We have compared the ability of a number of mu-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 signalling 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, whilst a few agonists, in particular endomorphin 1 and endomorphin 2, display apparent bias towards arrestin recruitment. The agonist-induced phosphorylation of MOPr at Serine(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.
McPherson, J., Rivero, G., Baptist, M., Llorente, J., Al-Sabah, S., Krasel, C., Dewey, W. L., Bailey, C. P., Rosethorne, E. M., Charlton, S. J., Henderson, G., & Kelly, E. (2010). μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Molecular Pharmacology, 78(4), 756-766. https://doi.org/10.1124/mol.110.066613