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Selective activation of Gαob by an adenosine A 1 receptor agonist elicits analgesia without cardiorespiratory depression
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(2022) Selective activation of Gαob by an adenosine A 1 receptor agonist elicits analgesia without cardiorespiratory depression. Nature Communications, 13 (1). 4150. doi:10.1038/s41467-022-31652-2 ISSN 2041-1723.
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WRAP-selective-activation-Gαob-adenosine-A1-receptor-agonist-elicits-analgesia-without-cardiorespiratory-depression-2022.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (4Mb) | Preview |
Official URL: https://doi.org/10.1038/s41467-022-31652-2
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.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||||||||||||||||||||||||||||||||||||||
| SWORD Depositor: | Library Publications Router | |||||||||||||||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | G proteins -- Receptors, Cellular signal transduction , Cardiopulmonary system , Adenosine -- Physiological effect | |||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Nature Communications | |||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | Nature Publishing Group | |||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 2041-1723 | |||||||||||||||||||||||||||||||||||||||||||||
| Official Date: | 18 July 2022 | |||||||||||||||||||||||||||||||||||||||||||||
| Dates: |
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| Volume: | 13 | |||||||||||||||||||||||||||||||||||||||||||||
| Number: | 1 | |||||||||||||||||||||||||||||||||||||||||||||
| Article Number: | 4150 | |||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1038/s41467-022-31652-2 | |||||||||||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 20 July 2022 | |||||||||||||||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 22 July 2022 | |||||||||||||||||||||||||||||||||||||||||||||
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