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

Cheng Zhu, Qingjian Han, Alexander Samoshkin, Marino Convertino, Alexander Linton, Edgar M. Faison, Ru Rong Ji, Luda Diatchenko, Nikolay V. Dokholyan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)878-884
Number of pages7
JournalProteins: Structure, Function and Bioinformatics
Volume87
Issue number10
DOIs
StatePublished - Oct 1 2019

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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