TY - JOUR T1 - Endomorphin-2: A Biased Agonist at the μ Opioid Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.078659 SP - mol.112.078659 AU - Guadalupe Rivero AU - Javier Llorente AU - Jamie McPherson AU - Alex Cooke AU - Stuart J. Mundell AU - Craig A. McArdle AU - Elizabeth M. Rosethorne AU - Steven J. Charlton AU - Cornelius Krasel AU - Christopher P. Bailey AU - Graeme Henderson AU - Eamonn Kelly Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/05/03/mol.112.078659.abstract N2 - 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 suggested that the endomorphins (endomorphin-1 and -2) may be biased towards arrestin recruitment. In the present study we have investigated this phenomenon in more detail for endomorphin-2, this time using endogenous MOPr in rat brain as well as MOPr stably expressed in HEK293 cells. For MOPr in neurons in 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. 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 and that the reason for this is likely to be the ability of endomorphin-2 to induce greater phosphorylation of MOPr than would be expected from its ability to activate MOPr and induce activation of G protein. ER -