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 receptors family includes eight members (mGluR1-8) that have been divided into three groups based on their sequence homology, pharmacology and signal transduction.

Group I of the metabotropic glutamate receptors includes the mGluR1 and mGluR5 receptors. The receptors present the typical G-protein coupled receptor (GPCR) signature topology: seven transmembrane domains with a large extracellular N-terminus domain and an intracellular C-terminus one. The N-terminus domain of group I receptors contains the glutamate binding site while the cytoplasmic C-terminus domain has an important role in the regulation of receptor activity through interactions with other proteins such as the Homer adaptor proteins.

mGluR1 and mGluR5 receptors signal through G_q/G₁₁ that activates phospholipase C and ultimately produces an increase in inositol trisphosphate and cytosolic Ca²⁺. More downstream signaling pathways include activation of PKC and modulation of Ca²⁺ and K⁺ ion channels. Activation of signaling pathways independent of G-proteins has also been reported.

mGluR5 is predominantly expressed in nervous tissue although expression in several non-neural cell types has also been described. In the brain it is highly expressed in the cortex, basal ganglia and hippocampus.

The mGluR5 receptor is involved in several physiological processes such as neuronal development, induction of long-term potentiation (LTP) and depression (LTD) as well as in pathological disorders such as brain trauma, chronic pain, Parkinson’s and Huntington’s disease.