Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.
EBioMedicine. 2023 Mar;89:104459. doi: 10.1016/j.ebiom.2023.104459. Epub 2023 Feb 14.
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 K7.1/KCNE1, which is the most frequently mutated ion channel in LQTS.
We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts.
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 K7.1/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.
We consider the endocannabinoids as an interesting class of hK7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts.
ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.
患有心脏通道病长 QT 综合征 (LQTS) 的基因型阳性患者可能表现出一系列临床表型，其病因通常未知。因此，需要确定影响疾病严重程度的因素，以便朝着 LQTS 的个体化临床管理方向发展。一个可能影响疾病表型的因素是内源性大麻素系统，它已成为心血管功能的调节剂。在这项研究中，我们旨在阐明内源性大麻素是否靶向心脏电压门控钾通道 K7.1/KCNE1，这是 LQTS 中最常突变的离子通道。
我们使用双电极电压钳、分子动力学模拟和 E4031 药物诱导的豚鼠离体心脏 LQT2 模型。
我们发现了一组内源性大麻素，它们促进通道激活，表现为通道开放的电压依赖性移位和整体电流幅度和电导增加。我们提出带负电荷的内源性大麻素与通道上带正电荷的氨基酸上已知的脂质结合位点相互作用，为为什么只有特定的内源性大麻素调节 K7.1/KCNE1 提供了结构见解。使用内源性大麻素 ARA-S 作为原型，我们表明该效应不依赖于 KCNE1 亚基或通道的磷酸化状态。在豚鼠心脏中，发现 ARA-S 可逆转 E4031 延长的动作电位持续时间和 QT 间期。
我们认为内源性大麻素是 hK7.1/KCNE1 通道的一类有趣调节剂，在 LQTS 情况下具有潜在的保护作用。
欧洲研究理事会（No. 850622）、加拿大卫生研究院、加拿大主席和 Compute Canada、瑞典国家计算基础设施。
