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

ABSTRACT: The G protein-coupled ?-opioid receptor (?-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 ?-OR represents a major hurdle to understanding its function. Here we computationally designed ?-OR mutants with altered stability to probe the relationship between cell-surface targeting, signal transduction, and agonist efficacy. The stabilizing mutation T315Y enhanced ?-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 ?-OR and reduced the response to morphine stimulation. These findings suggest that ?-OR stability is an important factor in regulating receptor signaling and provide a viable avenue to improve the efficacy of analgesics.

SUBMITTER: Zhu C 

PROVIDER: S-EPMC6718349 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature