1. Neuroscience

Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination

  1. Sven Dannhäuser
  2. Thomas J Lux
  3. Chun Hu
  4. Mareike Selcho
  5. Jeremy T-C Chen
  6. Nadine Ehmann
  7. Divya Sachidanandan
  8. Sarah Stopp
  9. Dennis Pauls
  10. Matthias Pawlak
  11. Tobias Langenhan
  12. Peter Soba
  13. Heike L Rittner  Is a corresponding author
  14. Robert J Kittel  Is a corresponding author
  1. Leipzig University, Germany
  2. University Hospital Würzburg, Germany
  3. University of Hamburg, Germany
  4. University of Würzburg, Germany
  5. University Hopsitals of Wuerzburg, Germany
https://doi.org/10.7554/eLife.56738
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  1. Sven Dannhäuser
  2. Thomas J Lux
  3. Chun Hu
  4. Mareike Selcho
  5. Jeremy T-C Chen
  6. Nadine Ehmann
  7. Divya Sachidanandan
  8. Sarah Stopp
  9. Dennis Pauls
  10. Matthias Pawlak
  11. Tobias Langenhan
  12. Peter Soba
  13. Heike L Rittner
  14. Robert J Kittel
(2020)
Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination
eLife 9:e56738.
https://doi.org/10.7554/eLife.56738
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Abstract

Adhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previously, we reported that the Drosophila aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors (Scholz et al., 2017). Here, we show that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathological conditions. Optogenetic in vivo experiments indicate that CIRL lowers cAMP levels in both mechanosensory submodalities. However, contrasting its role in touch-sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display decreased Cirl1 expression during allodynia. Thus, cAMP-downregulation by CIRL exerts opposing effects on low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action facilitates the separation of mechanosensory signals carrying different physiological information.

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The presented data are summarized in Tables 1-3.

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Author details

  1. Sven Dannhäuser

    Institute of Biology, Department of Animal Physiology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Thomas J Lux

    Center for Interdisciplinary Pain Medicine, Department of Anaesthesiology, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1049-9872

  3. Chun Hu

    Center for Molecular Neurobiology, University Medical Campus, University of Hamburg, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  4. Mareike Selcho

    Institute of Biology, Department of Animal Physiology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.

  5. Jeremy T-C Chen

    Center for Interdisciplinary Pain Medicine, Department of Anaesthesiology, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Nadine Ehmann

    Institute of Biology, Department of Animal Physiology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.

  7. Divya Sachidanandan

    Institute of Biology, Department of Animal Physiology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8219-8177

  8. Sarah Stopp

    Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.

  9. Dennis Pauls

    Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.

  10. Matthias Pawlak

    Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  11. Tobias Langenhan

    Rudolf-Schönheimer-Institute of Biochemistry, Division of General Biochemistry, Leipzig University, Leipzig, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9061-3809

  12. Peter Soba

    Center for Molecular Neurobiology, University Medical Campus, University of Hamburg, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.

  13. Heike L Rittner

    Anesthsiology, University Hopsitals of Wuerzburg, Wuerzburg, Germany
    For correspondence
    rittner_h@ukw.de
    Competing interests
    The authors declare that no competing interests exist.

  14. Robert J Kittel

    Institute of Biology, Department of Animal Physiology, Leipzig University, Leipzig, Germany
    For correspondence
    rjkittel@me.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9199-4826

Funding

Deutsche Forschungsgemeinschaft (PA3241/2-1)

  • Mareike Selcho

Deutsche Forschungsgemeinschaft (RI817/13-1)

  • Heike L Rittner

Deutsche Forschungsgemeinschaft (FOR 2149/P03,TRR 166/B04,KI1460/4-1,KI1460/5-1)

  • Robert J Kittel

Deutsche Forschungsgemeinschaft (SPP 1926/SO1337/2-2,SO1337/4-1)

  • Peter Soba

Deutsche Forschungsgemeinschaft (FOR 2149/P01 and P03)

  • Tobias Langenhan

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

Ethics

Animal experimentation: Animal care and protocols were performed in accordance with international guidelines for the care and use of laboratory animals (EU Directive 2010/63/EU for animal experiments) and were approved by the Government of Unterfranken (protocol numbers 2-733 and 2-264).

Copyright

© 2020, Dannhäuser 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. Sven Dannhäuser
  2. Thomas J Lux
  3. Chun Hu
  4. Mareike Selcho
  5. Jeremy T-C Chen
  6. Nadine Ehmann
  7. Divya Sachidanandan
  8. Sarah Stopp
  9. Dennis Pauls
  10. Matthias Pawlak
  11. Tobias Langenhan
  12. Peter Soba
  13. Heike L Rittner
  14. Robert J Kittel
(2020)
Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination
eLife 9:e56738.
https://doi.org/10.7554/eLife.56738

Share this article

https://doi.org/10.7554/eLife.56738

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Further reading

    1. Neuroscience

    Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons

    Nicole Scholz, Chonglin Guan ... Robert J Kittel
    Research Article

    Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.