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

Proteins. 2019 Oct;87(10):878-884. doi: 10.1002/prot.25751. Epub 2019 Jun 12.


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.

Keywords: GPCR; maturation; opioid receptor; protein engineering; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Conformation*
  • Protein Transport
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction


  • Receptors, Opioid, mu