μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.
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.
McPherson
Jamie
J
Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
Rivero
Guadalupe
G
Baptist
Myma
M
Llorente
Javier
J
Al-Sabah
Suleiman
S
Krasel
Cornelius
C
Dewey
William L
WL
Bailey
Chris P
CP
Rosethorne
Elizabeth M
EM
Charlton
Steven J
SJ
Henderson
Graeme
G
Kelly
Eamonn
E
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*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu