Related Experiment Video

Updated: Mar 22, 2026

Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis
07:48

Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis

Published on: July 3, 2015

9.3K

Lysosomal down-regulation of the mu opioid receptor is opposed by the Retromer complex

Aleksandra Dagunts1, Hayden Adoff1, Brandon Novy1

  • 1Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97239, USA.

Science Advances
|March 20, 2026
PubMed

Insights

The Retromer complex recycles the mu opioid receptor (MOR) from endosomes, preventing its lysosomal down-regulation. This bileucine motif pathway is crucial for regulating MOR activity and is also found in other membrane proteins like GLUT4.

Area of Science:

  • Cell Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) are regulated by agonist-induced endocytosis and lysosomal degradation.
  • The mu opioid receptor (MOR) undergoes lysosomal trafficking upon prolonged exposure to high-efficacy opioid drugs.

Purpose of the Study:

  • To identify cellular proteins controlling MOR lysosomal down-regulation.
  • To elucidate the mechanism by which MOR trafficking is regulated.

Main Methods:

  • Functional genomics screens were employed to identify key regulatory proteins.
  • Postendocytic trafficking pathways of MOR were investigated.

Main Results:

  • The Retromer complex was identified as a central regulator of MOR postendocytic trafficking.
  • Retromer promotes MOR recycling from endosomes to the plasma membrane, rescuing it from lysosomal down-regulation.
  • MOR utilizes a noncanonical bileucine recycling motif to access the Retromer pathway.
  • This bileucine-mediated Retromer recycling pathway is also observed in other membrane proteins, such as GLUT4.

Conclusions:

  • The Retromer complex, via a bileucine motif, plays a critical role in preventing MOR lysosomal down-regulation.
  • This mechanism provides a novel insight into the regulation of GPCRs and other membrane proteins, impacting cellular homeostasis and drug response.

More Related Videos

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence09:54

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence

Published on: March 8, 2020

5.7K
SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry10:16

SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry

Published on: January 6, 2017

7.7K

Related Concept Videos

Opioid Receptors: Overview01:22

Opioid Receptors: Overview

Opioid receptors, including the mu (μ, MOR), delta (δ, DOR), and kappa (κ, KOR) types, belong to the rhodopsin family of G protein-coupled receptors. These receptors are located throughout the central and peripheral nervous systems and in non-neuronal tissues such as macrophages and astrocytes. Opioid receptor ligands can be categorized into agonists or antagonists. Highly selective agonists include [d-Ala2, MePhe4, Gly(ol)5]-enkephalin or DAMGO for MOR, [D-Pen2,...
6.2K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
3.0K
Analgesia and Pain Management01:25

Analgesia and Pain Management

Pain is critical to various clinical pathologies, provoking an urgent need for effective management. Pain, whether acute or chronic, is a complex neurochemical process. Its alleviation depends on the type, with nonopioid analgesics effective for mild to moderate pain, such as musculoskeletal or inflammatory pain, while neuropathic pain responds best to anticonvulsants, tricyclic antidepressants, or serotonin/norepinephrine reuptake inhibitors. For severe acute or chronic pain, opioids may be...
2.8K
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.6K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
5.4K
Opioid Analgesics: Synthetic and Semisynthetic Opioids01:15

Opioid Analgesics: Synthetic and Semisynthetic Opioids

Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
1.4K