Biased Signaling of the Mu Opioid Receptor Revealed in Native Neurons.
Bioengineering
Biological Sciences
Cell Biology
Molecular Biology
Neuroscience
Physiology
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
26 Apr 2019
26 Apr 2019
Historique:
received:
11
09
2018
revised:
06
03
2019
accepted:
11
03
2019
pubmed:
30
3
2019
medline:
30
3
2019
entrez:
30
3
2019
Statut:
ppublish
Résumé
G protein-coupled receptors are key signaling molecules and major targets for pharmaceuticals. The concept of ligand-dependent biased signaling raises the possibility of developing drugs with improved efficacy and safety profiles, yet translating this concept to native tissues remains a major challenge. Whether drug activity profiling in recombinant cell-based assays, traditionally used for drug discovery, has any relevance to physiology is unknown. Here we focused on the mu opioid receptor, the unrivalled target for pain treatment and also the key driver for the current opioid crisis. We selected a set of clinical and novel mu agonists, and profiled their activities in transfected cell assays using advanced biosensors and in native neurons from knock-in mice expressing traceable receptors endogenously. Our data identify Gi-biased agonists, including buprenorphine, and further show highly correlated drug activities in the two otherwise very distinct experimental systems, supporting in vivo translatability of biased signaling for mu opioid drugs.
Identifiants
pubmed: 30925410
pii: S2589-0042(19)30077-X
doi: 10.1016/j.isci.2019.03.011
pmc: PMC6439305
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
47-57Subventions
Organisme : NIDA NIH HHS
ID : P50 DA005010
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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