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μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization

McPherson, Jamie and Rivero, Guadalupe and Baptist, Myma and Llorente, Javier and Al-Sabah, Suleiman and Krasel, Cornelius and Dewey, William L and Bailey, Chris P and Rosethorne, Liz and Charlton, Steven and Henderson, Graeme and Kelly, Eamonn (2010) μ-Opioid Receptors: Correlation of Agonist Efficacy for Signalling with Ability to Activate Internalization. Molecular Pharmacology, 78 (4). pp. 756-766. ISSN 0026-895X

Abstract

We have compared the ability of a number of μ-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser(375), considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2673

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