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μ-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization

Jamie McPherson1, Guadalupe Rivero, Myma Baptist

  • 1Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, UK.

Molecular Pharmacology
|July 22, 2010
PubMed

Insights

Most μ-opioid receptor (MOPr) ligands activate G proteins, recruit arrestin-3, and internalize the receptor. Ligand efficacy for G protein activation predicts these downstream effects, with some exceptions showing biased signaling.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) mediate cellular responses to diverse stimuli.
  • μ-opioid receptor (MOPr) signaling is crucial for pain perception and analgesia.
  • Ligand efficacy at GPCRs can lead to differential downstream signaling pathways.

Purpose of the Study:

  • To compare the signaling profiles of various MOPr ligands.
  • To investigate the correlation between G protein activation and other MOPr signaling events.
  • To understand biased agonism at the MOPr.

Main Methods:

  • Assessed MOPr ligand efficacy for G protein activation.
  • Measured MOPr phosphorylation at Ser(375).
  • Quantified arrestin-3 recruitment and MOPr internalization.

Main Results:

  • Strong correlation observed between G protein activation and arrestin-3 recruitment.
  • Agonist-induced MOPr phosphorylation and internalization correlated well with arrestin-3 recruitment.
  • Endomorphins 1 and 2 showed biased signaling toward arrestin recruitment.
  • Morphine exhibited low efficacy for MOPr internalization.

Conclusions:

  • MOPr ligand efficacy for G protein activation generally predicts downstream signaling outcomes.
  • Receptor phosphorylation and internalization are linked to arrestin-3 recruitment.
  • Evidence for biased agonism at the MOPr was demonstrated, impacting receptor regulation.

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