Abstract
As well as being expressed as a full-length transcript, the group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is expressed as an mRNA isoform which lacks exon 4 (GRM3Δ4) and which is predicted to encode a protein with a novel C terminus (called mGlu3Δ4). This variant may contribute to the mechanism by which GRM3 acts as a schizophrenia risk gene. However, little is known about the properties or function of mGlu3Δ4. Here, using transiently transfected HEK293T/17 cells, we confirm that GRM3Δ4 cDNA is translated, with mGlu3Δ4 existing as a homodimer as well as a monomer, and localizing primarily to cell membranes including the plasma membrane. Co-immunoprecipitation shows that mGlu3Δ4 interacts with canonical mGlu3. mGlu3Δ4 does not bind the mGlu2/3 antagonist [3H]LY341495, but the presence of mGlu3Δ4 reduces binding of [3H]LY341495 to mGlu3, paralleled by a decrease in the abundance of membrane-associated mGlu3. These experiments indicate that mGlu3Δ4 may negatively modulate mGlu3, and thereby impact on the roles of GRM3/mGlu3 in schizophrenia and as a therapeutic target.
Highlights
The group II metabotropic glutamate receptor 3 is a seven trans-membrane domain, G protein-coupled receptor (GPCR) encoded by the GRM3 gene on chromosome 7q21.1-2
We confirmed that after transfection of GRM3, canonical metabotropic glutamate receptor 3 (mGlu3) showed the expected localization to plasma membrane and other membranes (Figure 3(a)), corroborated by co-immunostaining with mGlu3Δ4 reduces [3H]LY341495 binding to mGlu3 and the membrane abundance of mGlu3
A transcript encoding a C-terminal variant isoform of mGlu3, GRM3Δ4, was previously identified (Sartorius et al, 2006) and its expression found to be influenced by a schizophreniaassociated GRM3 risk single nucleotide polymorphisms (SNPs) (Sartorius et al, 2008)
Summary
The group II metabotropic glutamate receptor 3 (mGlu3) is a seven trans-membrane domain, G protein-coupled receptor (GPCR) encoded by the GRM3 gene on chromosome 7q21.1-2. Involvement was initially suggested by the finding that mGlu2/3 agonism could reverse behavioural and cognitive deficits caused by NMDA receptor antagonism, a widely used model of the disorder, both in rodents and humans (Krystal et al, 2005; Moghaddam and Adams, 1998). These findings were complemented by candidate gene studies showing associations of GRM3 single nucleotide polymorphisms (SNPs) with schizophrenia and relevant endophenotypes (Egan et al, 2004; Tan et al, 2007). Promising clinical trial evidence that mGlu2/3 agonism is an effective antipsychotic strategy (Patil et al, 2007) has not been confirmed (Kinon et al, 2015), there remains considerable interest in the mechanisms by which GRM3/mGlu may contribute to schizophrenia and its treatment
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