Wang Yundi, Chan Magnus, Pourrier Marc, Eldstrom Jodene, Fedida David
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Channels (Austin). 2025 Dec;19(1):2539494. doi: 10.1080/19336950.2025.2539494. Epub 2025 Jul 29.
The current formed by the co-assembly of KCNE1 and KCNQ1 plays an important role in cardiac repolarization. Mefenamic acid, an NSAID, is known to enhance currents and has in turn been suggested as a therapeutic starting point for the development of compounds for the treatment of long QT syndrome. Our previous examinations of mefenamic acid's action revealed that residue K41 on KCNE1 was critical for mefenamic acid's activating effect on fully KCNE1 saturated, and partially saturated channel complexes. The present study extends our previous work by incorporating the K41C-KCNE1 mutation into individual subunits to destabilize local mefenamic acid binding and explore how many of the remaining mefenamic acid-bound WT KCNE1-KCNQ1 subunits are required to support the activating action of the drug. Our results show that the potency of mefenamic acid action is reduced by the presence of K41C-KCNE1 subunits in a graded and stoichiometric, but non-linear manner. Modeling results are consistent with the idea that WT subunits, in the presence of mefenamic acid, precede activation of K41C- subunits due to their augmented voltage sensor kinetics.
KCNE1和KCNQ1共同组装形成的电流在心脏复极化过程中起着重要作用。甲芬那酸是一种非甾体抗炎药，已知它能增强电流，因此被建议作为开发治疗长QT综合征化合物的治疗起点。我们之前对甲芬那酸作用的研究表明，KCNE1上的K41残基对于甲芬那酸对完全KCNE1饱和以及部分饱和通道复合物的激活作用至关重要。本研究通过将K41C-KCNE1突变引入单个亚基来扩展我们之前的工作，以破坏局部甲芬那酸结合，并探索需要多少剩余的与甲芬那酸结合的野生型KCNE1-KCNQ1亚基来支持该药物的激活作用。我们的结果表明，K41C-KCNE1亚基的存在以分级、化学计量但非线性的方式降低了甲芬那酸作用的效力。建模结果与以下观点一致：在甲芬那酸存在的情况下，野生型亚基由于其增强的电压感受器动力学而先于K41C-亚基激活。
