Metabotropic Glutamate Receptor 7: From Synaptic Function to Therapeutic Implications

Abstract

Metabotropic glutamate receptor 7 (mGluR7) is localized presynaptically at the active zone of neurotransmitter release. Unlike mGluR4 and mGluR8, which share mGluR7's presynaptic location, mGluR7 shows low affinity for glutamate and is activated only by high glutamate concentrations. Its wide distribution in the central nervous system (CNS) and evolutionary conservation across species suggest that mGluR7 plays a primary role in controlling excitatory synapse function. High mGluR7 expression has been observed in several brain regions that are critical for CNS functioning and are involved in neurological and psychiatric disorder development. Until the recent discovery of selective ligands for mGluR7, techniques to elucidate its role in neural function were limited to the use of knockout mice and gene silencing. Studies using these two techniques have revealed that mGluR7 modulates emotionality, stress and fear responses. N,N`-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) was reported as the first selective mGluR7 allosteric agonist. Pharmacological effects of AMN082 have not completely confirmed the mGluR7-knockout mouse phenotype; this has been attributed to rapid receptor internalization after drug treatment and to the drug's apparent lack of in vivo selectivity. Therefore, the more recently developed mGluR7 negative allosteric modulators (NAMs) are crucial for understanding mGluR7 function and for exploiting its potential as a target for therapeutic interventions. This review presents the main findings regarding mGluR7's effect on modulation of synaptic function and its role in normal CNS function and in models of neurologic and psychiatric disorders.

Fig. (1)

Synaptic distribution of mGluRs with group I localized mainly postsynaptically and group II and III localized presynaptically. The mGluR7 receptor is found on both glutamatergic and GABAergic terminals, functioning as an auto- and hetero-receptor and controlling neurotransmitter release. Together with excitatory amino acid transporters (EAAT), presynaptic mGluR7 receptors reduce glutamate levels under conditions of high glutamate concentration. mGluR7 binding and signaling proteins are also reported. VGAT, vesicular GABA transporter; vGluT, vesicular glutamate transporter; EAAT, excitatory amino acid transporter; NMDA, N-methyl-D-aspartate receptor; AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, KA, kainic acid receptor, CaM, Ca²⁺-calmodulin complex, PKC, protein kinase C, AC, adenylate cyclase, PICK1, PDZ domain-containing protein, Ca²⁺, N type Ca²⁺ channels, GIRKs, G-protein-coupled inwardly rectifying potassium channels.