Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval
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Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval. / Hiniesto-Iñigo, Irene; Castro-Gonzalez, Laura M.; Corradi, Valentina; Skarsfeldt, Mark A.; Yazdi, Samira; Lundholm, Siri; Nikesjö, Johan; Noskov, Sergei Yu; Bentzen, Bo Hjorth; Tieleman, D. Peter; Liin, Sara I.
In: EBioMedicine, Vol. 89, 104459, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT interval
AU - Hiniesto-Iñigo, Irene
AU - Castro-Gonzalez, Laura M.
AU - Corradi, Valentina
AU - Skarsfeldt, Mark A.
AU - Yazdi, Samira
AU - Lundholm, Siri
AU - Nikesjö, Johan
AU - Noskov, Sergei Yu
AU - Bentzen, Bo Hjorth
AU - Tieleman, D. Peter
AU - Liin, Sara I.
N1 - Publisher Copyright: © 2023 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Electrophysiology
KW - KCNQ1
KW - Kv7
KW - Long QT Syndrome
KW - Molecular dynamics
UR - http://www.scopus.com/inward/record.url?scp=85147993724&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104459
DO - 10.1016/j.ebiom.2023.104459
M3 - Journal article
C2 - 36796231
AN - SCOPUS:85147993724
VL - 89
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 104459
ER -
ID: 337573559