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Endomorphin-2: a biased agonist at the µ-opioid receptor

Guadalupe, Rivero and Llorente, Javier and McPherson, Jamie and Cooke, Alex and Mundell, Stuart J and McArdle, Craig A and Rosethorne, Elizabeth and Charlton, Steven and Cornelius, Krasel and Dewey, William L and Bailey, Christopher P and Henderson, Graeme and Kelly, Eamonn (2012) Endomorphin-2: a biased agonist at the µ-opioid receptor. Molecular Pharmacology, 82 (2). pp. 178-188. ISSN 0026-895X

Abstract

Previously we correlated the efficacy for G protein activation with that for arrestin recruitment for a number of agonists at the µ opioid receptor (MOPr) stably expressed in HEK293 cells (McPherson et al., 2010). We reported that the endomorphins (endomorphin-1 and -2) appeared to be biased towards arrestin recruitment. In the present study we have investigated this phenomenon in more detail for endomorphin-2 using a combination of experimental approaches and have studied endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in rat brainstem locus coeruleus (LC) slices, the peptide agonists [D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO) and endomorphin-2 activated inwardly-rectifying K+ current in a concentration-dependent manner and analysis of these responses using the operational model of pharmacological agonism confirmed that endomorphin-2 has a much lower operational efficacy for G protein-mediated responses than DAMGO at native MOPr in mature neurons. However endomorphin-2 induced faster desensitization of the K+ current than DAMGO. In addition, in HEK293 cells stably expressing MOPr, the ability of endomorphin-2 to induce phosphorylation of Ser375 in the COOH terminus of the receptor, to induce association of arrestin with the receptor, and to induce cell surface loss of receptor was much more efficient than would be predicted from its efficacy for G protein-mediated signalling. Together these results indicate that endomorphin-2 is an arrestin-biased agonist at MOPr.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7112

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