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Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling

Michelle L Halls1, Holly R Yeatman2, Cameron J Nowell2

  • 1Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. michelle.halls@monash.edu meri.canals@monash.edu.

Science Signaling
|February 11, 2016
PubMed

Insights

Ligand binding to the μ-opioid receptor (MOR) controls its location in the cell membrane, influencing downstream signaling. Receptor redistribution, not internalization, dictates the spatiotemporal signaling patterns of MOR.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Biophysics

Background:

  • The μ-opioid receptor (MOR) is a G protein-coupled receptor crucial for opioid analgesic effects.
  • Differential regulation of MOR signaling contributes to the dose-limiting side effects of opioids like morphine.
  • Understanding MOR spatiotemporal signaling is key to developing safer analgesics.

Purpose of the Study:

  • To investigate how different ligands modulate MOR spatiotemporal signaling dynamics.
  • To elucidate the mechanisms controlling MOR localization and downstream signaling pathways.
  • To determine whether receptor redistribution or internalization dictates signaling outcomes.

Main Methods:

  • Utilized biophysical approaches in human embryonic kidney (HEK) 293 cells overexpressing MOR.
  • Quantified spatiotemporal MOR signaling in response to morphine and DAMGO.
  • Assessed the roles of Gβγ subunits, protein kinase C (PKC), and MOR phosphorylation sites.

Main Results:

  • Morphine induced Gβγ-dependent PKC activity, restricting MOR to the plasma membrane and causing sustained extracellular signal-regulated kinase (ERK) signaling.
  • DAMGO promoted MOR redistribution, leading to transient ERK activation and subsequent receptor internalization.
  • Inhibition of Gβγ/PKC or mutation of MOR phosphorylation sites released morphine-activated MOR, causing transient ERK signaling without internalization.

Conclusions:

  • Ligand-induced redistribution of MOR within the plasma membrane is the primary determinant of its spatiotemporal signaling.
  • Receptor internalization is not the main driver of transient ERK signaling.
  • These findings offer insights into the differential signaling of MOR, potentially guiding the development of novel analgesics.

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