1. Structural Biology and Molecular Biophysics
  2. Neuroscience

Definition of two agonist types at the mammalian cold-activated channel TRPM8

  1. Janssens Annelies
  2. Maarten Gees
  3. Balazs Istvan Toth
  4. Debapriya Ghosh
  5. Marie Mulier
  6. Rudi Vennekens
  7. Joris Vriens
  8. Karel Talavera
  9. Thomas Voets  Is a corresponding author
  1. University of Leuven, Belgium
https://doi.org/10.7554/eLife.17240
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  1. Janssens Annelies
  2. Maarten Gees
  3. Balazs Istvan Toth
  4. Debapriya Ghosh
  5. Marie Mulier
  6. Rudi Vennekens
  7. Joris Vriens
  8. Karel Talavera
  9. Thomas Voets
(2016)
Definition of two agonist types at the mammalian cold-activated channel TRPM8
eLife 5:e17240.
https://doi.org/10.7554/eLife.17240
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  3. Download .RIS

Abstract

Various TRP channels act as polymodal sensors of thermal and chemical stimuli, but the mechanisms whereby chemical ligands impact on TRP channel gating are poorly understood. Here we show that AITC (allyl isothiocyanate; mustard oil) and menthol represent two distinct types of ligands at the mammalian cold sensor TRPM8. Kinetic analysis of channel gating revealed that AITC acts by destabilizing the closed channel, whereas menthol stabilizes the open channel, relative to the transition state. Based on these differences, we classify agonists as either type I (menthol-like) or type II (AITC-like), and provide a kinetic model that faithfully reproduces their differential effects. We further demonstrate that type I and type II agonists have a distinct impact on TRPM8 currents and TRPM8-mediated calcium signals in excitable cells. These findings provide a theoretical framework for understanding the differential actions of TRP channel ligands, with important ramifications for TRP channel structure-function analysis and pharmacology.

Article and author information

Author details

  1. Janssens Annelies

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  2. Maarten Gees

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  3. Balazs Istvan Toth

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  4. Debapriya Ghosh

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  5. Marie Mulier

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  6. Rudi Vennekens

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  7. Joris Vriens

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  8. Karel Talavera

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  9. Thomas Voets

    Laboratory of Ion Channel Research, University of Leuven, Leuven, Belgium
    For correspondence
    thomas.voets@med.kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5526-5821

Funding

Fonds Wetenschappelijk Onderzoek (G.0565.07)

  • Thomas Voets

Onderzoeksraad, KU Leuven (PF-TRPLe)

  • Rudi Vennekens
  • Thomas Voets

Belspo (IUAP P7/13)

  • Rudi Vennekens
  • Karel Talavera
  • Thomas Voets

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

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Ethics

Animal experimentation: All experiments were approved by the KU Leuven Ethical Committee Laboratory Animals under project number P192/2014.

Version history

  1. Received: April 25, 2016
  2. Accepted: July 22, 2016
  3. Accepted Manuscript published: July 23, 2016 (version 1)
  4. Accepted Manuscript updated: July 25, 2016 (version 2)
  5. Version of Record published: August 15, 2016 (version 3)

Copyright

© 2016, Annelies 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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  1. Janssens Annelies
  2. Maarten Gees
  3. Balazs Istvan Toth
  4. Debapriya Ghosh
  5. Marie Mulier
  6. Rudi Vennekens
  7. Joris Vriens
  8. Karel Talavera
  9. Thomas Voets
(2016)
Definition of two agonist types at the mammalian cold-activated channel TRPM8
eLife 5:e17240.
https://doi.org/10.7554/eLife.17240

Share this article

https://doi.org/10.7554/eLife.17240

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