RT Journal Article
SR Electronic
T1 μ- Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.066613
DO 10.1124/mol.110.066613
A1 Jamie McPherson
A1 Guadalupe Rivero
A1 Myma Baptist
A1 Javier Llorente
A1 Suleiman Al-Sabah
A1 Cornelius Krasel
A1 William L Dewey
A1 Chris P Bailey
A1 Elizabeth M Rosethorne
A1 Steven J Charlton
A1 Graeme Henderson
A1 Eamonn Kelly
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/07/20/mol.110.066613.abstract
AB 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 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 Serine375, 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.