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Molecular determinants of human ether-a-go-go-related gene 1 (hERG1) K+ channel activation by NS1643.

ABSTRACT: Human ether-à-go-go-related gene 1 (hERG1) channels conduct the rapid delayed rectifier K+ current, I(Kr), an important determinant of action potential repolarization in mammals, including humans. Reduced I(Kr) function caused by mutations in KCNH2 or drug block of hERG1 channels prolongs the QT interval of the electrocardiogram and increases the risk of ventricular fibrillation and sudden cardiac death. Several activators of hERG1 channels have been discovered in recent years. These compounds shorten the duration of cardiac action potentials and have been proposed as a new therapeutic approach for the treatment of acquired or congenital long QT syndrome. We defined previously the mechanism of action of 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643), a compound that increases hERG1 currents by shifting the voltage-dependence of inactivation to more positive potentials. Here, we use scanning mutagenesis of hERG1 and functional characterization of 56 mutant channels heterologously expressed in Xenopus laevis oocytes to define the molecular determinants of the binding site for NS1643. Most point mutations did not alter response to the drug; however, 10 mutant channels had reduced sensitivity, and F619A and I567A exhibited enhanced activation by the drug. Some of these residues form a cluster and, together with molecular modeling, suggest that NS1643 binds to a pocket near the extracellular ends of the S5/S6 segments of two adjacent hERG1 channel subunits. This putative binding site differs from the sites described previously for two other hERG1 activators, (3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) and 2-(4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid (PD-118057).

SUBMITTER: Grunnet M

PROVIDER: S-EPMC3014275 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Molecular determinants of human ether-à-go-go-related gene 1 (hERG1) K+ channel activation by NS1643.

Grunnet Morten M Abbruzzese Jennifer J Sachse Frank B FB Sanguinetti Michael C MC

Molecular pharmacology 20100927 1

Human ether-à-go-go-related gene 1 (hERG1) channels conduct the rapid delayed rectifier K+ current, I(Kr), an important determinant of action potential repolarization in mammals, including humans. Reduced I(Kr) function caused by mutations in KCNH2 or drug block of hERG1 channels prolongs the QT interval of the electrocardiogram and increases the risk of ventricular fibrillation and sudden cardiac death. Several activators of hERG1 channels have been discovered in recent years. These compounds s ...[more]

PMID: 20876384

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Project description:Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed.To meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments.This new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

Dataset Information

Molecular determinants of human ether-a-go-go-related gene 1 (hERG1) K+ channel activation by NS1643.

Publications

Molecular determinants of human ether-à-go-go-related gene 1 (hERG1) K+ channel activation by NS1643.

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