mGluR

Metabotropic glutamate receptors, abbreviated mGluRs, are a family of G protein-coupled receptors that respond to the neurotransmitter glutamate. They are distinct from the ionotropic glutamate receptors (AMPA, NMDA, kainate) and function to modulate synaptic transmission and neuronal excitability throughout the central nervous system. The eight subtypes, named mGluR1 through mGluR8, are encoded by GRM genes and organized into three pharmacological groups with different signaling properties.

Group I includes mGluR1 and mGluR5, which primarily couple to Gq/11 proteins. Activation of these receptors stimulates phospholipase C, increasing inositol triphosphate and diacylglycerol signaling, and raising intracellular calcium. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR6, mGluR7, mGluR8) couple to Gi/o proteins, inhibiting adenylyl cyclase, reducing cAMP production, and often dampening neurotransmitter release through modulation of presynaptic ion channels.

Localization and function: mGluRs are found both pre- and postsynaptically in various brain regions. Presynaptic receptors commonly act as autoreceptors or heteroreceptors to limit glutamate and other neurotransmitter release, while postsynaptic receptors modulate receptor sensitivity and contribute to synaptic plasticity, learning, and memory.

Pharmacology and therapeutic interest: mGluRs can be targeted by selective agonists, antagonists, and allosteric modulators. Notable examples include selective mGluR5 antagonists, certain Group II agonists, and Group III agonists, as well as positive and negative allosteric modulators that offer subtype-selective control. These agents are explored for treating anxiety, depression, schizophrenia, chronic pain, and neurodegenerative diseases.

Notable features: mGluR6 is expressed in retinal ON-bipolar cells, where it participates in the retinal signal transduction pathway. The mGluR family remains an active area of research for understanding synaptic regulation and developing CNS therapeutics.