Metabotropic glutamate receptor 2; Metabotropic glutamate receptor 3 (mGluR2 (for metabotropic glutamate receptor 2), mGluR3 (for metabotropic glutamate receptor 3))

Metabotropic glutamate receptor 2 (mGluR2) and metabotropic glutamate receptor 3 (mGluR3) are closely related G protein-coupled receptors in the group II mGluR family, encoded by the GRM2 and GRM3 genes, respectively. They are highly expressed in the brain, localizing primarily to pre- and peri-synaptic neuronal and astrocytic membranes where they function as modulators of glutamatergic synaptic transmission. Upon activation (by endogenous glutamate or pharmacological agonists), they couple to Gi/o proteins, leading to inhibition of adenylate cyclase, reduced cyclic AMP levels, and subsequent inhibition of neurotransmitter release—chiefly glutamate. mGluR2/3 are implicated in a range of neurological and psychiatric disorders including schizophrenia, gliomas, pain states, and neurodegenerative conditions, and have been validated as therapeutic targets for both small molecule agonists and positive allosteric modulators, though clinical success has to date been limited. Their modulatory role, rather than direct mediation of excitation, provides a rationale for targeting these receptors in order to achieve efficacy with potentially fewer side effects compared to other glutamate receptors.

Other names

mGlu2, mGlu3GRM2 (gene for mGluR2), GRM3 (gene for mGluR3)Group II metabotropic glutamate receptorMetabotropic glutamate receptor type 2/type 3

Agonists: Activate mGluR2/3, leading to inhibition of adenylate cyclase, reduced cAMP, inhibition of voltage-gated calcium channels, and reduced neurotransmitter (glutamate) release. Positive allosteric modulators (PAMs): Enhance the receptor’s response to endogenous glutamate, modulating signaling without direct active site occupancy. Antagonists/negative allosteric modulators (NAMs): Block receptor activation and signaling, sometimes used in experimental settings.