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GRIN1 regulates micro-opioid receptor activities by tethering the receptor and G protein in the lipid raft

Xin Ge1, Yu Qiu1, Horace H Loh1

  • 1Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455.

The Journal of Biological Chemistry
|October 29, 2009
PubMed

Insights

GRIN1 anchors mu-opioid receptors (MOR) in lipid rafts, enhancing their signaling for neurite outgrowth. This discovery reveals a new mechanism for regulating MOR activity and neuronal development.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Mu-opioid receptor (MOR) activity is dictated by its localization within lipid rafts.
  • The precise mechanism anchoring MOR in lipid rafts remains unclear.

Purpose of the Study:

  • To identify proteins responsible for tethering MOR within lipid rafts.
  • To elucidate the role of GRIN1 in MOR localization and signaling.

Main Methods:

  • Targeted proteomics and mass spectrometry to identify interacting proteins.
  • Glutathione S-transferase (GST) pulldown assays and receptor mutational analysis.
  • Co-immunoprecipitation, cell-based signaling assays (Src kinase activation), and neurite outgrowth experiments.

Main Results:

  • GRIN1 was identified as a protein that tethers MOR to the G protein alpha-subunit (Gα).
  • GRIN1 interaction with MOR involves a distinct sequence (267)GSKEK(271) not involved in Gα binding.
  • GRIN1 overexpression increased MOR in lipid rafts, enhanced Src kinase activation, and promoted pertussis toxin-sensitive neurite outgrowth.
  • Knockdown of GRIN1 or disruption of lipid rafts attenuated agonist-induced neurite outgrowth.

Conclusions:

  • GRIN1 stabilizes MOR within lipid rafts by tethering it to Gα.
  • GRIN1 potentiates MOR signaling, significantly impacting neurite outgrowth processes.
  • This study reveals GRIN1 as a key regulator of MOR function and neuronal development.

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