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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhu, C; Han, Q; Samoshkin, A; Convertino, M; Linton, A; Faison, EM; Ji, R-R; Diatchenko, L; Dokholyan, NV

Published Date

  • May 29, 2019

Published In

PubMed ID

  • 31141214

Pubmed Central ID

  • 31141214

Electronic International Standard Serial Number (EISSN)

  • 1097-0134

Digital Object Identifier (DOI)

  • 10.1002/prot.25751

Language

  • eng

Conference Location

  • United States