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

Publication ,  Journal Article
Zhu, C; Han, Q; Samoshkin, A; Convertino, M; Linton, A; Faison, EM; Ji, R-R; Diatchenko, L; Dokholyan, NV
Published in: Proteins
October 2019

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.

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Published In

Proteins

DOI

EISSN

1097-0134

Publication Date

October 2019

Volume

87

Issue

10

Start / End Page

878 / 884

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Opioid, mu
  • Protein Transport
  • Protein Conformation
  • Models, Molecular
  • Humans
  • HEK293 Cells
  • Bioinformatics
  • 49 Mathematical sciences
  • 31 Biological sciences
 

Citation

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Zhu, C., Han, Q., Samoshkin, A., Convertino, M., Linton, A., Faison, E. M., … Dokholyan, N. V. (2019). Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling. Proteins, 87(10), 878–884. https://doi.org/10.1002/prot.25751
Zhu, Cheng, Qingjian Han, Alexander Samoshkin, Marino Convertino, Alexander Linton, Edgar M. Faison, Ru-Rong Ji, Luda Diatchenko, and Nikolay V. Dokholyan. “Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling.Proteins 87, no. 10 (October 2019): 878–84. https://doi.org/10.1002/prot.25751.
Zhu C, Han Q, Samoshkin A, Convertino M, Linton A, Faison EM, et al. Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling. Proteins. 2019 Oct;87(10):878–84.
Zhu, Cheng, et al. “Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling.Proteins, vol. 87, no. 10, Oct. 2019, pp. 878–84. Pubmed, doi:10.1002/prot.25751.
Zhu C, Han Q, Samoshkin A, Convertino M, Linton A, Faison EM, Ji R-R, Diatchenko L, Dokholyan NV. Stabilization of μ-opioid receptor facilitates its cellular translocation and signaling. Proteins. 2019 Oct;87(10):878–884.
Journal cover image

Published In

Proteins

DOI

EISSN

1097-0134

Publication Date

October 2019

Volume

87

Issue

10

Start / End Page

878 / 884

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptors, Opioid, mu
  • Protein Transport
  • Protein Conformation
  • Models, Molecular
  • Humans
  • HEK293 Cells
  • Bioinformatics
  • 49 Mathematical sciences
  • 31 Biological sciences