Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 104459 |
| Tidsskrift | EBioMedicine |
| Vol/bind | 89 |
| Antal sider | 17 |
| ISSN | 2352-3964 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The Ci-VSP clone was a generous gift from Dr. H.P. Larsson, who also provided insightful comments on the manuscript. We thank Dr. Xiongyu Wu for synthesis of different endocannabinoids and Veronika A. Linhart for help with illustrations. This work was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 850622) and the Canadian Institutes of Health Research (DPT). Computational resources were provided by the Swedish National Infrastructure for Computing (2021/5-41), and by Compute Canada , funded by the Canada Foundation for Innovation and partners . Further support came from the Canada Research Chairs Program (DPT). The funding sources played no role in the study design, execution, or process of publishing.
Funding Information:
ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.The Ci-VSP clone was a generous gift from Dr. H.P. Larsson, who also provided insightful comments on the manuscript. We thank Dr. Xiongyu Wu for synthesis of different endocannabinoids and Veronika A. Linhart for help with illustrations. This work was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 850622) and the Canadian Institutes of Health Research (DPT). Computational resources were provided by the Swedish National Infrastructure for Computing (2021/5-41), and by Compute Canada, funded by the Canada Foundation for Innovation and partners. Further support came from the Canada Research Chairs Program (DPT). The funding sources played no role in the study design, execution, or process of publishing.
Publisher Copyright:
© 2023 The Author(s)
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