A novel G protein-biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.

التفاصيل البيبلوغرافية
العنوان:	A novel G protein-biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.
المؤلفون:	Groom S; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Blum NK; Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany., Conibear AE; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Disney A; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK., Hill R; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.; School of Life Sciences, University of Nottingham, Nottingham, UK., Husbands SM; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK., Li Y; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina, USA., Toll L; Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida, USA., Kliewer A; Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany., Schulz S; Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University, Jena, Germany., Henderson G; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Kelly E; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Bailey CP; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
المصدر:	British journal of pharmacology [Br J Pharmacol] 2023 Apr; Vol. 180 (7), pp. 943-957. Date of Electronic Publication: 2020 Dec 27.
نوع المنشور:	Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE
أسماء مطبوعة:	Publication: London : Wiley Original Publication: London, Macmillian Journals Ltd.
مواضيع طبية MeSH:	Analgesics, Opioid/pharmacology , Receptors, Opioid, mu/metabolism, Rats ; Humans ; Animals ; GTP-Binding Proteins/metabolism ; Morphine/pharmacology ; Signal Transduction ; G-Protein-Coupled Receptor Kinases/metabolism ; Mammals/metabolism
مستخلص:	Background and Purpose: G protein-biased μ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased μ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones. Experimental Approach: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells. Desensitisation of opioid-induced currents were studied in rat locus coeruleus neurones using whole-cell patch-clamp electrophysiology. The mechanism of Compound 1-induced μ receptor desensitisation was probed using kinase inhibitors. Key Results: Compound 1 has similar intrinsic activity for G protein signalling as morphine. As predicted for a G protein-biased μ agonist, Compound 1 induced minimal agonist-induced internalisation and phosphorylation at intracellular μ receptor serine/threonine residues known to be involved in G protein-coupled receptor kinase (GRK)-mediated desensitisation. However, Compound 1 induced robust rapid μ receptor desensitisation in locus coeruleus neurons, to a greater degree than morphine. The extent of Compound 1-induced desensitisation was unaffected by activation or inhibition of protein kinase C (PKC) but was significantly reduced by inhibition of GRK. Conclusion and Implications: Compound 1 is a novel G protein-biased μ agonist that induces substantial rapid receptor desensitisation in mammalian neurons. Surprisingly, Compound 1-induced desensitisation was demonstrated to be GRK dependent despite its G protein bias. Our findings refute the assumption that G protein-biased agonists will evade receptor desensitisation and tolerance. Linked Articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc. (© 2020 The British Pharmacological Society.)
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معلومات مُعتمدة:	British Pharmacological Society (BPS); R01 DA007315 United States DA NIDA NIH HHS; R01 DA036975 United States DA NIDA NIH HHS
فهرسة مساهمة:	Keywords: G protein-coupled receptor kinases; arrestins; biased agonism; electrophysiology; opiates; opioids; receptor desensitisation
المشرفين على المادة:	0 (Analgesics, Opioid) 0 (Receptors, Opioid, mu) EC 3.6.1.- (GTP-Binding Proteins) 76I7G6D29C (Morphine) EC 2.7.11.16 (G-Protein-Coupled Receptor Kinases)
تواريخ الأحداث:	Date Created: 20201127 Date Completed: 20230303 Latest Revision: 20230314
رمز التحديث:	20240628
DOI:	10.1111/bph.15334
PMID:	33245558
قاعدة البيانات:	MEDLINE

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تدمد:	1476-5381
DOI:	10.1111/bph.15334