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A TRP channel trio mediates acute noxious heat sensing

Nature volume 555, pages 662666 (29 March 2018) | Download Citation

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Abstract

Acute pain represents a crucial alarm signal to protect us from injury1. Whereas the nociceptive neurons that convey pain signals were described more than a century ago2, the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified3,4,5,6. Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional. However, combined genetic or pharmacological elimination of all three channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and Aδ sensory nerve fibres that innervate the skin. Strikingly, Trpv1−/−Trpm3−/−Trpa1−/− triple knockout (TKO) mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. These findings indicate that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on three functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.

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Acknowledgements

We thank all members of the Laboratories of Ion Channel Research and Experimental Gynecology and Obstetrics for comments and discussion, and K. Luyten for assistance with histological and in situ staining. This work was supported by grants from the KU Leuven Research Council (PF-TRPLe and C1-TRPLe to Tho.V. and R.V.), the Research Foundation-Flanders (FWO G.084515N to J.V. and Tho.V. and G.099114N to Tho.V. and Thi.V.), the Queen Elisabeth Medical Foundation for Neurosciences (to Tho.V.), the Belgian Foundation Against Cancer (to J.V. and Tho.V.) and the Planckaert-De Waele fund (to J.V.). K.D.C. and K.H. are holders of a doctoral fellowship of the FWO Belgium.

Author information

Author notes

    • Joris Vriens
    •  & Thomas Voets

    These authors jointly supervised this work.

Affiliations

  1. Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium

    • Ine Vandewauw
    • , Katrien De Clercq
    • , Marie Mulier
    • , Katharina Held
    • , Silvia Pinto
    • , Nele Van Ranst
    • , Andrei Segal
    • , Rudi Vennekens
    •  & Thomas Voets
  2. VIB Center for Brain & Disease Research, Leuven, Belgium

    • Ine Vandewauw
    • , Katrien De Clercq
    • , Marie Mulier
    • , Katharina Held
    • , Silvia Pinto
    • , Nele Van Ranst
    • , Andrei Segal
    • , Rudi Vennekens
    •  & Thomas Voets
  3. Laboratory of Experimental Gynecology and Obstetrics, Department of Development and Regeneration, University of Leuven, Leuven, Belgium

    • Katrien De Clercq
    • , Katharina Held
    •  & Joris Vriens
  4. Laboratory of Reproductive Genomics, Department of Human Genetics, University of Leuven, Leuven, Belgium

    • Thierry Voet
  5. Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany.

    • Katharina Zimmermann

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Contributions

I.V., M.M. and J.V. performed cellular calcium imaging experiments. I.V. designed, performed and analysed all skin nerve recordings, with technical input and guidance from K.Z. and A.S. K.H., J.V. and Tho.V. performed patch-clamp experiments. I.V., K.D.C, K.H., S.P., M.M. and J.V. performed behavioural experiments. K.D.C. and N.V.R. performed histological analyses. I.V., Thi.V. and A.S. performed and analysed RNA-seq experiments. S.P. generated DKO and TKO mice, with supervision by R.V. I.V. and Tho.V. wrote the manuscript with input from all co-authors. J.V. and Tho.V. initiated and supervised the entire project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Joris Vriens or Thomas Voets.

Reviewer Information Nature thanks J. Wood and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Videos

  1. 1.

    Tail immersion assay of a WT and a TKO mouse.

    Video showing the tail immersion assay at 57 °C in a wild type and a TKO mouse.

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DOI

https://doi.org/10.1038/nature26137

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