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Research ArticleArticle

Potassium Channel Block by a Tripartite Complex of Two Cationophilic Ligands and a Potassium Ion

Pavel I. Zimin, Bojan Garic, Silke B. Bodendiek, Cédrick Mahieux, Heike Wulff and Boris S. Zhorov
Molecular Pharmacology October 2010, 78 (4) 588-599; DOI: https://doi.org/10.1124/mol.110.064014
Pavel I. Zimin
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Bojan Garic
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Silke B. Bodendiek
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Cédrick Mahieux
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Heike Wulff
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Boris S. Zhorov
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Abstract

Voltage-gated potassium channels (Kv) are targets for drugs of large chemical diversity. Although hydrophobic cations block Kv channels with Hill coefficients of 1, uncharged electron-rich (cationophilic) molecules often display Hill coefficients of 2. The mechanism of the latter block is unknown. Using a combination of computational and experimental approaches, we mapped the receptor for the immunosuppressant PAP-1 (5-(4-phenoxybutoxy)psoralen), a high-affinity blocker of Kv1.3 channels in lymphocytes. Ligand-docking using Monte Carlo minimizations suggested a model in which two cationophilic PAP-1 molecules coordinate a K+ ion in the pore with their coumarin moieties, whereas the hydrophobic phenoxyalkoxy side chains extend into the intrasubunit interfaces between helices S5 and S6. We tested the model by generating 58 point mutants involving residues in and around the predicted receptor and then determined their biophysical properties and sensitivity to PAP-1 by whole-cell patch-clamp. The model correctly predicted the key PAP-1-sensing residues in the outer helix, the P-loop, and the inner helix and explained the Hill coefficient of 2 by demonstrating that the Kv1.3 pore can accommodate two or even four PAP-1 molecules. The model further explained the voltage-dependence of block by PAP-1 and its thousand-fold selectivity for Kv1.3 over non-Kv1 channels. The 23- to 125-fold selectivity of PAP-1 for Kv1.3 over other Kv1 channels is probably due to its preferential affinity to the C-type inactivated state, in which cessation of K+ flux stabilizes the tripartite PAP-1:K+:PAP-1 complex in the pore. Our study provides a new concept for potassium channel block by cationophilic ligands.

Footnotes

  • B.S.Z. and H.W. are joint senior authors.

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

  • This work was supported by the Natural Sciences and Engineering Research Council of Canada; Canadian Institutes of Health Research [Grant MOP-53229]; the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM076063]; and a predoctoral fellowship from the Howard Hughes Medical Institutes. The 800 MHz NMR experiments were made possible by the National Science Foundation [Grant DBI722538].

  • Computations were made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (available at http://www.sharcnet.ca).

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

    doi:10.1124/mol.110.064014.

  • ABBREVIATIONS:

    Kv
    voltage-gated potassium channel
    MC
    Monte Carlo
    MCM
    Monte Carlo minimization
    TEA
    tetraethylammonium
    k
    linkers L45
    o
    outer helix
    p
    a P-loop
    i
    inner helix
    AS-85
    5-[4-(4-phenoxyphenoxy)butoxy]psoralen
    SB4
    1,2-dihydro-N-methyl-4-(4-phenoxybutoxy)quinolin-2-one
    SB9
    5-(4-phenoxybutoxy)-2H-[1]benzopyran-2-one
    SB7
    9-(phenoxybutoxy)-9H-dibenzo[b,e]pyran
    SB23
    1-(4-phenoxybutoxy)anthraquinone
    SB24
    9-(4-phenoxybutoxy)phenanthrene
    PAP-1
    5-(4-phenoxybutoxy)psoralen
    PAPS
    4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione
    MK-499
    (+)-N-[1′ (6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4′-piperidin)-6-yl]methanesulfonamide] monohydrochloride
    TRAM-34
    1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole.

  • Received February 8, 2010.
  • Accepted June 30, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

Potassium Channel Block by a Tripartite Complex of Two Cationophilic Ligands and a Potassium Ion

Pavel I. Zimin, Bojan Garic, Silke B. Bodendiek, Cédrick Mahieux, Heike Wulff and Boris S. Zhorov
Molecular Pharmacology October 1, 2010, 78 (4) 588-599; DOI: https://doi.org/10.1124/mol.110.064014

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Research ArticleArticle

Potassium Channel Block by a Tripartite Complex of Two Cationophilic Ligands and a Potassium Ion

Pavel I. Zimin, Bojan Garic, Silke B. Bodendiek, Cédrick Mahieux, Heike Wulff and Boris S. Zhorov
Molecular Pharmacology October 1, 2010, 78 (4) 588-599; DOI: https://doi.org/10.1124/mol.110.064014
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