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Molecular Pharmacology

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Research ArticleArticle

Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter

Christian Lerche, Iva Bruhova, Holger Lerche, Klaus Steinmeyer, Aguan D. Wei, Nathalie Strutz-Seebohm, Florian Lang, Andreas E. Busch, Boris S. Zhorov and Guiscard Seebohm
Molecular Pharmacology June 2007, 71 (6) 1503-1511; DOI: https://doi.org/10.1124/mol.106.031682
Christian Lerche
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Iva Bruhova
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Holger Lerche
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Klaus Steinmeyer
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Aguan D. Wei
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Nathalie Strutz-Seebohm
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Florian Lang
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Andreas E. Busch
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Boris S. Zhorov
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Guiscard Seebohm
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This article has a correction. Please see:

  • Correction to “Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter” - September 01, 2007

Abstract

The chromanol 293B (293B, trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chroman) is a lead compound of potential class III antiarrhythmics that inhibit cardiac IKs potassium channels. These channels are formed by the coassembly of KCNQ1 (Kv7.1, KvLQT1) and KCNE1 subunits. Although homomeric KCNQ1 channels are the principal molecular targets, entry of KCNE1 to the channel complex enhances the chromanol block. Because closely related neuronal KCNQ2 potassium channels are insensitive to the drug, we used KCNQ1/KCNQ2 chimeras to identify the binding site of the inhibitor. We localized the putative drug receptor to the H5 selectivity filter and the S6 transmembrane segment. Single residues affecting 293B inhibition were subsequently identified through systematic exchange of amino acids that were either different in KCNQ1 and KCNQ2 or predicted by a docking model of 293B in the open and closed conformation of KCNQ1. Mutant channel proteins T312S, I337V, and F340Y displayed dramatically lowered sensitivity to chromanol block. The predicted drug binding receptor lies in the inner pore vestibule containing the lower part of the selectivity filter, and the S6 transmembrane domain also reported to be important for binding of benzodiazepines. We propose that the block of the ion permeation pathway involves hydrophobic interactions with the S6 transmembrane residues Ile337 and Phe340, and stabilization of chromanol 293B binding through electrostatic interactions of its oxygen atoms with the most internal potassium ion within the selectivity filter.

Footnotes

  • This work was supported by Aventis Pharma Deutschland GmbH and a grant from the National Sciences and Engineering Research Council of Canada (to B.S.Z.). Computations were performed, in part, using the SHARCNET Supercomputer Centre at McMaster University.

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

  • doi:10.1124/mol.106.031682.

  • ABBREVIATIONS: HERG, human ether-a-go-go-related gene; 293B, chromanol 293B (trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chroman); TEVC, two-electrode voltage-clamp technique.

    • Received October 19, 2006.
    • Accepted March 6, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter

Christian Lerche, Iva Bruhova, Holger Lerche, Klaus Steinmeyer, Aguan D. Wei, Nathalie Strutz-Seebohm, Florian Lang, Andreas E. Busch, Boris S. Zhorov and Guiscard Seebohm
Molecular Pharmacology June 1, 2007, 71 (6) 1503-1511; DOI: https://doi.org/10.1124/mol.106.031682

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Research ArticleArticle

Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter

Christian Lerche, Iva Bruhova, Holger Lerche, Klaus Steinmeyer, Aguan D. Wei, Nathalie Strutz-Seebohm, Florian Lang, Andreas E. Busch, Boris S. Zhorov and Guiscard Seebohm
Molecular Pharmacology June 1, 2007, 71 (6) 1503-1511; DOI: https://doi.org/10.1124/mol.106.031682
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