mGluR4

mGluR4, or metabotropic glutamate receptor 4, is a G protein-coupled receptor of the metabotropic glutamate receptor family encoded by the GRM4 gene. It belongs to group III mGluRs, which also includes mGluR6, mGluR7, and mGluR8. These receptors modulate synaptic transmission rather than mediate fast synaptic responses.

mGluR4 is widely expressed in the central nervous system with notable presynaptic localization on terminals in the cerebellum, striatum, and cortex, where it modulates neurotransmitter release. Its presynaptic distribution allows it to influence excitatory signaling and local circuitry.

Functionally, mGluR4 couples to Gi/o proteins, inhibiting adenylyl cyclase and reducing cAMP formation. Activation decreases voltage-gated calcium influx and neurotransmitter release, thereby dampening synaptic transmission and contributing to synaptic plasticity in various circuits.

Pharmacologically, mGluR4 is activated by orthosteric group III agonists such as L-AP4. It is also subject to modulation by allosteric ligands, with several positive and negative allosteric modulators described. These tools enable selective modulation of receptor activity without directly activating the receptor.

Clinical relevance and research use focus on its role in limiting excitatory signaling, making mGluR4 a target of interest for disorders such as Parkinson's disease, anxiety, chronic pain, and substance use disorders. Ongoing preclinical studies aim to define the therapeutic potential, optimal targeting strategies, and safety profile of mGluR4 modulation.

Genetic and experimental studies using GRM4 models have helped characterize its expression patterns and function, supporting its continued investigation as a CNS pharmacological target.