L-glutamate, the major excitatory neurotransmitter in the central nervous system, operates through several receptors that are categorized as ionotropic (ligand-gated cation channels) or metabotropic (G-protein coupled receptors). The metabotropic glutamate receptor family includes eight members (mGluR1-8) that have been divided into three groups based on their sequence homology, pharmacology and signal transduction.

Group II of the metabotropic glutamate receptors includes the mGluR2 and mGluR3 receptors. The receptors present the typical G-protein coupled receptor (GPCR) signature topology: seven transmembrane domains with a large extracellular N-terminus that contains the glutamate binding site, and an intracellular C-terminus.^1,2 mGluR2 and mGluR3 are coupled to G_i/G₀ and hence inhibit cAMP formation following receptor activation.^1,2

mGluR3 is expressed in neurons and glia in many brain regions including the cerebral cortex, hippocampus and brain stem. mGluR3 expression is predominantly presynaptic consistent with its role as an inhibitory autoreceptor, that is, activation of mGluR3 by glutamate inhibits additional glutamate release from the same neurons.^1,2

Several lines of evidence suggest that mGluR3 is important for long term depression, glial function and neuroprotection. Some studies, though not all, have shown a genetic association of mGluR3 gene polymorphisms with psychosis and with schizophrenia-related phenotypes. Based in these findings, mGluR3 has been suggested as a therapeutic target for both psychosis and schizophrenia.³