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A group II metabotropic glutamate receptor 3 (mGlu3, GRM3) isoform implicated in schizophrenia interacts with

Aintzane García-Bea1, Isabel Bermudez2, Paul J Harrison1,3

  • 11 Department of Psychiatry, University of Oxford, Warneford Hospital, UK.

Journal of Psychopharmacology (Oxford, England)
|June 29, 2017
PubMed

Insights

A novel variant of the metabotropic glutamate receptor 3 (mGlu3) gene, mGlu3Δ4, is expressed and interacts with the standard mGlu3 protein. This interaction may negatively modulate mGlu3 function, impacting its role in schizophrenia.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • The group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is implicated in schizophrenia risk.
  • A known mRNA isoform, GRM3Δ4, produces a protein variant (mGlu3Δ4) with a novel C terminus.
  • The properties and function of mGlu3Δ4 remain largely uncharacterized.

Purpose of the Study:

  • To investigate the properties and function of the mGlu3Δ4 protein variant.
  • To determine how mGlu3Δ4 interacts with the canonical mGlu3 receptor.
  • To explore the potential role of mGlu3Δ4 in the context of GRM3's function in schizophrenia.

Main Methods:

  • Transient transfection of HEK293T/17 cells with GRM3Δ4 cDNA.
  • Confirmation of mGlu3Δ4 translation and protein characterization (monomer/dimer formation, cellular localization).
  • Co-immunoprecipitation assays to assess interactions between mGlu3Δ4 and mGlu3.
  • Radioligand binding assays using [3H]LY341495 to evaluate antagonist binding and the effect of mGlu3Δ4 on mGlu3 binding.

Main Results:

  • GRM3Δ4 cDNA is translated into the mGlu3Δ4 protein, which forms monomers and homodimers.
  • mGlu3Δ4 localizes to cell membranes, including the plasma membrane.
  • mGlu3Δ4 interacts with canonical mGlu3 and negatively modulates its function by reducing antagonist binding and decreasing membrane-associated mGlu3 abundance.

Conclusions:

  • The mGlu3Δ4 protein variant is expressed, forms dimers, and localizes to cell membranes.
  • mGlu3Δ4 interacts with mGlu3 and appears to negatively modulate its activity.
  • These findings suggest a novel mechanism by which GRM3 contributes to schizophrenia risk and may represent a therapeutic target.
Keywords:
G protein-coupled receptorMetabotropic glutamate receptoralternative splicingisoformschizophrenia

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