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Molecular Pharmacology

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Research ArticleArticle

Molecular Determinants for Activation of Human Ether-à-go-go-related Gene 1 Potassium Channels by 3-Nitro-N-(4-phenoxyphenyl) Benzamide

Vivek Garg, Anna Stary-Weinzinger, Frank Sachse and Michael C. Sanguinetti
Molecular Pharmacology October 2011, 80 (4) 630-637; DOI: https://doi.org/10.1124/mol.111.073809
Vivek Garg
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Anna Stary-Weinzinger
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Frank Sachse
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Michael C. Sanguinetti
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Abstract

Human ether-à-go-go-related gene 1 (hERG1) channels mediate repolarization of cardiac action potentials. Inherited long QT syndrome (LQTS) caused by loss-of-function mutations, or unintended blockade of hERG1 channels by many drugs, can lead to severe arrhythmia and sudden death. Drugs that activate hERG1 are a novel pharmacological approach to treat LQTS. 3-Nitro-n-(4-phenoxyphenyl) benzamide [ICA-105574 (ICA)] has been discovered to activate hERG1 by strong attenuation of pore-type inactivation. Here, we used scanning mutagenesis of hERG1 to identify the molecular determinants of ICA action. Three mutations abolished the activator effects of 30 μM ICA, including L622C in the pore helix, F557L in the S5 segment, and Y652A in the S6 segment. One mutation in S6 (A653M) switched the activity of ICA from an activator to an inhibitor, revealing its partial agonist activity. This was confirmed by showing that the noninactivating mutant hERG1 channel (G628C/S631C) was inhibited by ICA and that the addition of the F557L mutation rendered the channel drug-insensitive. Simulated molecular docking of ICA to homology models of hERG1 corroborated the scanning mutagenesis findings. Together, our findings indicate that ICA is a mixed agonist of hERG1 channels. Activation or inhibition of currents is mediated by the same or overlapping binding site located in the pore module between two adjacent subunits of the homotetrameric channel.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL055236]; an American Heart Association (Western States Affiliate) postdoctoral fellowship; and The Austrian Science Fund [Grant P22395].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.073809.

  • ABBREVIATIONS:

    hERG1
    human ether-à-go-go-related gene 1
    Itest
    current activated by membrane depolarization
    Itail
    tail current
    LQTS
    long QT syndrome
    ICA
    ICA-105574, 3-nitro-N-(4-phenoxyphenyl) benzamide
    Vt
    test potential
    WT
    wild type
    DMSO
    dimethyl sulfoxide
    PH/SF
    pore helix/selectivity filter
    TdP
    torsades de pointes
    P
    pore
    RPR260243
    (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)-3-oxo-propyl)-1-(3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl)-piperidine-3-carboxylic acid
    PD-118057
    2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid
    MES
    4-morpholine ethanesulfonic acid
    MD
    molecular dynamics
    NS1643
    1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea
    (±)BayK 8644
    1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester.

  • Received June 2, 2011.
  • Accepted July 8, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (4)
Molecular Pharmacology
Vol. 80, Issue 4
1 Oct 2011
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Research ArticleArticle

hERG1 Channel Activator

Vivek Garg, Anna Stary-Weinzinger, Frank Sachse and Michael C. Sanguinetti
Molecular Pharmacology October 1, 2011, 80 (4) 630-637; DOI: https://doi.org/10.1124/mol.111.073809

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Research ArticleArticle

hERG1 Channel Activator

Vivek Garg, Anna Stary-Weinzinger, Frank Sachse and Michael C. Sanguinetti
Molecular Pharmacology October 1, 2011, 80 (4) 630-637; DOI: https://doi.org/10.1124/mol.111.073809
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