDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Corresponding author. Department of Biomedical and Clinical Sciences, Linköping University, SE-581 85, Linköping, Sweden.Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS. Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts. Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. Interpretation: We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts. Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.http://www.sciencedirect.com/science/article/pii/S2352396423000245ArrhythmiaElectrophysiologyKCNQ1Kv7Long QT SyndromeMolecular dynamics |
| spellingShingle | Irene Hiniesto-Iñigo Laura M. Castro-Gonzalez Valentina Corradi Mark A. Skarsfeldt Samira Yazdi Siri Lundholm Johan Nikesjö Sergei Yu Noskov Bo Hjorth Bentzen D. Peter Tieleman Sara I. Liin Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context EBioMedicine Arrhythmia Electrophysiology KCNQ1 Kv7 Long QT Syndrome Molecular dynamics |
| title | Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context |
| title_full | Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context |
| title_fullStr | Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context |
| title_full_unstemmed | Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context |
| title_short | Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context |
| title_sort | endocannabinoids enhance hkv7 1 kcne1 channel function and shorten the cardiac action potential and qt intervalresearch in context |
| topic | Arrhythmia Electrophysiology KCNQ1 Kv7 Long QT Syndrome Molecular dynamics |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423000245 |
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