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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

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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.

G-protein-coupled receptors (GPCRs) are the largest family of membrane receptors and the most prevalent target class of drugs approved for clinical use4. Recent structural biology advancements could facilitate the development of novel therapeutic GPCR ligands5, including analgesics6. The Gi/o-coupled GPCR A1R, which is endogenously activated by the nucleoside adenosine (ADO), is a promising analgesic target due to its localization on the terminals of peripheral noci-responsive sensory neurons (nociceptors) in the spinal cord dorsal horn and its antinociceptive action7,8,9. However, both the insufficient selectivity of A1R agonists for A1R over other ADO GPCRs and the presence of A1Rs in other tissues have limited the therapeutic utility of this receptor type7,10. In contrast, PAMs signal in cooperation with endogenous orthosteric agonists, the abundances of which vary in a tissue-specific manner. Thus, by increasing the affinity and/or efficacy of the endogenous agonist, PAMs enhance receptor activity according to the temporal and spatial features of endogenous biological activity, enabling precision pharmacology to treat disease with reduced side effects11. Given that increased ADO levels are detected in the spinal cord dorsal horn following nerve injury7,12, a PAM acting on the A1R could potentiate ADO activity to reduce neuropathic pain with minimal effects on other A1R-expressing tissues.

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

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Acknowledgements

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

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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

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  1. David F. Lee
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Correspondence to Grégory Scherrer.

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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

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