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

Author

Listed:
  • Mark J. Wall

    (University of Warwick)

  • Emily Hill

    (University of Warwick)

  • Robert Huckstepp

    (University of Warwick)

  • Kerry Barkan

    (University of Cambridge)

  • Giuseppe Deganutti

    (Coventry University
    University of Essex)

  • Michele Leuenberger

    (University of Bern)

  • Barbara Preti

    (University of Bern)

  • Ian Winfield

    (University of Cambridge)

  • Sabrina Carvalho

    (University of Cambridge)

  • Anna Suchankova

    (University of Cambridge)

  • Haifeng Wei

    (NeuroSolutions Ltd)

  • Dewi Safitri

    (University of Cambridge
    Pharmacology and Clinical Pharmacy Research Group, School of Pharmacy, Bandung Institute of Technology)

  • Xianglin Huang

    (University of Cambridge)

  • Wendy Imlach

    (Monash University)

  • Circe Mache

    (University of Warwick)

  • Eve Dean

    (University of Warwick)

  • Cherise Hume

    (University of Warwick)

  • Stephanie Hayward

    (University of Warwick)

  • Jess Oliver

    (University of Warwick)

  • Fei-Yue Zhao

    (NeuroSolutions Ltd)

  • David Spanswick

    (NeuroSolutions Ltd
    Monash University
    University of Warwick)

  • Christopher A. Reynolds

    (Coventry University
    University of Essex)

  • Martin Lochner

    (University of Bern)

  • Graham Ladds

    (University of Cambridge)

  • Bruno G. Frenguelli

    (University of Warwick)

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 A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-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 A1Rs 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 A1R, 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.

Suggested Citation

  • 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 , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31652-2
    DOI: 10.1038/s41467-022-31652-2
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    1. Hideaki Yano & Ning-Sheng Cai & Min Xu & Ravi Kumar Verma & William Rea & Alexander F. Hoffman & Lei Shi & Jonathan A. Javitch & Antonello Bonci & Sergi Ferré, 2018. "Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Tilman Flock & Alexander S. Hauser & Nadia Lund & David E. Gloriam & Santhanam Balaji & M. Madan Babu, 2017. "Selectivity determinants of GPCR–G-protein binding," Nature, Nature, vol. 545(7654), pages 317-322, May.
    3. Besma Benredjem & Jonathan Gallion & Dennis Pelletier & Paul Dallaire & Johanie Charbonneau & Darren Cawkill & Karim Nagi & Mark Gosink & Viktoryia Lukasheva & Stephen Jenkinson & Yong Ren & Christoph, 2019. "Exploring use of unsupervised clustering to associate signaling profiles of GPCR ligands to clinical response," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    4. Carmen Klein Herenbrink & David A. Sykes & Prashant Donthamsetti & Meritxell Canals & Thomas Coudrat & Jeremy Shonberg & Peter J. Scammells & Ben Capuano & Patrick M. Sexton & Steven J. Charlton & Jon, 2016. "The role of kinetic context in apparent biased agonism at GPCRs," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    5. Christopher J. Draper-Joyce & Maryam Khoshouei & David M. Thal & Yi-Lynn Liang & Anh T. N. Nguyen & Sebastian G. B. Furness & Hariprasad Venugopal & Jo-Anne Baltos & Jürgen M. Plitzko & Radostin Danev, 2018. "Structure of the adenosine-bound human adenosine A1 receptor–Gi complex," Nature, Nature, vol. 558(7711), pages 559-563, June.
    6. Yi-Lynn Liang & Maryam Khoshouei & Giuseppe Deganutti & Alisa Glukhova & Cassandra Koole & Thomas S. Peat & Mazdak Radjainia & Jürgen M. Plitzko & Wolfgang Baumeister & Laurence J. Miller & Deborah L., 2018. "Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor," Nature, Nature, vol. 561(7724), pages 492-497, September.
    7. Hideaki E. Kato & Yan Zhang & Hongli Hu & Carl-Mikael Suomivuori & Francois Marie Ngako Kadji & Junken Aoki & Kaavya Krishna Kumar & Rasmus Fonseca & Daniel Hilger & Weijiao Huang & Naomi R. Latorraca, 2019. "Conformational transitions of a neurotensin receptor 1–Gi1 complex," Nature, Nature, vol. 572(7767), pages 80-85, August.
    8. Daniel M. Rosenbaum & Søren G. F. Rasmussen & Brian K. Kobilka, 2009. "The structure and function of G-protein-coupled receptors," Nature, Nature, vol. 459(7245), pages 356-363, May.
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