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Quantifying Agonist Activity at G Protein-coupled Receptors
11:45

Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery

L M Bohn1, L A Dykstra, R J Lefkowitz

  • 1Department of Pharmacology, Ohio State University College of Medicine and Public Health, Columbus, USA.

Molecular Pharmacology
|June 24, 2004
PubMed

Insights

Beta-arrestin2 (betaarr2) is crucial for regulating micro opioid receptor (microOR) function in vivo. Its absence enhances and prolongs microOR-mediated pain relief, suggesting a key role in opioid tolerance.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Molecular Biology

Background:

  • G protein-coupled receptor (GPCR) regulation by kinases and beta-arrestins typically leads to receptor desensitization and internalization.
  • In vitro studies suggest beta-arrestins have a limited role in micro opioid receptor (microOR) responsiveness.
  • Beta-arrestin2 (betaarr2) knockout mice exhibit enhanced and prolonged microOR-mediated antinociception and lack morphine tolerance.

Purpose of the Study:

  • To investigate the role of beta-arrestin2 (betaarr2) in micro opioid receptor (microOR) regulation.
  • To examine betaarr2's contribution to microOR function in human embryonic kidney 293 cells and betaarr2 knockout mice.
  • To elucidate the mechanism behind the paradoxical relationship between beta-arrestins and microOR regulation by opiate agonists.

Main Methods:

  • Utilized human embryonic kidney 293 cells and betaarr2 knockout mice.
  • Administered various opiate agonists to assess microOR regulation.
  • Employed green fluorescent protein (GFP)-tagged betaarr2 to visualize receptor-betaarr2 interactions in living cells.

Main Results:

  • Opiate agonists inducing robust betaarr2-GFP translocation showed similar analgesic effects in wild-type and betaarr2-KO mice.
  • Agonists not promoting significant betaarr2 recruitment, like morphine and heroin, resulted in enhanced and prolonged analgesia in betaarr2-KO mice.
  • Morphine-like agonists were found to be inefficient in promoting microOR internalization and resensitization.

Conclusions:

  • Beta-arrestin2 plays a critical role in vivo for micro opioid receptor (microOR) desensitization and tolerance development.
  • The efficiency of betaarr2 recruitment by opiate agonists dictates the in vivo antinociceptive outcome and tolerance.
  • Morphine and heroin exhibit unique signaling pathways that bypass robust betaarr2 engagement, explaining their distinct effects on microOR regulation.

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