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 journalArticle

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

Fingerprint

Opioid Receptors
Morphine
Stabilization
Signal transduction
Mutation
Cell membranes
G-Protein-Coupled Receptors
GTP-Binding Proteins
Analgesia
Analgesics
Signal Transduction
Chemical activation
Cell Membrane
Efficiency
Pain

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology

Cite this

Zhu, Cheng ; Han, Qingjian ; Samoshkin, Alexander ; Convertino, Marino ; Linton, Alexander ; Faison, Edgar M. ; Ji, Ru Rong ; Diatchenko, Luda ; Dokholyan, Nikolay V. / Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling. In: Proteins: Structure, Function and Bioinformatics. 2019 ; Vol. 87, No. 10. pp. 878-884.
@article{07895945ca4f403697528feb0ca166b9,
title = "Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling",
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.",
author = "Cheng Zhu and Qingjian Han and Alexander Samoshkin and Marino Convertino and Alexander Linton and Faison, {Edgar M.} and Ji, {Ru Rong} and Luda Diatchenko and Dokholyan, {Nikolay V.}",
year = "2019",
month = "10",
day = "1",
doi = "10.1002/prot.25751",
language = "English (US)",
volume = "87",
pages = "878--884",
journal = "Proteins: Structure, Function and Genetics",
issn = "0887-3585",
publisher = "Wiley-Liss Inc.",
number = "10",

}

Zhu, C, Han, Q, Samoshkin, A, Convertino, M, Linton, A, Faison, EM, Ji, RR, Diatchenko, L & Dokholyan, NV 2019, 'Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling', Proteins: Structure, Function and Bioinformatics, vol. 87, no. 10, pp. 878-884. https://doi.org/10.1002/prot.25751

Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling. / Zhu, Cheng; Han, Qingjian; Samoshkin, Alexander; Convertino, Marino; Linton, Alexander; Faison, Edgar M.; Ji, Ru Rong; Diatchenko, Luda; Dokholyan, Nikolay V.

In: Proteins: Structure, Function and Bioinformatics, Vol. 87, No. 10, 01.10.2019, p. 878-884.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling

AU - Zhu, Cheng

AU - Han, Qingjian

AU - Samoshkin, Alexander

AU - Convertino, Marino

AU - Linton, Alexander

AU - Faison, Edgar M.

AU - Ji, Ru Rong

AU - Diatchenko, Luda

AU - Dokholyan, Nikolay V.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85067418642&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067418642&partnerID=8YFLogxK

U2 - 10.1002/prot.25751

DO - 10.1002/prot.25751

M3 - Article

C2 - 31141214

AN - SCOPUS:85067418642

VL - 87

SP - 878

EP - 884

JO - Proteins: Structure, Function and Genetics

JF - Proteins: Structure, Function and Genetics

SN - 0887-3585

IS - 10

ER -