Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression
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Published:2022-07-18
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wall Mark J.ORCID, Hill EmilyORCID, Huckstepp RobertORCID, Barkan Kerry, Deganutti GiuseppeORCID, Leuenberger MicheleORCID, Preti Barbara, Winfield Ian, Carvalho Sabrina, Suchankova Anna, Wei Haifeng, Safitri DewiORCID, Huang Xianglin, Imlach WendyORCID, La Mache CirceORCID, Dean Eve, Hume Cherise, Hayward Stephanie, Oliver Jess, Zhao Fei-Yue, Spanswick DavidORCID, Reynolds Christopher A.ORCID, Lochner MartinORCID, Ladds GrahamORCID, Frenguelli Bruno G.ORCID
Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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