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Molecular Pharmacology

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Research ArticleArticle

Cd2+ Block and Permeation of CaV3.1 (α1G) T-Type Calcium Channels: Candidate Mechanism for Cd2+ Influx

Kyle V. Lopin, Frank Thévenod, Jessica C. Page and Stephen W. Jones
Molecular Pharmacology December 2012, 82 (6) 1183-1193; DOI: https://doi.org/10.1124/mol.112.080176
Kyle V. Lopin
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (K.V.L., S.W.J.); Center for Biomedical Research and Education, Institute for Physiology and Pathophysiology, Witten/Herdecke University, Witten, Germany (F.T.); and University of Buffalo, Buffalo, New York (J.C.P.)
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Frank Thévenod
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (K.V.L., S.W.J.); Center for Biomedical Research and Education, Institute for Physiology and Pathophysiology, Witten/Herdecke University, Witten, Germany (F.T.); and University of Buffalo, Buffalo, New York (J.C.P.)
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Jessica C. Page
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (K.V.L., S.W.J.); Center for Biomedical Research and Education, Institute for Physiology and Pathophysiology, Witten/Herdecke University, Witten, Germany (F.T.); and University of Buffalo, Buffalo, New York (J.C.P.)
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Stephen W. Jones
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (K.V.L., S.W.J.); Center for Biomedical Research and Education, Institute for Physiology and Pathophysiology, Witten/Herdecke University, Witten, Germany (F.T.); and University of Buffalo, Buffalo, New York (J.C.P.)
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Abstract

Cd2+ is an industrial pollutant that can cause cytotoxicity in multiple organs. We examined the effects of extracellular Cd2+ on permeation and gating of Cav3.1 (α1G) channels stably transfected in HEK293 cells, by using whole-cell recording. With the use of instantaneous I-V currents (measured after strong depolarization) to isolate the effects on permeation, Cd2+ rapidly blocked currents with 2 mM Ca2+ in a voltage-dependent manner. The block caused by Cd2+ was relieved at more-hyperpolarized potentials, which suggests that Cd2+ can permeate through the selectivity filter of the channel into the cytosol. In the absence of other permeant ions (Ca2+ and Na+ replaced by N-methyl-d-glucamine), Cd2+ carried sizable inward currents through Cav3.1 channels (210 ± 20 pA at −60 mV with 2 mM Cd2+). Cav3.1 channels have a significant “window current” at that voltage (open probability, ∼1%), which makes them a candidate pathway for Cd2+ entry into cells during Cd2+ exposure. Incubation with radiolabeled 109Cd2+ confirmed uptake of Cd2+ into cells with Cav3.1 channels.

Footnotes

  • This work was supported in part by the Deutsche Forschungsgemeinschaft [Grant TH345/11-1] and the Stiftung Westermann-Westdorp.

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

    http://dx.doi.org/10.1124/mol.112.080176.

  • ABBREVIATIONS:

    ZIP
    Zrt- and Irt-like protein
    HBSS
    Hanks' balanced salt solution
    NMDG
    N-methyl-d-glucamine
    GHK
    Goldman-Hodgkin-Katz
    [Cd2+]o
    extracellular Cd2+ concentration
    NNC 55-0396
    (1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride.

  • Received May 22, 2012.
  • Accepted September 11, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Cd2+ Block and Permeation of CaV3.1 T-Type Calcium Channels

Kyle V. Lopin, Frank Thévenod, Jessica C. Page and Stephen W. Jones
Molecular Pharmacology December 1, 2012, 82 (6) 1183-1193; DOI: https://doi.org/10.1124/mol.112.080176

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Research ArticleArticle

Cd2+ Block and Permeation of CaV3.1 T-Type Calcium Channels

Kyle V. Lopin, Frank Thévenod, Jessica C. Page and Stephen W. Jones
Molecular Pharmacology December 1, 2012, 82 (6) 1183-1193; DOI: https://doi.org/10.1124/mol.112.080176
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