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Ubiquitination of the μ-opioid receptor regulates receptor internalization without affecting Gi/o-mediated

Kentaro Miyoshi1, Satoshi Shimizu2, Atsuko Shiraki1

  • 1Department of Anesthesia, Kyoto University Hospital, 54 Shogoin-kawahara-cho, Sakyo-ku, Kyoto City, Kyoto Prefecture, Japan.

Biochemical and Biophysical Research Communications
|January 2, 2023
PubMed

Insights

Ubiquitination is not required for Gi/o signaling or opioid receptor phosphorylation. However, this modification is crucial for efficient internalization of the desensitized μ-opioid receptor (MOP).

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Opioids are potent analgesics that induce tolerance.
  • Phosphorylation of the μ-opioid receptor (MOP) is key to receptor desensitization and cellular sensitivity.
  • Ubiquitination, a posttranslational modification, is increasingly recognized for its role in receptor signaling and regulation.

Purpose of the Study:

  • To investigate the role of MOP ubiquitination in Gi/o-mediated signaling, desensitization, and internalization.
  • To determine if ubiquitination is essential for opioid-induced cellular responses.

Main Methods:

  • Generation of a ubiquitination-deficient MOP mutant.
  • Assays to measure Gi/o pathway activation.
  • Analysis of receptor phosphorylation.
  • Assessment of receptor desensitization and internalization.

Main Results:

  • Gi/o-mediated signaling and MOP phosphorylation proceed independently of ubiquitination.
  • Ubiquitination is not required for receptor desensitization.
  • Ubiquitination significantly enhances the efficiency of MOP internalization, particularly for desensitized receptors.

Conclusions:

  • Ubiquitination is a critical regulator of μ-opioid receptor internalization, not its initial signaling or desensitization.
  • Targeting MOP ubiquitination may offer novel strategies for modulating opioid efficacy and managing tolerance.
Keywords:
PhosphorylationPosttranslational modificationToleranceUbiquitinationμ-opioid receptor

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