Metabotropic glutamate receptor 2 and 3 (mGlu2/3)

Metabotropic glutamate receptor 2 and 3 (mGlu2/3) are Group II members of the metabotropic glutamate receptor family, belonging to the Class C G protein-coupled receptors [3, 4]. These receptors are primarily localized on presynaptic terminals where they function as autoreceptors to negatively regulate the release of glutamate and other neurotransmitters, such as dopamine, via Gi/o protein signaling [1, 11]. By modulating excitatory neurotransmission, mGlu2/3 receptors play a critical role in maintaining synaptic homeostasis and are involved in processes like long-term depression and neuroprotection [4, 8]. They have emerged as significant therapeutic targets for various central nervous system disorders, including schizophrenia, anxiety, and drug addiction, where agonists are used to dampen excessive glutamate release [2, 5, 7]. Conversely, mGlu2/3 antagonists and negative allosteric modulators are being investigated for rapid-acting antidepressant properties, as they can enhance glutamatergic signaling in a manner similar to ketamine [12, 14]. While mGlu2 is predominantly expressed in neurons and is linked to antipsychotic activity, mGlu3 is also found on glial cells and contributes to neuroprotective functions [8, 15]. Despite strong preclinical evidence, the clinical development of mGlu2/3 ligands has faced hurdles, such as the failure of several high-profile Phase III trials for schizophrenia due to a lack of sustained efficacy [7, 9].

Other names

mGluR2/3Group II metabotropic glutamate receptorsGRM2/GRM3Group II mGlu receptors

Agonism (inhibits glutamate release via Gi/o coupling), Positive Allosteric Modulation (PAM), Antagonism/Negative Allosteric Modulation (enhances glutamate release for antidepressant effects)