Subunit-specific modulation of T-type calcium channels by zinc

Authors

  • Achraf Traboulsie,

    1. Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France
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  • Jean Chemin,

    1. Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France
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  • Marc Chevalier,

    1. Laboratoire de Signalisation et Interactions Cellulaires, CNRS UMR 5017, Université de Bordeaux II, UFR Sciences Pharmaceutiques, 146 rue Léo Saignat, 33076 Bordeaux cedex, France
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  • Jean-François Quignard,

    1. Laboratoire de Signalisation et Interactions Cellulaires, CNRS UMR 5017, Université de Bordeaux II, UFR Sciences Pharmaceutiques, 146 rue Léo Saignat, 33076 Bordeaux cedex, France
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  • Joël Nargeot,

    1. Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France
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  • Philippe Lory

    1. Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France
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Corresponding author P. Lory: Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203, INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier cedex 05, France. Email: philippe.lory@igf.cnrs.fr

Abstract

Zinc (Zn2+) functions as a signalling molecule in the nervous system and modulates many ionic channels. In this study, we have explored the effects of Zn2+ on recombinant T-type calcium channels (CaV3.1, CaV3.2 and CaV3.3). Using tsA-201 cells, we demonstrate that CaV3.2 current (IC50, 0.8 μm) is significantly more sensitive to Zn2+ than are CaV3.1 and CaV3.3 currents (IC50, 80 μm and ∼160 μm, respectively). This inhibition of CaV3 currents is associated with a shift to more negative membrane potentials of both steady-state inactivation for CaV3.1, CaV3.2 and CaV3.3 and steady-state activation for CaV3.1 and CaV3.3 currents. We also document changes in kinetics, especially a significant slowing of the inactivation kinetics for CaV3.1 and CaV3.3, but not for CaV3.2 currents. Notably, deactivation kinetics are significantly slowed for CaV3.3 current (∼100-fold), but not for CaV3.1 and CaV3.2 currents. Consequently, application of Zn2+ results in a significant increase in CaV3.3 current in action potential clamp experiments, while CaV3.1 and CaV3.2 currents are significantly reduced. In neuroblastoma NG 108-15 cells, the duration of CaV3.3-mediated action potentials is increased upon Zn2+ application, indicating further that Zn2+ behaves as a CaV3.3 channel opener. These results demonstrate that Zn2+ exhibits differential modulatory effects on T-type calcium channels, which may partly explain the complex features of Zn2+ modulation of the neuronal excitability in normal and disease states.

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