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Proteins. 2019 Oct;87(10):878-884. doi: 10.1002/prot.25751. Epub 2019 Jun 12.

Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling.

Author information

1
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
2
Department of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania.
3
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
4
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina.
5
Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.
6
School of the Clinical Medicine, University of Cambridge, Cambridge, UK.
7
Department of Biochemistry & Molecular Biology, Penn State University College of Medicine, Hershey, Pennsylvania.
8
Department of Biomedical Engineering, Penn State University, Pennsylvania.
9
Department of Chemistry, Penn State University, Pennsylvania.

Abstract

The G protein-coupled μ-opioid receptor (μ-OR) mediates the majority of analgesia effects for morphine and other pain relievers. Despite extensive studies of its structure and activation mechanisms, the inherently low maturation efficiency of μ-OR represents a major hurdle to understanding its function. Here we computationally designed μ-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced μ-OR trafficking to the plasma membrane and significantly promoted the morphine-mediated inhibition of downstream signaling. In contrast, the destabilizing mutation R165Y led to intracellular retention of μ-OR and reduced the response to morphine stimulation. These findings suggest that μ-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics.

KEYWORDS:

GPCR; maturation; opioid receptor; protein engineering; signal transduction

PMID:
31141214
PMCID:
PMC6718349
[Available on 2020-10-01]
DOI:
10.1002/prot.25751

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