Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • News & Views
  • Published:

RECEPTOR PHARMACOLOGY

A modulator-bound GPCR structure enables allosteric non-opioid analgesia

Nature Structural & Molecular Biology volume 28, pages 871–872 (2021)Cite this article

Subjects

Structural studies of a positive allosteric modulator of the adenosine A1 receptor demonstrate the mechanisms by which stabilization of the GPCR–G protein complex bound to its endogenous agonist yields analgesic efficacy in an animal model of neuropathic pain.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Allosteric modulation of the A1R promotes agonist–A1R–PAM–G protein complex stability and analgesia in a disease-state-specific manner.

References

  1. Vos, T. et al. Lancet 388, 1545–1602 (2016).

    Article  Google Scholar 

  2. Volkow, N. D. & McLellan, A. T. N. Engl. J. Med. 374, 1253–1263 (2016).

    Article  CAS  Google Scholar 

  3. Draper-Joyce, C. J. et al. Nature 597, 571–576 (2021).

    Article  CAS  Google Scholar 

  4. Santos, R. et al. Nat. Rev. Drug Discov. 16, 19–34 (2017).

    Article  CAS  Google Scholar 

  5. Shoichet, B. K. & Kobilka, B. K. Trends Pharmacol. Sci. 33, 268–272 (2012).

    Article  CAS  Google Scholar 

  6. Manglik, A. et al. Nature 537, 185–190 (2016).

    Article  CAS  Google Scholar 

  7. Zylka, M. J. Trends Mol. Med. 17, 188–196 (2011).

    Article  CAS  Google Scholar 

  8. Sosnowski, M., Stevens, C. W. & Yaksh, T. L. J. Pharmacol. Exp. Ther. 250, 915–922 (1989).

    CAS  PubMed  Google Scholar 

  9. Li, J. & Perl, E. R. J. Neurophysiol. 72, 1611–1621 (1994).

    Article  CAS  Google Scholar 

  10. Headrick, J. P., Ashton, K. J., Rose’meyer, R. B. & Peart, J. N. Pharmacol. Ther. 140, 92–111 (2013).

    Article  CAS  Google Scholar 

  11. Thal, D. M., Glukhova, A., Sexton, P. M. & Christopoulos, A. Nature 559, 45–53 (2018).

    Article  CAS  Google Scholar 

  12. Sawynok, J. Handb. Exp. Pharmacol. 309–328 (2007).

  13. Aurelio, L. et al. J. Med. Chem. 52, 4543–4547 (2009).

    Article  CAS  Google Scholar 

  14. Sharma, N. et al. Nature 577, 392–398 (2020).

    Article  CAS  Google Scholar 

  15. Usoskin, D. et al. Nat. Neurosci. 18, 145–153 (2015).

    Article  CAS  Google Scholar 

  16. Renthal, W. et al. Neuron 108, 128–144.e9 (2020).

    Article  CAS  Google Scholar 

  17. Araldi, D., Ferrari, L. F. & Levine, J. D. Pain 157, 698–709 (2016).

    Article  CAS  Google Scholar 

  18. Corder, G. et al. Nat. Med. 23, 164–173 (2017).

    Article  CAS  Google Scholar 

  19. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cell 139, 267–284 (2009).

    Article  CAS  Google Scholar 

  20. Yudin, Y. & Rohacs, T. Mol. Pain 14, 1744806918763646 (2018).

    Article  CAS  Google Scholar 

  21. Avlani, V. A. et al. J. Biol. Chem. 282, 25677–25686 (2007).

    Article  CAS  Google Scholar 

  22. Cao, A.-M. et al. Nat. Commun. 12, 5426 (2021).

    Article  CAS  Google Scholar 

  23. Kandasamy, R. et al. Proc. Natl. Acad. Sci. USA 118, e2000017118 (2021).

    Article  CAS  Google Scholar 

  24. Che, T. & Roth, B. L. Annu. Rev. Biochem. 90, 739–761 (2021).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

G.S. is a New York Stem Cell Foundation – Robertson Investigator. We thank Joshua Blair for editing the manuscript.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David F. Lee, Matan Geron & Grégory Scherrer

  2. UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David F. Lee, Matan Geron & Grégory Scherrer

  3. Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David F. Lee, Matan Geron & Grégory Scherrer

  4. Pharmacology Curriculum, Biological & Biomedical Sciences Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    David F. Lee

  5. New York Stem Cell Foundation–Robertson Investigator, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Grégory Scherrer

Authors
  1. David F. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matan Geron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Grégory Scherrer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Grégory Scherrer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, D.F., Geron, M. & Scherrer, G. A modulator-bound GPCR structure enables allosteric non-opioid analgesia. Nat Struct Mol Biol 28, 871–872 (2021). https://doi.org/10.1038/s41594-021-00681-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41594-021-00681-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research