Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression

Mark J. Wall, Emily Hill, Robert Huckstepp, Kerry Barkan, Giuseppe Deganutti, Michele Leuenberger, Barbara Preti, Ian Winfield, Sabrina Carvalho, Anna Suchankova, Haifeng Wei, Dewi Safitri, Xianglin Huang, Wendy Imlach, Circe La Mache, Eve Dean, Cherise Hume, Stephanie Hayward, Jess Oliver, Fei-Yue ZhaoDavid Spanswick, Christopher A. Reynolds, Martin Lochner, Graham Ladds, Bruno G. Frenguelli

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    17 Citations (Scopus)
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    Abstract

    The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A 1 receptors (A 1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A 1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A 1Rs arises from BnOCPA’s unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of β-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A 1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.

    Original languageEnglish
    Article number4150
    Number of pages22
    JournalNature Communications
    Volume13
    Issue number1
    DOIs
    Publication statusPublished - 18 Jul 2022

    Bibliographical note

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    Funder

    We gratefully acknowledge the support of the University of Warwick (URSS Awards to S.H. and J.O.; Warwick Ventures Proof of Concept Fund awards to M.J.W. & B.G.F.), the Leverhulme Trust (RPG-2017-255, CAR and G.L. to fund K.B. and G.D.), the BBSRC (BB/M00015X/2, G.L., and BB/M01116X/1, Ph.D. studentship to E.H.), the MRC (MR/J003964/1; I.W. and 2270402, iCASE PhD Studentship with NeuroSolutions to C.L.M.) and The Swiss National Science Foundation (PP00P2_123536 and PP00P2_146321, M.Lo). A.S. is supported by a European Scholarship from the Cambridge Trust, S.C. is funded by an AstraZeneca Ph.D. studentship and X.H. is funded by a China Scholarship Council Cambridge International Scholarship. RH is supported by an MRC Discovery Award (MC_PC_15070). C.A.R. is a Royal Society Industry Fellow. We would like to thank: Stephen Hill, Stephen Briddon, and Mark Soave (University of Nottingham) for gifting the Nluc-tagged adenosine receptor cell lines, the fluorescent antagonist AV039, and technical advice; Kathleen Caron and Duncan Mackie (University of North Carolina) for the β-arrestin1/2-YFP constructs, and Annette Gilchrist (Midwestern University) and Heidi Hamm (Vanderbilt University) for assistance with the Gαo interfering peptide plasmids. We are grateful to Kevin Moffat and the Biochemistry students of the School of Life Sciences at the University of Warwick for access to their frog heart preparations; Nick Dale, Mark Wigglesworth, Jens Kleinjung for discussions and comments on draft manuscripts, and Arthur Christopoulos for a pre-publication copy of the adenosine A1 R cryo-EM structure. In vivo studies on neuropathic pain were funded and undertaken by NeuroSolutions Ltd. Illustrative figures in Figs. 1bi, c ; 2a–d, i, j ; 3i, j ; 5a ; 6a ; 7a, b were created with BioRender.com. Venn diagram in Fig. 2e was made at http://bioinformatics.psb.ugent.be/webtools/Venn/.

    Keywords

    • General Biochemistry, Genetics and Molecular Biology
    • General Chemistry
    • General Physics and Astronomy
    • Multidisciplinary

    ASJC Scopus subject areas

    • General
    • Physics and Astronomy(all)
    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)

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