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

J McPherson, G Rivero, M Baptist, J Llorente, S Al-Sabah, C Krasel, W L Dewey, Christopher P Bailey, E M Rosethorne, S J Charlton, G Henderson, E Kelly

Research output: Contribution to journalArticle

142 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)756-766
Number of pages11
JournalMolecular Pharmacology
Volume78
Issue number4
Early online date19 Jul 2010
DOIs
Publication statusPublished - Oct 2010

Fingerprint

mu Opioid Receptor
GTP-Binding Proteins
Phosphorylation
Arrestin
G-Protein-Coupled Receptors
Serine
Morphine
Ligands
beta-Arrestin 2

Cite this

McPherson, J., Rivero, G., Baptist, M., Llorente, J., Al-Sabah, S., Krasel, C., ... 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

μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. / McPherson, J; Rivero, G; Baptist, M; Llorente, J; Al-Sabah, S; Krasel, C; Dewey, W L; Bailey, Christopher P; Rosethorne, E M; Charlton, S J; Henderson, G; Kelly, E.

In: Molecular Pharmacology, Vol. 78, No. 4, 10.2010, p. 756-766.

Research output: Contribution to journalArticle

McPherson, J, Rivero, G, Baptist, M, Llorente, J, Al-Sabah, S, Krasel, C, Dewey, WL, Bailey, CP, Rosethorne, EM, Charlton, SJ, Henderson, G & Kelly, E 2010, 'μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization', Molecular Pharmacology, vol. 78, no. 4, pp. 756-766. https://doi.org/10.1124/mol.110.066613
McPherson, J ; Rivero, G ; Baptist, M ; Llorente, J ; Al-Sabah, S ; Krasel, C ; Dewey, W L ; Bailey, Christopher P ; Rosethorne, E M ; Charlton, S J ; Henderson, G ; Kelly, E. / μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. In: Molecular Pharmacology. 2010 ; Vol. 78, No. 4. pp. 756-766.
@article{4d68a06d8697447a924f789248213cdf,
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 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.",
author = "J McPherson and G Rivero and M Baptist and J Llorente and S Al-Sabah and C Krasel and Dewey, {W L} and Bailey, {Christopher P} and Rosethorne, {E M} and Charlton, {S J} and G Henderson and E Kelly",
year = "2010",
month = "10",
doi = "10.1124/mol.110.066613",
language = "English",
volume = "78",
pages = "756--766",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

TY - JOUR

T1 - μ-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization

AU - McPherson, J

AU - Rivero, G

AU - Baptist, M

AU - Llorente, J

AU - Al-Sabah, S

AU - Krasel, C

AU - Dewey, W L

AU - Bailey, Christopher P

AU - Rosethorne, E M

AU - Charlton, S J

AU - Henderson, G

AU - Kelly, E

PY - 2010/10

Y1 - 2010/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957221089&partnerID=8YFLogxK

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

U2 - 10.1124/mol.110.066613

DO - 10.1124/mol.110.066613

M3 - Article

VL - 78

SP - 756

EP - 766

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 4

ER -