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

TL;DR

This study shows how the Retromer complex prevents the breakdown of opioid receptors in cells, offering new insights into opioid drug effects.

Contribution

The study identifies the Retromer complex as a key regulator of mu opioid receptor recycling, revealing a new mechanism for receptor regulation.

Findings

The Retromer complex prevents MOR from being sent to the lysosome for degradation.

MOR uses a noncanonical bileucine motif to access the Retromer recycling pathway.

This recycling mechanism is also present in other membrane proteins like GLUT4.

Abstract

A critical homeostatic mechanism for regulating G protein–coupled receptor (GPCR) activity is agonist-induced GPCR endocytosis and trafficking to the lysosome for proteolytic down-regulation. The mu opioid receptor (MOR) is a notable example of this type of cellular regulation, where prolonged exposure to high-efficacy opioid drugs causes MOR to traffic to the lysosome. Here, we used functional genomics to identify cellular proteins that control MOR lysosomal down-regulation. We found that the central regulator of MOR postendocytic trafficking is the Retromer complex, which rescues MOR from opioid-induced down-regulation by promoting MOR recycling from endosomes to the plasma membrane. Critically, MOR accesses the Retromer recycling pathway through its noncanonical bileucine recycling motif, and this mechanism controls how MOR is regulated following chronic exposure to opioid drugs. Additionally, we show that this bileucine pathway for Retromer-based recycling is present in other classes of membrane proteins including the glucose transporter GLUT4.

The Retromer complex rescues mu opioid receptors from lysosomal down-regulation after exposure to high-efficacy opioids.

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