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- Erlandsdotter, Lisa-Marie, et al.
(författare)
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Long-QT mutations in KCNE1 modulate the 1713-estradiol response of Kv7.1/KCNE1
- 2023
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Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Estradiol (1713-E2) is implicated in higher arrhythmia risk of women with congenital or acquired long-QT syn-drome (LQTS) compared to men. However, the underlying mechanisms remain poorly understood, and little is known about the impact of LQTS-associated mutations. We show that 1713-E2 inhibits the human cardiac Kv7.1/ KCNE1 channel expressed in Xenopus oocytes. We find that the 1713-E2 effect depends on the Kv7.1 to KCNE1 stoichiometry, and we reveal a critical function of the KCNE1 carboxyl terminus for the effect. LQTS-associated mutations in the KCNE1 carboxyl terminus show a range of responses to 1713-E2, from a wild-type like response to impaired or abolished response. Together, this study increases our understanding of the mechanistic basis for 1713-E2 inhibition of Kv7.1/KCNE1 and demonstrates mutation-dependent responses to 1713-E2. These findings suggest that the 1713-E2 effect on Kv7.1/KCNE1 might contribute to the higher arrhythmia risk of women, par-ticularly in carriers with specific LQTS-associated mutations.
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| 2. |
- Hiniesto Iñigo, Irene, et al.
(författare)
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Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval
- 2023
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Ingår i: EBioMedicine. - : ELSEVIER. - 2352-3964. ; 89
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Tidskriftsartikel (refereegranskat)abstract
- 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 cardio-vascular 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.Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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