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Molecular Pharmacology

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Research ArticleArticle

Verapamil Block of T-Type Calcium Channels

Pamela Bergson, Gregory Lipkind, Steven P. Lee, Mark-Eugene Duban and Dorothy A. Hanck
Molecular Pharmacology March 2011, 79 (3) 411-419; DOI: https://doi.org/10.1124/mol.110.069492
Pamela Bergson
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Gregory Lipkind
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Steven P. Lee
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Mark-Eugene Duban
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Dorothy A. Hanck
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Abstract

Verapamil is a prototypical phenylalkylamine (PAA), and it was the first calcium channel blocker to be used clinically. It tonically blocks L-type channels in the inner pore with micromolar affinity, and its affinity increases at depolarized membrane potentials. In T-type calcium channels, verapamil blocks with micromolar affinity and has modestly increased affinity at depolarized potentials. We found that a related PAA, 4-desmethoxyverapamil (D888), is comparable with verapamil both in affinity and in state-dependence. Permanently charged verapamil was more effective intracellularly than neutral verapamil. Charged PAAs were able to access their binding site from both inside and outside the cell. Furthermore, membrane-impermeant [2-(trimethylammonium)ethyl]methanethiosulfonate was able to access the inner pore from outside of the cell. We examined a homology model of the T-type calcium channel to look for possible routes of drug entry. Mutation of L1825W produced a channel that was blocked significantly more slowly by charged verapamil from the outside, with an increase in apparent affinity when the drug was applied from the inside. Data suggest that T-type channels have a back pathway through which charged drugs can access the inner pore of the channel without passing through the plasma membrane.

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 [Grants R01-HL65680, T32-HL007381].

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

    doi:10.1124/mol.110.069492.

  • ABBREVIATIONS:

    CaV3.1
    the T-type voltage-gated calcium channel isoform
    PAA
    phenylalkylamine
    MTSET
    [2-(trimethylammonium)ethyl] methanethiosulfonate
    WT
    wild type
    HEK
    human embryonic kidney
    D888
    4-desmethoxyverapamil
    MTS
    methanethiosulfonate
    QX314
    2-((2,6-dimethylphenyl)amino)-N,N,N-triethyl-2-oxoethanaminium
    QX222
    2-((2,6-dimethylphenyl)amino)-N,N,N-trimethyl-2-oxoethanaminium.

  • Received October 19, 2010.
  • Accepted December 13, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Verapamil Block of T-Type Calcium Channels

Pamela Bergson, Gregory Lipkind, Steven P. Lee, Mark-Eugene Duban and Dorothy A. Hanck
Molecular Pharmacology March 1, 2011, 79 (3) 411-419; DOI: https://doi.org/10.1124/mol.110.069492

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Research ArticleArticle

Verapamil Block of T-Type Calcium Channels

Pamela Bergson, Gregory Lipkind, Steven P. Lee, Mark-Eugene Duban and Dorothy A. Hanck
Molecular Pharmacology March 1, 2011, 79 (3) 411-419; DOI: https://doi.org/10.1124/mol.110.069492
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