Affinage

GRM2

Metabotropic glutamate receptor 2 · UniProt Q14416

Length
872 aa
Mass
95.6 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM2 encodes mGluR2, a class C G-protein-coupled receptor that serves as the principal presynaptic group II autoreceptor for synaptically released glutamate at multiple forebrain synapses, where it limits neurotransmitter release (PMID:12213275). Cryo-EM structures establish that mGluR2 signals as an asymmetric dimer: agonist binding drives sequential Venus flytrap domain closure followed by transmembrane domain rearrangement from a symmetric inactive to an asymmetric active conformation, with the resulting Gi heterotrimer engaging a non-canonical intracellular site formed by three intracellular loops and helices III and IV (PMID:34135510, PMID:34135509, PMID:37286794). Presynaptically, mGluR2/3 inhibits release through ERK/MAPK-dependent phosphorylation and subsequent proteasomal degradation of Munc18-1 (PMID:27056679), and postsynaptically it hyperpolarizes neurons by activating GIRK channels, as shown at cerebellar granule cell–Golgi cell synapses (PMID:12948448). Receptor output is gated by PKA phosphorylation at Ser843, which uncouples mGluR2 from G proteins (PMID:10908604), while mGluR2 is uniquely resistant to GRK2-mediated homologous desensitization of its cAMP pathway compared with mGluR3 (PMID:19164443). mGluR2 assembles a functional heteromeric complex with the 5-HT2A receptor in frontal cortex via residues at the intracellular end of transmembrane domain 4 (PMID:23129762); within this complex 5-HT2A drives trans-receptor phosphorylation of mGluR2 at Ser843 to enhance Gi/o signaling (PMID:29858599) and mGluR2 stimulation cross-activates Gq/11 through the 5-HT2A partner (PMID:26758213), a complex required for the behavioral and binding effects of hallucinogens (PMID:21276828). GRM2 transcription is epigenetically controlled, including 5-HT2A/Egr1-dependent regulation at the Grm2 promoter (PMID:23508685). mGluR2 mediates the antipsychotic-like and antidepressant-relevant actions of group II ligands and of (2R,6R)-hydroxynorketamine (PMID:18057917, PMID:30867285, PMID:31735403). Beyond its neuronal roles, mGluR2 is exploited as a host endocytic receptor: influenza hemagglutinin binds it directly to drive clathrin-mediated endocytosis via KCa1.1-dependent F-actin polymerization (PMID:38849624), and rabies virus uses mGluR2 in cooperation with transferrin receptor 1 (PMID:36779763).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1993 Medium

    Establishing where and how mGluR2 signals required defining its expression and G-protein coupling; this showed mGluR2 is a neuronal receptor coupled to the inhibitory cAMP cascade.

    Evidence In situ hybridization mapping mGluR2 mRNA distribution and cAMP coupling across CNS

    PMID:8389425

    Open questions at the time
    • mRNA distribution does not establish subcellular protein localization
    • functional consequence at synapses not addressed
  2. 1996 High

    Whether mGluR2 acts pre- or postsynaptically was unresolved; ultrastructural localization placed it at presynaptic, postsynaptic, and glial compartments of excitatory synapses, concentrated at mossy fiber and perforant path terminals.

    Evidence Electron microscopy immunocytochemistry across multiple brain regions

    PMID:8684625

    Open questions at the time
    • does not assign functional role to each compartment
    • antibody cross-reactivity with mGluR3 not fully separated
  3. 2000 High

    How mGluR2 output is regulated was unknown; PKA was shown to phosphorylate Ser843 on the C-terminus, uncoupling the receptor from G proteins and inhibiting presynaptic responses.

    Evidence Site-directed mutagenesis, in vitro kinase assays, and electrophysiology with a PKA inhibitor

    PMID:10908604

    Open questions at the time
    • upstream signals driving PKA activation at the receptor not defined
    • stoichiometry and kinetics of dephosphorylation unaddressed
  4. 2003 High

    The postsynaptic effector of mGluR2 was undefined; knockout electrophysiology showed mGluR2 hyperpolarizes Golgi cells via GIRK channels to produce long-lasting silencing.

    Evidence Whole-cell recording in mGluR2-deficient vs wild-type mouse cerebellum

    PMID:12948448

    Open questions at the time
    • G-protein subtype linking mGluR2 to GIRK not detailed
    • generality across brain regions unestablished
  5. 2002 High

    Distinguishing mGluR2 from mGluR3 autoreceptor roles was needed; genetic and pharmacological dissection identified mGluR2 as the major autoreceptor activated by synaptic glutamate at perforant path synapses.

    Evidence Field EPSP recordings in mGlu2-/- mice with LY341495 unmasking

    PMID:12213275

    Open questions at the time
    • intracellular cascade reducing release not yet identified
    • contribution at other synapse types varies
  6. 2009 High

    Whether mGluR2 desensitizes like other GPCRs mattered for tolerance; mGluR2 was found resistant to GRK2 desensitization of its cAMP pathway, unlike mGluR3, in a signal-dependent manner.

    Evidence HEK293 cAMP/MAPK assays with kinase-dead GRK2 plus in vivo knockout pharmacology

    PMID:19164443

    Open questions at the time
    • structural basis for differential GRK2 sensitivity unknown
    • arrestin engagement on MAPK pathway only partially resolved
  7. 2016 High

    The presynaptic mechanism coupling mGluR2/3 to reduced release was unknown; ERK-dependent phosphorylation of Munc18-1 followed by its proteasomal degradation was shown to mediate the inhibition.

    Evidence Electrophysiology, biochemistry, and phosphomimetic/phospho-null Munc18-1 mutants

    PMID:27056679

    Open questions at the time
    • link between receptor activation and ERK at the terminal not fully mapped
    • shared mechanism with CB1R leaves receptor specificity step undefined
  8. 2021 High

    How mGluR2 transduces signal at atomic resolution was unknown; cryo-EM revealed asymmetric dimer activation through sequential VFT closure and TMD rearrangement and a non-canonical Gi-binding site on helices III/IV and three intracellular loops.

    Evidence Cryo-EM of inactive/active homodimers and heterodimers with functional mutagenesis

    PMID:34135509 PMID:34135510 PMID:37286794

    Open questions at the time
    • how heteromerization with 5-HT2A maps onto these conformational states is not resolved
    • dynamics in native membranes not captured
  9. 2024 High

    Whether mGluR2 has roles beyond glutamatergic signaling was unclear; it was shown to be a host endocytic receptor directly bound by influenza HA driving KCa1.1/F-actin-dependent clathrin-mediated endocytosis, and used by rabies virus in cooperation with TfR1.

    Evidence siRNA screen, Co-IP of HA and TfR1 with mGluR2, actin/CME assays, and in vivo knockout viral challenge

    PMID:36779763 PMID:38849624

    Open questions at the time
    • relationship between viral-entry signaling and canonical Gi/o coupling unresolved
    • structural basis of HA–mGluR2 binding undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The 5-HT2A–mGluR2 heteromer was progressively defined as physically and functionally coupled and pharmacologically consequential, but how it is regulated and its causal role in human disease remains open.
  • one report found no signaling consequence of co-expression in HEK293 (idx 28)
  • stoichiometry and dynamics of the heteromer in vivo unresolved
  • translation to human therapeutics not established by direct causal evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0038024 cargo receptor activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
EGR1GRK2HTR2AMUNC18-1TFR1
Complex memberships
5-HT2A–mGluR2 heteromer

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 mGluR2 and mGluR3 are localized in postsynaptic, presynaptic, and glial compartments at excitatory synapses, with presynaptic staining concentrated in mossy fiber and perforant path glutamatergic terminals in the hippocampus, as determined by ultrastructural immunocytochemistry. Electron microscopy immunocytochemistry with affinity-purified antibody Neuroscience High 8684625
1993 mGluR2 mRNA is coupled to the inhibitory cAMP cascade and is expressed predominantly in neurons (not glia) throughout the CNS, with highest expression in cerebellar Golgi cells, mitral cells of the accessory olfactory bulb, and entorhinal/parasubicular cortex neurons. In situ hybridization Neuroscience Medium 8389425
2000 PKA directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail, and this phosphorylation inhibits coupling of mGluR2 to GTP-binding proteins; cAMP/PKA activation inhibits presynaptic mGluR2-mediated responses at the medial perforant path synapse. Site-directed mutagenesis, biochemical phosphorylation assays, in vitro kinase assay, electrophysiology with selective PKA inhibitor The Journal of neuroscience High 10908604
2003 mGluR2 acts as a postsynaptic receptor at granule cell–Golgi cell synapses in the cerebellum; glutamate from granule cells activates postsynaptic mGluR2, which hyperpolarizes Golgi cells via G protein-coupled inwardly rectifying K+ (GIRK) channels, producing long-lasting silencing dependent on stimulus strength. Whole-cell recording in GFP-positive Golgi cells of wild-type vs. mGluR2-deficient mice Neuron High 12948448
2002 mGlu2 is the major presynaptic group II autoreceptor activated by synaptically released glutamate at perforant path inputs to the dentate gyrus and CA1 stratum lacunosum moleculare; mGlu3 can regulate transmission but contributes less to autoreceptor function at these synapses. Field EPSP recordings in mGlu2-/- mice vs. wild-type; LY341495-mediated unmasking of autoreceptor activity Neuropharmacology High 12213275
2007 The mGlu2 receptor subtype (not mGlu3) specifically mediates the antipsychotic-like actions of the mGluR2/3 agonist LY379268 in reversing PCP- and amphetamine-evoked hyperactivity, as demonstrated using mGluR2 and mGluR3 knockout mice. Locomotor activity assays in mGluR2-KO, mGluR3-KO, and wild-type mice with LY379268 Psychopharmacology High 18057917
2011 The 5-HT2A receptor–mGluR2 heteromeric complex is required for the pharmacological and behavioral effects of hallucinogens: mGluR2 knockout abolishes DOI-induced high-affinity binding of DOI to 5-HT2A receptors, eliminates head-twitch behavior, and prevents hallucinogen-specific egr-2 induction. Radioligand binding ([(3)H]ketanserin displacement), immunofluorescence, behavioral assays in mGluR2-KO mice Neuroscience letters High 21276828
2012 Three specific residues at the intracellular end of transmembrane domain 4 of mGluR2 (Ala-677, Ala-681, Ala-685) are required for assembly of the 5-HT2A–mGluR2 GPCR heteromeric complex in mouse frontal cortex; mutation of these residues abolishes heteromer formation, reduces heteromeric ligand binding, and attenuates hallucinogen-induced psychosis-like effects in mice. Site-directed mutagenesis, Co-IP, BRET, behavioral assays in mice with viral-mediated expression of mutant mGluR2 The Journal of biological chemistry High 23129762
2016 In cells co-expressing mGluR2 and 5-HT2A receptors, stimulation of mGluR2 leads to activation of Gq/11 proteins via the 5-HT2A receptor in the heteromeric complex; this cross-G-protein signaling requires one mGluR2 subunit to couple to Gi/o, and this mGluR2-dependent Gq/11 activation is reduced in frontal cortex of 5-HT2A-KO mice and in postmortem schizophrenic brains. Single-cell BRET signaling experiments with mutant mGluR2 variants, G-protein coupling assays, postmortem brain analysis Science signaling High 26758213
2021 Cryo-EM structures of human mGluR2 bound to heterotrimeric Gi reveal a G-protein-binding site formed by three intracellular loops and helices III and IV, distinct from other GPCR structures. Asymmetric dimerization of the transmembrane domain is crucial for receptor activation and asymmetric signal transduction. Cryo-electron microscopy structural determination with functional validation Nature High 34135510
2021 Cryo-EM structures of inactive mGluR2 homodimer, agonist/PAM-bound active mGluR2 homodimer, and inactive mGluR2-mGluR7 heterodimer reveal: a unique helix IV-mediated dimer interface in inactive mGluR2 that limits activity; sequential Venus flytrap domain closure followed by transmembrane domain rearrangement from symmetric inactive to asymmetric active conformation; and the mGluR7 subunit dominates G-protein activation in the mGluR2-mGluR7 heterodimer. Cryo-EM structure determination with functional assays Nature High 34135509
2023 Twelve cryo-EM structures of mGluR2-mGluR3 and mGluR2-mGluR4 heterodimers in inactive, intermediate, and active states reveal sequential Venus flytrap domain conformational changes, substantial transmembrane domain rearrangement from symmetric inactive to asymmetric active dimer, and stability of inactive conformations as a determinant of asymmetric signal transduction. A novel PAM binding site was identified at the asymmetric dimer interface. Cryo-EM structural determination across multiple conformational states, combined with functional assays Cell research High 37286794
2009 mGluR2 is resistant to homologous desensitization by GRK2 for the cAMP signaling pathway, whereas mGluR3 is fully desensitized by GRK2 and beta-arrestin1. This difference is signal-dependent: GRK2 desensitizes the MAPK pathway mediated by both mGluR2 and mGluR3. In vivo agonist pretreatment desensitizes cAMP response only in mGluR3, not mGluR2, supporting its resistance to tolerance. HEK293 cell transfection, cAMP assays, MAPK assays, kinase-dead GRK2 mutant, in vivo knockout mouse pharmacology Molecular pharmacology High 19164443
2018 The 5-HT2A receptor promotes phosphorylation of mGluR2 at Ser843 in cells co-expressing both receptors and in mouse prefrontal cortex in vivo; Ser843 phosphorylation is required for efficient Gi/o signaling elicited by either mGluR2 or 5-HT2A receptor stimulation in co-expressing cells, establishing a trans-receptor phosphorylation mechanism underlying 5-HT2A–mGluR2 crosstalk. Phosphoproteomics, site-directed mutagenesis (Ser843Ala), co-expression in HEK293 cells, prefrontal cortex analysis in 5-HT2A KO mice Molecular psychiatry High 29858599
2016 CB1R- and mGluR2/3-induced presynaptic inhibition of synaptic transmission requires ERK/MAPK-dependent phosphorylation of Munc18-1, which ultimately leads to Munc18-1 degradation via the ubiquitin-proteasome system; blocking ERK-dependent Munc18-1 phosphorylation prevents mGluR2/3-induced synaptic inhibition. Electrophysiology, biochemistry, pharmacological inhibitors of ERK/MEK, phosphomimetic and phospho-null Munc18-1 mutants The EMBO journal High 27056679
2016 mGluR2 receptors on astrocytes in the thalamic ventrobasal nucleus reduce inhibitory transmission (miniature IPSC frequency) from the thalamic reticular nucleus and disinhibit thalamocortical sensory responses to vibrissae stimulation in vivo; the glial inhibitor fluorocitrate abolishes the mGluR2 PAM effect, confirming the astrocytic locus of action. Electrophysiology in thalamic slices (mIPSC recording), calcium imaging of astrocytes, in vivo thalamic neuron recording with vibrissae stimulation, fluorocitrate glial blockade Neuropharmacology High 28416443
2011 mGlu2 receptors play the predominant role over mGlu3 in the endogenous control of inflammatory pain; the analgesic activity of mixed mGlu2/3 agonists (LY379268) is entirely mediated by mGlu2 subtype activation, as the analgesic effect is absent in mGlu2-/- but preserved (though tolerance develops) in mGlu3-/- mice. Formalin test in mGlu2-/- and mGlu3-/- knockout mice with systemic LY379268 administration Molecular pain High 21543601
2013 mGlu2 receptor-induced hyperthermia is mediated specifically by mGlu2 (not mGlu3) receptors, as the agonist LY379268-induced temperature increase is abolished in mGlu2-/- mice but not mGlu3-/- mice; this in vivo readout predicts antidepressant-like efficacy of mGluR2/3 antagonists via mGlu2. Body temperature measurement in mGlu2-/-, mGlu3-/-, and mGlu2/3-/- knockout mice; forced swim test CNS & neurological disorders drug targets High 23574174
2019 The antidepressant-relevant behavioral effects and gamma-range (30-80 Hz) cortical EEG oscillation increases produced by (2R,6R)-hydroxynorketamine are absent in mGlu2 (Grm2) but not mGlu3 (Grm3) knockout mice, and are blocked by mGlu2/3 agonist pretreatment, demonstrating that (2R,6R)-HNK acts via mGlu2 receptor signaling. Behavioral assays, quantitative EEG in Grm2-/- and Grm3-/- mice, pharmacological blockade with mGlu2/3 agonist Proceedings of the National Academy of Sciences of the United States of America High 30867285
2019 Selective mGlu2 NAM enhances thalamocortical transmission and inhibits long-term depression via presynaptic mechanisms in the PFC, while mGlu3 NAM acts via postsynaptic mechanisms; both NAMs activate distinct PFC pyramidal cell ensembles and produce antidepressant-like effects in chronic stress models. Electrophysiology in PFC slices, transgenic mice, viral-assisted optogenetics, behavioral tests in chronic stress models Neuron High 31735403
2024 Influenza virus hemagglutinin (HA) directly interacts with mGluR2, using it as an endocytic receptor to initiate clathrin-mediated endocytosis (CME); mGluR2 then activates KCa1.1, leading to F-actin polymerization, clathrin-coated pit maturation, and completion of CME. mGluR2-knockout mice are significantly more resistant to multiple influenza subtypes. siRNA screen, Co-IP of HA with mGluR2, mGluR2 knockout mice challenged with influenza, actin polymerization assays Nature microbiology High 38849624
2023 mGluR2 mediates RABV internalization in vitro and infection in vivo (mGluR2-KO mice survive lethal RABV challenge); transferrin receptor 1 (TfR1) interacts with mGluR2, co-internalizes with mGluR2 and RABV in the same clathrin-coated pit, and TfR1 knockdown blocks agonist-triggered mGluR2 internalization. Co-IP of mGluR2 with TfR1, knockdown of TfR1, mGluR2-KO in vivo RABV challenge, confocal colocalization Journal of virology High 36779763
2016 Glutamate signals through mGluR2 in Schwann cells to induce ERK phosphorylation via ErbB2/3 receptor tyrosine kinase, with Gβγ and Src involved downstream; mGluR2 activation transforms myelinating Schwann cells to a proliferating state, and inhibition of mGluR2 signaling reduces demyelination of injured nerves in vivo. Cell culture signaling assays (Erk and Akt phosphorylation), ErbB2/3 phosphorylation assays, in vivo nerve injury model with mGluR2 inhibition Scientific reports Medium 27432639
2006 LY354740-induced c-Fos expression increases in the central amygdala, bed nucleus of stria terminalis, and other limbic/non-limbic structures are abolished by mGlu2 (but not mGlu3) receptor deletion; mGlu3 receptor deletion specifically increases basal hippocampal c-Fos and prevents LY354740-mediated suppression of hippocampal activity. c-Fos immunohistochemistry in mGlu2-KO and mGlu3-KO mice after LY354740 administration Neuropharmacology Medium 16733060
2013 L-acetylcarnitine (LAC) produces antidepressant effects by epigenetically upregulating mGlu2 receptor expression: LAC increases acetylated H3K27 bound to the Grm2 promoter and acetylation of NF-κB-p65, enhancing Grm2 transcription in hippocampus and prefrontal cortex. LAC has no effect in mGlu2 knockout mice exposed to chronic unpredictable stress. ChIP (H3K27 acetylation at Grm2 promoter), NF-κB acetylation assays, mGlu2 KO mice behavioral assays, HDAC inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 23382250
2013 5-HT2A receptor-dependent signaling epigenetically controls mGlu2 transcription: disruption of 5-HT2A signaling in KO mice reduces H3 and H4 acetylation and increases H3K27me3 at the mGlu2 promoter; the transcription factor Egr1 binds the mGlu2 promoter in a 5-HT2A-dependent manner, and viral overexpression of Egr1 increases mGlu2 expression. ChIP for multiple histone marks at mGlu2 promoter in 5-HT2A KO mice, Egr1 ChIP, viral-mediated Egr1 overexpression Molecular pharmacology High 23508685
2008 mGluR2 activation in neuronal cell cultures leads to activation of ERK/MAPK pathways and increased tau phosphorylation, and reduces oxidative stress-mediated cytotoxicity. Cell culture signaling assays (ERK phosphorylation), tau phosphorylation assays, oxidative stress viability assay Brain research Low 19026996
2009 mGluR2 knockout striata show elevated proportion of dopamine D2(High) receptors (220% increase) and 67-fold functional supersensitivity to the D2 agonist (+)PHNO, suggesting that mGluR2 normally regulates dopamine D2 receptor affinity state. Radioligand binding (D2(High) proportion measurement), GTPγS incorporation assays in mGluR2-KO and mGluR3-KO striata Synapse Medium 19084908
2012 mGluR2 forms a heteromeric complex with 5-HT2A receptor; additionally, mGluR2 forms complexes with 5-HT2B and mGluR5 but not 5-HT2C, indicating selective but not exclusive heterocomplex formation. However, co-expression of mGluR2 and 5-HT2A had no relevant effects on individual receptor signaling (Gq/11, Gi, or cAMP) in HEK-293 cells under the tested conditions. Quantitative SNAP/CLIP-tag HTRF assay for heterocomplex formation, cAMP and calcium signaling assays in HEK293 cells, radioligand competition binding in medial PFC membranes Neuropharmacology Medium 22300836
2003 mGluR2/3 receptor activation supports the proliferation of human glioma cells in culture; mGluR2/3 antagonist LY341495 reduces glioma cell proliferation, inhibits EGF-induced MAPK pathway activation, and reduces cyclin D1 induction, with these effects partially reversed by mGluR2/3 agonist co-addition. [3H]-thymidine incorporation, Western blot for MAPK and cyclin D1, pharmacological antagonism/agonism in primary human glioma cultures Journal of neurochemistry Medium 12614329
2018 mGluR2/3 activation in spinal cord glutamatergic nerve endings via mGluR2/3 autoreceptors suppresses glutamate exocytosis; the 5-HT2A receptor co-localizes and co-immunoprecipitates with mGluR2/3 in spinal cord synaptosomes, and 5-HT2A agonist activation antagonizes mGluR2/3-mediated inhibition of glutamate release, while 5-HT2A antagonists potentiate it and increase mGluR2/3 membrane expression. [3H]D-aspartate release from synaptosomes, Co-IP of mGluR2/3 and 5-HT2A, Western blot, confocal microscopy Neuropharmacology Medium 29499271

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 509 8684625
1993 Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 445 8389425
2013 L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proceedings of the National Academy of Sciences of the United States of America 218 23382250
1995 Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. Journal of neurophysiology 207 7608756
1994 Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex. Neuron 194 8043281
2011 Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neuroscience letters 177 21276828
2003 LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. Stress (Amsterdam, Netherlands) 170 13129812
2007 Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 156 17712352
2007 The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity. Psychopharmacology 153 18057917
2015 The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 150 26245499
2019 (2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions. Proceedings of the National Academy of Sciences of the United States of America 130 30867285
2021 Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4. Nature 128 34135510
2010 Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. European journal of pharmacology 124 20371233
2021 Structures of human mGlu2 and mGlu7 homo- and heterodimers. Nature 115 34135509
2012 Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. The Journal of biological chemistry 107 23129762
2010 Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Molecular pharmacology 105 21159998
2017 Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine. The international journal of neuropsychopharmacology 101 27765808
2012 mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 98 22640631
1996 Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus. Brain research 94 8930327
2016 Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Science signaling 92 26758213
2016 The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits. The Journal of pharmacology and experimental therapeutics 92 27189960
2012 Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology 83 22300836
2012 Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target. Neuropharmacology 83 22992331
2003 Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. Journal of neurochemistry 75 12614329
2003 mGluR2 postsynaptically senses granule cell inputs at Golgi cell synapses. Neuron 70 12948448
2002 Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? Current drug targets. CNS and neurological disorders 70 12769628
2013 mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure. Journal of molecular psychiatry 67 25408908
2019 mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects. Neuron 65 31735403
2017 mGlu2/3 Receptor Antagonists as Novel Antidepressants. Trends in pharmacological sciences 64 28413097
2010 The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 61 20555310
2014 Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics. Journal of psychiatry & neuroscience : JPN 60 24949866
2013 The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 58 23624743
2010 Metabotropic glutamate2/3 (mGlu2/3) receptors, schizophrenia and cognition. European journal of pharmacology 58 20371229
2014 Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment. Neuropharmacology 57 25150943
2014 5-HT(2A) and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains. Neuroscience 56 24412375
2013 The two faces of the pharmacological interaction of mGlu2 and 5-HT₂A - relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology 55 23466331
2000 cAMP-dependent protein kinase inhibits mGluR2 coupling to G-proteins by direct receptor phosphorylation. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 10908604
2015 Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? Progress in neuro-psychopharmacology & biological psychiatry 52 25724760
2006 Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats. European journal of pharmacology 52 17113075
2023 Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. Cell research 50 37286794
2020 Encapsulation mechanisms and structural studies of GRM2 bacterial microcompartment particles. Nature communications 49 31959751
2016 Development and Antiparkinsonian Activity of VU0418506, a Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor 4 Homomers without Activity at mGlu2/4 Heteromers. ACS chemical neuroscience 48 27441572
2008 Altered hippocampal expression of glutamate receptors and transporters in GRM2 and GRM3 knockout mice. Synapse (New York, N.Y.) 48 18720515
2002 Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice. Neuropharmacology 47 12213275
2011 mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. Molecular pain 46 21235748
2009 Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization. Molecular pharmacology 46 19164443
2024 Influenza virus uses mGluR2 as an endocytic receptor to enter cells. Nature microbiology 43 38849624
2002 Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus. Neuropharmacology 43 12128001
2016 Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour. Neuropharmacology 42 26987983
2009 Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. Pain 40 19782473
2014 Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor. Pharmacology research & perspectives 39 25692015
2016 Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18-1. The EMBO journal 38 27056679
2001 Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia. Molecular psychiatry 38 11317221
1999 Localization of metabotropic glutamate receptors mGluR1alpha and mGluR2/3 in the cat retina. The Journal of comparative neurology 38 10320222
2018 Metabotropic Glutamate Receptor 2/3 (mGluR2/3) Activation Suppresses TRPV1 Sensitization in Mouse, But Not Human, Sensory Neurons. eNeuro 36 29662945
2014 The role of group II metabotropic glutamate receptors in cognition and anxiety: comparative studies in GRM2(-/-), GRM3(-/-) and GRM2/3(-/-) knockout mice. Neuropharmacology 36 25158312
2006 Effects of mGlu2 or mGlu3 receptor deletions on mGlu2/3 receptor agonist (LY354740)-induced brain c-Fos expression: specific roles for mGlu2 in the amygdala and subcortical nuclei, and mGlu3 in the hippocampus. Neuropharmacology 36 16733060
2006 Abnormal mGluR2/3 expression in the perforant path termination zones and mossy fibers of chronically epileptic rats. Brain research 36 16793029
2016 The mGluR2 Positive Allosteric Modulator, AZD8529, and Cue-Induced Relapse to Alcohol Seeking in Rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 35 27339394
2011 Hippocampal mossy fiber long-term depression in Grm2/3 double knockout mice. Synapse (New York, N.Y.) 35 21360593
2020 mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects. Pharmacology, biochemistry, and behavior 33 31954773
2013 mGluR2 positive allosteric modulators: a patent review (2009 - present). Expert opinion on therapeutic patents 33 23452205
2011 Study of novel selective mGlu2 agonist in the temporo-ammonic input to CA1 neurons reveals reduced mGlu2 receptor expression in a Wistar substrain with an anxiety-like phenotype. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 21543601
2008 The effect of mGluR2 activation on signal transduction pathways and neuronal cell survival. Brain research 31 19026996
2004 Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists. Biochemical Society transactions 31 15494040
2015 Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring. Neuropharmacology 30 26051401
2013 Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice. Molecular pharmacology 30 23508685
2009 Combined administration of an mGlu2/3 receptor agonist and a 5-HT 2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants. Psychopharmacology 29 19707745
2017 Astrocytes modulate thalamic sensory processing via mGlu2 receptor activation. Neuropharmacology 28 28416443
2003 A role for noradrenergic transmission in the actions of phencyclidine and the antipsychotic and antistress effects of mGlu2/3 receptor agonists. Annals of the New York Academy of Sciences 28 14684454
2018 5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice. Neuropharmacology 27 29738849
2009 Association analysis of group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 27 19386277
2022 Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism. Pharmaceuticals (Basel, Switzerland) 26 35215237
2013 mGlu2/3 agonist-induced hyperthermia: an in vivo assay for detection of mGlu2/3 receptor antagonism and its relation to antidepressant-like efficacy in mice. CNS & neurological disorders drug targets 26 23574174
2012 Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist. Neuropharmacology 26 22445601
2009 Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(High) receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse (New York, N.Y.) 26 19084908
2005 Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo. Neuropharmacology 26 16023151
2018 5-HT2A receptor-dependent phosphorylation of mGlu2 receptor at Serine 843 promotes mGlu2 receptor-operated Gi/o signaling. Molecular psychiatry 25 29858599
2016 Glutamate signals through mGluR2 to control Schwann cell differentiation and proliferation. Scientific reports 25 27432639
2013 Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD-induced impairment in glutamate clearance in astrocytes. The European journal of neuroscience 25 24206109
2006 The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neuroscience letters 25 16469447
2019 mGluR2 positive allosteric modulators: an updated patent review (2013-2018). Expert opinion on therapeutic patents 24 31242055
2017 Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice. Frontiers in pharmacology 24 29104538
2017 mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy. Annals of clinical and translational neurology 24 29296613
2016 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behavioural pharmacology 24 26292187
2005 Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2). Current topics in medicinal chemistry 24 16178732
2023 The crosstalk between 5-HT2AR and mGluR2 in schizophrenia. Neuropharmacology 23 36889432
2018 5-HT2A-mGlu2/3 receptor complex in rat spinal cord glutamatergic nerve endings: A 5-HT2A to mGlu2/3 signalling to amplify presynaptic mechanism of auto-control of glutamate exocytosis. Neuropharmacology 23 29499271
2010 Association analysis of GRM2 and HTR2A with methamphetamine-induced psychosis and schizophrenia in the Japanese population. Progress in neuro-psychopharmacology & biological psychiatry 22 20211215
2019 Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine. International journal of molecular sciences 21 30871246
2009 Use of MGLUR2 and MGLUR3 knockout mice to explore in vivo receptor specificity of the MGLUR2/3 selective antagonist LY341495. Neuropharmacology 21 19477188
2022 Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism. Expert opinion on drug discovery 20 35934973
2019 Glu-mGluR2/3-ERK Signaling Regulates Apoptosis of Hippocampal Neurons in Diabetic-Depression Model Rats. Evidence-based complementary and alternative medicine : eCAM 20 31281399
2017 Preclinical predictors that the orthosteric mGlu2/3 receptor antagonist LY3020371 will not engender ketamine-associated neurotoxic, motor, cognitive, subjective, or abuse-liability-related effects. Pharmacology, biochemistry, and behavior 20 28285123
2016 Presynaptic, release-regulating mGlu2 -preferring and mGlu3 -preferring autoreceptors in CNS: pharmacological profiles and functional roles in demyelinating disease. British journal of pharmacology 20 26791341
2023 mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development. European archives of psychiatry and clinical neuroscience 19 36715750
2023 Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2. Journal of virology 19 36779763
2022 Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents. The international journal of neuropsychopharmacology 19 34534292
2018 Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801. Pharmacology, biochemistry, and behavior 19 30240581
2018 Downregulation of mGluR2/3 receptors during morphine withdrawal in rats impairs mGluR2/3- and NMDA receptor-dependent long-term depression in the nucleus accumbens. Neuroscience letters 19 30315852

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