mGlu

Metabotropic glutamate receptors, or mGluRs, are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. They are encoded by GRM1 to GRM8 genes and are expressed across the central nervous system and in some peripheral tissues. Unlike ionotropic glutamate receptors, mGluRs modulate neuronal excitability, synaptic transmission, and plasticity, and thereby influence learning and memory processes.

mGluRs are classified into three groups based on sequence similarity, pharmacology, and signaling. Group I consists of mGlu1 and mGlu5, which couple to Gq/11 proteins to activate phospholipase C, producing IP3 and DAG and typically enhancing postsynaptic excitability. Group II comprises mGlu2 and mGlu3, which couple to Gi/o proteins to inhibit adenylyl cyclase and reduce cAMP, primarily modulating presynaptic glutamate release. Group III includes mGlu4, mGlu6, mGlu7, and mGlu8, also Gi/o-coupled and mainly acting to limit neurotransmitter release at presynaptic sites.

Structurally, mGluRs are class C GPCRs with a large extracellular ligand-binding domain (the Venus flytrap) and seven transmembrane segments. Pharmacology often relies on allosteric ligands that bind sites distinct from the orthosteric glutamate pocket, enabling subtype-selective modulation. Positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) provide tools to tune receptor activity with greater specificity than orthosteric ligands.

Clinical relevance of mGluRs spans anxiety, depression, schizophrenia, chronic pain, neurodegenerative diseases, and Fragile X syndrome. They remain important drug discovery targets, with ongoing research into subtype-selective modulators and their therapeutic potential, though translational success has varied across indications.