Category: receptor_pharmacology
Metabotropic glutamate receptors (mGluR1–8) are class C GPCRs — distinct from the fast ionotropic AMPA/NMDA/kainate channels. Three families with distinct G-protein coupling and synaptic localization: Group I (mGluR1, mGluR5) — Gq-coupled, postsynaptic, depolarizing — drives synaptic plasticity, LTD, Fragile-X synthesis; positive modulators trialed for cognition; negative modulators (mavoglurant — fragile X failed). Group II (mGluR2, mGluR3) — Gi/o-coupled, presynaptic autoreceptors — inhibit glutamate release; agonists (LY379268, LY2140023 — pomaglumetad) trialed for schizophrenia + anxiety; reverses 5-HT2A psychedelic effects (ketanserin/mGluR2 agonist crosstalk). Group III (mGluR4/6/7/8) — Gi/o, presynaptic + mGluR6 in retinal ON-bipolar cells; allosteric agonists trialed for Parkinson + anxiety. Distinct from iGluRs in being slower, modulatory, and pharmacologically tractable via allosteric sites (less off-target than the orthosteric glutamate site). Clinical relevance: ketamine's rapid antidepressant action involves disinhibition of glutamate release → AMPA → BDNF/mTOR (cross-link); group II agonists antagonize this (perampanel + LY379268). Riluzole (ALS) inhibits glutamate release in part through group I mGluR modulation. Fragile X is the prototypical mGluR-disorder (Bear hypothesis — excess mGluR5-LTD → phenotype; mGluR5 NAMs trialed but mostly failed). Cross-links: [[glutamate_receptor_pharmacology]] (parent), [[bdnf_trkb_neurotrophic]] (downstream of ketamine/glutamate disinhibition), [[serotonin_5ht2a_psychedelic_signaling]] (mGluR2 cross-talk).