G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons

  1. Talisia Quallo  Is a corresponding author
  2. Omar Alkhatib
  3. Clive Gentry
  4. David A Andersson
  5. Stuart Bevan  Is a corresponding author
  1. King's College London, United Kingdom

Abstract

Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by phosphoinositide PI(4,5)P2 hydrolysis and changes in the level of protein kinase mediated phosphorylation following activation of various G protein coupled receptors. We now show that the activity of TRPM3 expressed in mouse dorsal root ganglion (DRG) neurons is inhibited by agonists of the Gi-coupled µ opioid, GABA-B and NPY receptors. These agonist effects are mediated by direct inhibition of TRPM3 by Gβγ subunits, rather than by a canonical cAMP mediated mechanism. The activity of TRPM3 in DRG neurons is also negatively modulated by tonic, constitutive GPCR activity as TRPM3 responses can be potentiated by GPCR inverse agonists. GPCR regulation of TRPM3 is also seen in vivo where Gi/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.

Article and author information

Author details

  1. Talisia Quallo

    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
    For correspondence
    talisia.quallo@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1998-5597
  2. Omar Alkhatib

    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Clive Gentry

    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1148-8203
  4. David A Andersson

    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7451-8548
  5. Stuart Bevan

    Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom
    For correspondence
    stuart.bevan@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8977-1797

Funding

Medical Research Council (MR/L010747/1)

  • David A Andersson
  • Stuart Bevan

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 animal studies were carried out according to the U.K. Home Office Animal Procedures (1986) Act and were approved by the King's College London Animal Welfare and Ethical Review Board (UK Home Office PPL 70/7510). Mice were killed by cervical dislocation.

Version history

  1. Received: February 20, 2017
  2. Accepted: July 24, 2017
  3. Accepted Manuscript published: August 15, 2017 (version 1)
  4. Version of Record published: September 11, 2017 (version 2)

Copyright

© 2017, Quallo 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.

Metrics

  • 3,191
    Page views
  • 527
    Downloads
  • 69
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Talisia Quallo
  2. Omar Alkhatib
  3. Clive Gentry
  4. David A Andersson
  5. Stuart Bevan
(2017)
G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons
eLife 6:e26138.
https://doi.org/10.7554/eLife.26138

Share this article

https://doi.org/10.7554/eLife.26138

Further reading

    1. Neuroscience
    Sandeep Dembla, Marc Behrendt ... Johannes Oberwinkler
    Research Article Updated

    Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.

    1. Neuroscience
    László Csanády
    Insight

    G protein-coupled receptor stimulation inhibits TRPM3 channel activity through direct binding of the Gβγ subunit to the channel.