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Stabilization of μ‐opioid receptor facilitates its cellular translocation and signaling
Author(s) -
Zhu Cheng,
Han Qingjian,
Samoshkin Alexander,
Convertino Marino,
Linton Alexander,
Faison Edgar M.,
Ji RuRong,
Diatchenko Luda,
Dokholyan Nikolay V.
Publication year - 2019
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25751
Subject(s) - chromosomal translocation , opioid , opioid receptor , receptor , signal transduction , microbiology and biotechnology , pharmacology , chemistry , biology , biochemistry , gene
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.