1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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Structural determinants of voltage-gating properties in calcium channels

  1. Monica L Fernández-Quintero
  2. Yousra El Ghaleb
  3. Petronel Tuluc
  4. Marta Campiglio
  5. Klaus R Liedl
  6. Bernhard E Flucher  Is a corresponding author
  1. Medical University Innsbruck, Austria
  2. University of Innsbruck, Austria
Research Article
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Cite this article as: eLife 2021;10:e64087 doi: 10.7554/eLife.64087

Abstract

Voltage-gated calcium channels control key functions of excitable cells, like synaptic transmission in neurons and the contraction of heart and skeletal muscles. To accomplish such diverse functions, different calcium channels activate at different voltages and with distinct kinetics. To identify the molecular mechanisms governing specific voltage-sensing properties we combined structure modeling, mutagenesis, and electrophysiology to analyze the structures, free energy, and transition kinetics of the activated and resting states of two functionally distinct voltage-sensing domains (VSDs) of the eukaryotic calcium channel CaV1.1. Both VSDs displayed the typical features of the sliding helix model; however, they greatly differed in ion-pair formation of the outer gating charges. Specifically, stabilization of the activated state enhanced the voltage-dependence of activation, while stabilization of resting states slowed the kinetics. This mechanism provides a mechanistic model explaining how specific ion-pair formation in separate VSDs can realize the characteristic gating properties of voltage-gated cation channels.

Article and author information

Author details

  1. Monica L Fernández-Quintero

    Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6811-6283
  2. Yousra El Ghaleb

    Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  3. Petronel Tuluc

    Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  4. Marta Campiglio

    Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9629-2073
  5. Klaus R Liedl

    Theoretical Chemistry, University of Innsbruck, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0985-2299
  6. Bernhard E Flucher

    Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
    For correspondence
    bernhard.e.flucher@i-med.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5255-4705

Funding

Austrian Science Fund (P30402)

  • Bernhard E Flucher

Austrian Science Fund (DOC30)

  • Bernhard E Flucher

Austrian Science Fund (T855)

  • Marta Campiglio

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Toby W Allen, RMIT University, Australia

Publication history

  1. Received: October 16, 2020
  2. Accepted: March 29, 2021
  3. Accepted Manuscript published: March 30, 2021 (version 1)

Copyright

© 2021, Fernández-Quintero et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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