A group II metabotropic glutamate receptor 3 (mGlu3, GRM3) isoform implicated in schizophrenia interacts with canonical mGlu3 and reduces ligand binding

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.

The contribution of alternative splicing to genetic risk for psychiatric disorders

“…There is some evidence that expression of this transcript is increased in DLPFC samples of schizophrenia patients and predicted by the exon 3 rs2228595 SNV . A potential mechanism for molecular action in disease has been indicated by the interaction of the exon 4 missing protein with the full‐length protein, leading to decreased levels of the full‐length protein …”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…The most abundant GRM3 variant lacks exon 4 (GRM3Delta4), encoding a truncated membraneassociated protein that retains the extracellular VFT but lacks the 7TM, which is replaced with a unique 96-amino acid C terminus. mGlu 3delta4 can bind orthosteric ligands and interact with the full-length protein and may thus have a dominant negative effect (García-Bea et al, 2017). Spontaneous mutations in mGlu 3 are associated with melanoma (Prickett et al, 2011;Neto and Ceol, 2018), whereas single nucleotide polymorphisms in GRM3 are linked to cognitive performance in individuals with schizophrenia and are postulated to influence pharmacotherapy (reviewed in Maj et al, 2016 andSaini et al, 2017).…”

A metabotropic glutamate receptor 3 (mGlu3R) isoform playing neurodegenerative roles in astrocytes is prematurely up‐regulated in an Alzheimerʼs model

“…Expression of this isoform at the protein level (mGlu3Δ4) was also demonstrated in human brains and can even be detected in human lymphoblasts (Sartorius et al, 2006). Interestingly, despite lacking the transmembrane domain, mGlu3Δ4 is mainly present in membrane fractions (Garcia‐Bea et al, 2017; Sartorius et al, 2006). Recent results from Garcia‐Bea et al (2017) indicate that mGlu3Δ4 co‐precipitates with canonical mGlu3R and reduces mGlu3R levels in HEK cell membranes.…”

“…Interestingly, despite lacking the transmembrane domain, mGlu3Δ4 is mainly present in membrane fractions (Garcia‐Bea et al, 2017; Sartorius et al, 2006). Recent results from Garcia‐Bea et al (2017) indicate that mGlu3Δ4 co‐precipitates with canonical mGlu3R and reduces mGlu3R levels in HEK cell membranes. Also, mGlu3Δ4 significantly reduces 3H‐LY341495 binding to mGlu3R.…”