Choi, Kee-Hyun Song, Chiman Shin, Dongyun Park, Sungnam 2024-01-20T17:01:36Z 2024-01-20T17:01:36Z 2021-09-05 2011-06 0005-2736 https://pubs.kist.re.kr/handle/201004/130302 The human ether-a-go-go related gene potassium channel is a key player in cardiac rhythm regulation, thus being an important subject for a cardiac toxicity test. Ever since human ether-a-go-go related gene channel inhibition-related cardiac arrest was proven to be fatal, numerous numbers of data on human ether-a-go-go related gene channel inhibition have been piled up. However, there has been no quantitative study on human ether-a-go-go related gene channel inhibition by quaternary ammonium derivatives, well-known potassium channel blockers. Here, we present human ether-a-go-go related gene channel blockade by externally applied quaternary ammonium derivatives using automated whole-cell patch-clamp recordings as well as ab initio quantum calculations. The inhibitory constants and the relative binding energies for human ether-a-go-go related gene channel inhibition were obtained from quaternary ammoniums with systematically varied head and tail groups, indicating that more hydrophobic quaternary ammoniums have higher affinity blockade while cation-pi interactions or size effects are not a deterministic factor for human ether-a-go-go related gene channel inhibition by quaternary ammoniums. Further studies on the effect of quaternary ammoniums on human ether-a-go-go related gene channel inactivation implied that hydrophobic quaternary ammoniums either with a longer tail group or with a bigger head group than tetraethylammonium permeate the cell membrane to easily access the high-affinity internal binding site in human ether-a-go-go related gene channel and exert stronger blockade. These results may be informative for the rational drug design to avoid cardiac toxicity. (C) 2011 Elsevier B.V. All rights reserved. English ELSEVIER SCIENCE BV LONG QT SYNDROME POTASSIUM CHANNELS BINDING-SITE THROUGHPUT ELECTROPHYSIOLOGY TETRAETHYLAMMONIUM ION CARDIAC-ARRHYTHMIA STRUCTURAL BASIS DRUG-BINDING INACTIVATION PROLONGATION hERG channel blockade by externally applied quaternary ammonium derivatives Article 10.1016/j.bbamem.2011.02.008 1 BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, v.1808, no.6, pp.1560 - 1566 BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 1808 6 1560 1566 scie scopus 000290705700016 2-s2.0-79954838525 Biochemistry & Molecular Biology Biophysics Biochemistry & Molecular Biology Biophysics Article LONG QT SYNDROME POTASSIUM CHANNELS BINDING-SITE THROUGHPUT ELECTROPHYSIOLOGY TETRAETHYLAMMONIUM ION CARDIAC-ARRHYTHMIA STRUCTURAL BASIS DRUG-BINDING INACTIVATION PROLONGATION hERG channel Quaternary ammonium Hydrophobicity Cation-pi interaction Inactivation