Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels
- Philipps-Universität Marburg, Germany
- Max-Planck-Institut für experimentelle Medizin, Germany
- Universität des Saarlandes, Germany
- Medical Faculty Mannheim of Heidelberg University, Germany
- University of Freiburg, Germany
- Universität Tübingen, Germany
- Dalhousie University, Canada
- Philipp University of Marburg, Germany
- University of Illinois College of Medicine, United States
Abstract
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 ganglion cells 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.
Article and author information
Author details
Johannes Oberwinkler
Funding
Deutsche Forschungsgemeinschaft (Emmy Noether Programm)
- Manuela Schmidt
Deutsche Forschungsgemeinschaft (GK 1326)
- Johannes Oberwinkler
Max-Planck-Gesellschaft (PhD fellowship)
- Julia Sondermann
Philipps-Universität Marburg (MARA PhD fellowship)
- Christian Goecke
Deutsche Forschungsgemeinschaft (SFB 593)
- Johannes Oberwinkler
Deutsche Forschungsgemeinschaft (SFB 894)
- Johannes Oberwinkler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experimentation was approved and carried out in strict compliance withinstitutional guidelines of the Max Planck Society and guidelines of the Landesamt fürVerbraucherschutz und Lebensmittelsicherheit of Lower Saxony, Germany (AZ 33.9-42502-04-14/1638)
Copyright
© 2017, Dembla 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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Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels
eLife 6:e26280.
https://doi.org/10.7554/eLife.26280
Further reading
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- Neuroscience
Transient receptor potential melastatin 3 (TRPM3) channels are activated by heat, and chemical ligands such as pregnenolone sulphate (PregS) and CIM0216. Here, we show that activation of receptors coupled to heterotrimeric Gi/o proteins inhibits TRPM3 channels. This inhibition was alleviated by co-expression of proteins that bind the βγ subunits of heterotrimeric G-proteins (Gβγ). Co-expression of Gβγ, but not constitutively active Gαi or Gαo, inhibited TRPM3 currents. TRPM3 co-immunoprecipitated with Gβ, and purified Gβγ proteins applied to excised inside-out patches inhibited TRPM3 currents, indicating a direct effect. Baclofen and somatostatin, agonists of Gi-coupled receptors, inhibited Ca2+ signals induced by PregS and CIM0216 in mouse dorsal root ganglion (DRG) neurons. The GABAB receptor agonist baclofen also inhibited inward currents induced by CIM0216 in DRG neurons, and nocifensive responses elicited by this TRPM3 agonist in mice. Our data uncover a novel signaling mechanism regulating TRPM3 channels.
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- Neuroscience
G protein-coupled receptor stimulation inhibits TRPM3 channel activity through direct binding of the Gβγ subunit to the channel.
