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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 K V 7.1/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 K V 7.1/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 hK V 7.1/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., Competing Interests: Declaration of interests A patent application (#62/032,739) including a description of the interaction of charged lipophilic compounds with the K(V)7.1 channel has been submitted by the University of Miami with S.I.L. identified as one of the inventors. The other authors have no conflict of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)