title: μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.
abstract: 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 signaling 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, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser(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.
authors.affiliation: Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: McPherson
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Rivero
authors.forename: Myma
authors.initials: M
authors.lastname: Baptist
authors.forename: Javier
authors.initials: J
authors.lastname: Llorente
authors.forename: Suleiman
authors.initials: S
authors.lastname: Al-Sabah
authors.forename: Cornelius
authors.initials: C
authors.lastname: Krasel
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.forename: Chris P
authors.initials: CP
authors.lastname: Bailey
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Graeme
authors.initials: G
authors.lastname: Henderson
authors.forename: Eamonn
authors.initials: E
authors.lastname: Kelly
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu