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

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