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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

Agonist-selective signaling is determined by the receptor location within the membrane domains

Hui Zheng1, Ji Chu, Yu Qiu

  • 1Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street Southeast, Minneapolis, MN 55455-0217, USA. zhen0091@umn.edu

Proceedings of the National Academy of Sciences of the United States of America
|July 5, 2008
PubMed

Insights

Agonist-selective signaling depends on mu-opioid receptor (MOR) location. Etorphine causes MOR to move to non-raft domains, while morphine keeps it in lipid rafts, affecting downstream signaling pathways.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Molecular Biology

Background:

  • The mu-opioid receptor (MOR) mediates diverse cellular responses to opioid agonists.
  • Understanding how different agonists trigger distinct signaling pathways is crucial for drug development.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying agonist-selective signaling of the mu-opioid receptor (MOR).
  • To determine the role of receptor localization within cellular compartments in mediating differential signaling outcomes.

Main Methods:

  • Utilized mu-opioid receptor (MOR) as a model system.
  • Employed techniques to track receptor localization (lipid raft vs. non-raft domains).
  • Investigated protein-protein interactions involving MOR, G proteins (Galpha i2), and beta-arrestin.

Main Results:

  • Etorphine, but not morphine, induced MOR translocation from lipid rafts to non-raft domains.
  • MOR translocation required prior dissociation from Galpha i2 and subsequent beta-arrestin binding.
  • Morphine-MOR complexes remained in lipid rafts due to low beta-arrestin affinity and Galpha i2 re-binding.
  • Disrupting MOR-Galpha i2 interaction led to MOR translocation to non-raft domains.
  • Lipid raft localization was essential for G protein-dependent signaling (adenylyl cyclase inhibition, ERK phosphorylation).
  • Translocation to non-raft domains was necessary for beta-arrestin-dependent ERK phosphorylation.

Conclusions:

  • Agonist-selective signaling is regulated by the dynamic localization of the mu-opioid receptor (MOR) within cellular compartments.
  • The differential interactions of MOR with G proteins and beta-arrestin dictate its subcellular location and subsequent signaling pathway activation.

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