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 Zhao; David Spanswick; Christopher A. Reynolds; Martin Lochner; Graham Ladds; Bruno G. Frenguelli

doi:10.1038/s41467-022-31652-2

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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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 language	English
Article number	4150
Number of pages	22
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31652-2
Publication status	Published - 18 Jul 2022

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

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/.

Funding

Funders	Funder number
NeuroSolutions Ltd
University of Warwick
AstraZeneca
Midwestern University
Medical Research Council	2270402, MR/J003964/1
Biotechnology and Biological Sciences Research Council	BB/M01116X/1, BB/M00015X/2
Leverhulme Trust	RPG-2017-255
The Royal Society
University of Warwick
University of Nottingham	AV039
University of Nottingham
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	PP00P2_146321, PP00P2_123536
China Scholarship Council	MC_PC_15070
Canadian Association of Radiologists
Korea University

Keywords

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

ASJC Scopus subject areas

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

Access to Document

10.1038/s41467-022-31652-2Licence: CC BY

PublishedFinal published version, 5.26 MBLicence: CC BY

Cite this

Wall, M. J., Hill, E., Huckstepp, R., Barkan, K., Deganutti, G., Leuenberger, M., Preti, B., Winfield, I., Carvalho, S., Suchankova, A., Wei, H., Safitri, D., Huang, X., Imlach, W., Mache, C. L., Dean, E., Hume, C., Hayward, S., Oliver, J., ... Frenguelli, B. G. (2022). Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression. Nature Communications, 13(1), Article 4150. https://doi.org/10.1038/s41467-022-31652-2

Wall, MJ, Hill, E, Huckstepp, R, Barkan, K, Deganutti, G, Leuenberger, M, Preti, B, Winfield, I, Carvalho, S, Suchankova, A, Wei, H, Safitri, D, Huang, X, Imlach, W, Mache, CL, Dean, E, Hume, C, Hayward, S, Oliver, J, Zhao, F-Y, Spanswick, D, Reynolds, CA, Lochner, M, Ladds, G & Frenguelli, BG 2022, 'Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression', Nature Communications, vol. 13, no. 1, 4150. https://doi.org/10.1038/s41467-022-31652-2

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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{\textquoteright}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. ",

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

Abstract

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