μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization

Reference:

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. and Kelly, E., 2010. μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Molecular Pharmacology, 78 (4), pp. 756-766.

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Official URL:

http://dx.doi.org/10.1124/mol.110.066613

Abstract

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.

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