Affinage

GRM7

Metabotropic glutamate receptor 7 · UniProt Q14831

Length
915 aa
Mass
102.3 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM7 encodes mGluR7, a presynaptic Gi/o-coupled class C GPCR that inhibits forskolin-stimulated adenylyl cyclase upon agonist binding and serves as a low-affinity autoreceptor and heteroreceptor controlling neurotransmitter release at central synapses (PMID:8288585, PMID:17650109). It is concentrated in presynaptic active zones of both glutamatergic and GABAergic terminals, including target-cell-specific GABAergic terminals innervating somatostatin and other interneurons (PMID:8787837, PMID:12823458, PMID:22564442). Mechanistically, mGluR7 suppresses glutamate release principally by inhibiting P/Q-type Ca2+ channels through a pertussis-toxin-sensitive, PKC-independent Gi/o pathway, with a parallel cAMP-lowering arm; prolonged activation can switch signaling from inhibition to PLC/Munc13-1-dependent potentiation of release (PMID:17650109, PMID:20375012). Through these actions it sets short-term plasticity, acting as a metaplastic switch that gates LTD versus LTP at mossy fiber–interneuron synapses and is required for STP and frequency facilitation, perforant-path presynaptic inhibition, amygdala fear-memory extinction, and tonic suppression of pathological thalamocortical synchrony (PMID:12805997, PMID:15152022, PMID:15820696, PMID:17712315, PMID:27199672). Surface availability is governed by an integrated post-translational network: PKC/PKA/PKG phosphorylation of Ser862 competitively blocks calmodulin binding, PICK1 PDZ-domain binding and Ser862 phosphorylation jointly maintain surface expression, PP1γ1 dephosphorylates Ser862, SUMOylation at Lys889 and Nedd4/β-arrestin-mediated ubiquitination regulate constitutive Arf6- and clathrin-independent endocytosis and degradation, neddylation stabilizes presynaptic clusters, and N-glycosylation is required for ER exit and forward trafficking (PMID:11007882, PMID:12021391, PMID:18549785, PMID:23612982, PMID:26631532, PMID:31373553, PMID:16890965, PMID:32931036, PMID:33767338). The transsynaptic ligand Elfn1 recruits and constitutively (glutamate-independently) activates and clusters mGluR7 at synapses onto somatostatin interneurons, tonically lowering release probability (PMID:25047565, PMID:30940718). mGluR7 forms homodimers and an mGlu2–mGlu7 heterodimer in which the mGlu7 subunit dominates G-protein activation, and assembles mGlu7/8 heterodimers with distinct allosteric pharmacology (PMID:34135509, PMID:36063995). Pathogenic GRM7 mutations cause receptor degradation, loss of surface expression, and impaired axon outgrowth via MAPK-cAMP-PKA signaling, linking the gene to neurodevelopmental disorders; reduced mGlu7 expression also underlies plasticity and behavioral deficits in Rett syndrome models, where positive allosteric modulation restores function (PMID:33500274, PMID:28814546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    Established mGluR7 as a functional receptor by showing it couples negatively to adenylyl cyclase, defining its core signaling output.

    Evidence Heterologous expression in CHO cells with agonist-driven cAMP accumulation assay

    PMID:8288585

    Open questions at the time
    • Did not address subcellular localization or native synaptic role
    • Downstream effectors beyond cAMP unresolved
  2. 1996 High

    Determined where the receptor acts by localizing it presynaptically in axon terminals and at ribbon-synapse active zones, supporting an autoreceptor function.

    Evidence Immunohistochemistry with dorsal rhizotomy lesion and EM double-labeling in spinal cord and retina

    PMID:8764662 PMID:8787837

    Open questions at the time
    • Functional consequence of active-zone restriction not tested
    • Postsynaptic pool function in amacrine cells uncharacterized
  3. 2000 High

    Identified scaffolding and phosphoregulatory control by showing PICK1 binds the C-terminal PDZ motif and assembles a complex with PKCα that regulates receptor phosphorylation.

    Evidence Yeast two-hybrid, GST pulldown, co-IP from brain, and in vitro kinase assays

    PMID:11007882

    Open questions at the time
    • Functional impact on surface expression not yet shown
    • Phosphosite not yet mapped
  4. 2002 High

    Mapped the phosphoregulatory switch to Ser862, where PKC/PKA/PKG phosphorylation blocks calmodulin binding, defining a competitive CaM/phosphorylation node.

    Evidence Ser862 mutagenesis, in vitro kinase and CaM-binding assays, GIRK current recordings

    PMID:12021391

    Open questions at the time
    • GIRK inhibition shown independent of Ser862/CaM, leaving that effector pathway unexplained
    • In vivo relevance not tested
  5. 2004 High

    Assigned mGluR7 a specific circuit role in presynaptic inhibition at perforant-path synapses and linked its loss to epileptogenesis.

    Evidence Field EPSP recordings in multiple KO strains with selective agonists; pilocarpine status epilepticus model

    PMID:15152022

    Open questions at the time
    • Mechanism of post-seizure downregulation unresolved
    • Molecular effector at this synapse not defined
  6. 2007 High

    Defined the proximal release-inhibition mechanism as P/Q-type Ca2+ channel suppression via Gi/o, distinguishing it from the cAMP-lowering arm.

    Evidence Synaptosome glutamate release assays with conotoxin, pertussis toxin, and kinase inhibitors plus cAMP measurement

    PMID:17650109

    Open questions at the time
    • Direct Gβγ-channel interaction not demonstrated
    • Relative contribution of two arms in vivo unclear
  7. 2008 High

    Integrated trafficking control by demonstrating that both Ser862 phosphorylation and PICK1 binding are required for surface expression and mGluR7-dependent plasticity.

    Evidence Ser862 mutagenesis, surface biotinylation, co-IP, and slice electrophysiology in PICK1-KO mice

    PMID:18549785

    Open questions at the time
    • Endocytic machinery executing internalization not identified here
    • Temporal dynamics of surface regulation unresolved
  8. 2010 High

    Revealed signaling plasticity: prolonged activation switches mGluR7 from release inhibition to PLC/Munc13-1-dependent potentiation via a PTX-insensitive G protein.

    Evidence Cerebrocortical synaptosome release assays with PLC inhibitors, ionomycin, and Munc13-1 fractionation

    PMID:20375012

    Open questions at the time
    • Identity of the PTX-insensitive G protein not defined
    • In vivo behavioral relevance of the switch untested
  9. 2013 Medium

    Expanded the post-translational network by identifying PP1γ1 as the Ser862 phosphatase and GRK/β-arrestin isoform-specific control of downstream MAPK arms.

    Evidence Phospho-immunoblotting, surface biotinylation, PP1 manipulation in neurons; GRK/β-arrestin overexpression with AC/ERK/JNK readouts

    PMID:23612982 PMID:24148810

    Open questions at the time
    • GRK/β-arrestin study lacks in vivo validation
    • Biased agonism between L-AP4 and AMN082 not mechanistically resolved
  10. 2014 High

    Identified Elfn1 as the transsynaptic organizer that recruits mGluR7 to specific somatostatin-interneuron synapses, defining target-cell-specific receptor placement.

    Evidence Co-IP, immunohistochemistry, and electrophysiology in Elfn1-KO mice with human genetic correlation

    PMID:25047565

    Open questions at the time
    • Whether recruitment alters receptor signaling state not yet shown here
    • Structural basis of the interaction undefined
  11. 2015 Medium

    Showed Ca2+/calmodulin potentiates mGluR7 signaling and that the receptor also regulates neural progenitor proliferation via CaM-dependent CREB/YAP/CyclinD1 control, extending its role to development.

    Evidence Oocyte GIRK recordings with optogenetic Ca2+ control; in utero electroporation knockdown with co-IP in mouse cortex

    PMID:18599484 PMID:25921811

    Open questions at the time
    • Developmental signaling shown in single lab without genetic KO
    • Link between CaM binding and proliferation effectors incompletely mapped
  12. 2015 Medium

    Established SUMOylation at Lys889 as an agonist-sensitive modification gating receptor internalization, adding a further trafficking control layer.

    Evidence SUMO conjugation assays, SENP1 manipulation, and internalization assays in neurons

    PMID:26631532

    Open questions at the time
    • Effector linking deSUMOylation to endocytosis not identified
    • In vivo synaptic consequence untested
  13. 2017 High

    Connected mGluR7 to disease by showing MECP2 mutations reduce its expression and that positive allosteric modulation restores LTP and behavior in Rett models.

    Evidence Immunohistochemistry, slice LTP, behavior, and in vivo pharmacology in Mecp2 mutant mice with patient tissue

    PMID:28814546

    Open questions at the time
    • Mechanism by which MECP2 controls GRM7 expression unresolved
    • Durability of PAM rescue not addressed
  14. 2019 High

    Resolved the constitutive endocytic and degradation machinery: β-arrestins recruit Nedd4 to ubiquitinate mGluR7, driving proteasomal and lysosomal degradation and MAPK signaling.

    Evidence Co-IP, ubiquitination, endocytosis, and signaling assays with proteasome/lysosome inhibitors in cells and neurons

    PMID:31373553

    Open questions at the time
    • Ubiquitination site(s) not mapped
    • Balance between proteasomal and lysosomal routing not quantified
  15. 2019 High

    Clarified that Elfn1 produces glutamate-independent constitutive activation and clustering of mGluR7, distinguishing it from canonical autoreceptor signaling.

    Evidence Cortical slice electrophysiology in Elfn1-KO mice with pharmacological dissection across cortical layers

    PMID:30940718

    Open questions at the time
    • Structural mechanism of ligand-independent activation undefined
    • Whether other partners drive constitutive activity elsewhere unknown
  16. 2020 High

    Defined N-glycosylation as a prerequisite for ER exit and forward trafficking, with deglycosylated receptor degraded autophagolysosomally and impaired Elfn1 binding.

    Evidence Glycosylation-deficient mutagenesis, surface biotinylation, ER-retention and co-IP assays in cells and neurons

    PMID:32931036

    Open questions at the time
    • Quality-control machinery recognizing unglycosylated receptor not identified
    • Whether glycosylation tunes signaling beyond trafficking unknown
  17. 2021 High

    Identified neddylation as a stabilizing modification required for presynaptic clustering and terminal maturation, and provided high-resolution structures of mGlu7 dimers showing mGlu7 dominance in heterodimeric G-protein activation.

    Evidence Neddylation assays with MLN4924 and clustering readouts; cryo-EM of mGlu2/mGlu7 homo- and heterodimers with functional validation

    PMID:33767338 PMID:34135509

    Open questions at the time
    • Neddylation site and interplay with ubiquitination not fully resolved
    • Functional role of mGlu7 homodimer interface in vivo untested
  18. 2021 High

    Demonstrated disease causality by showing pathogenic GRM7 mutations cause receptor degradation, loss of surface expression, and impaired axon outgrowth via MAPK-cAMP-PKA signaling, with mutation-dependent pharmacological rescue.

    Evidence Mutant expression in cells and neurons with biotinylation, axon outgrowth, terminal counting, signaling assays, and agonist rescue

    PMID:33500274

    Open questions at the time
    • In vivo modeling of patient mutations not performed
    • Genotype–phenotype correlation across the disorder spectrum incomplete
  19. 2022 High

    Defined heterodimer-specific pharmacology by showing mGlu7/8 heterodimers and mGlu7/7 homodimers respond differentially to NAMs, explaining native synaptic drug responses.

    Evidence CODA-RET heterodimer activation assays plus hippocampal slice electrophysiology with differential NAMs

    PMID:36063995

    Open questions at the time
    • Stoichiometry and abundance of native heterodimers unresolved
    • Distinct signaling outputs of each dimer species not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational modifications, dimerization states, and Elfn1-driven constitutive activation are coordinated in space and time to set synapse-specific output remains unresolved.
  • No integrated model linking glycosylation, SUMOylation, ubiquitination, neddylation, and phosphorylation dynamics
  • Native dimer composition at defined synapses unknown
  • Structural basis of Elfn1-induced constitutive activation undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
CALM1ELFN1GRM2GRM8NEDD4PICK1PPP1CC
Complex memberships
mGlu2–mGlu7 heterodimermGlu7/8 heterodimermGluR7–PICK1–PKCα complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 mGluR7 is a Gi/o-coupled GPCR that inhibits forskolin-stimulated cyclic AMP accumulation in response to agonist (L-AP4, L-serine-O-phosphate) in transfected CHO cells, establishing it as a negatively coupled adenylyl cyclase receptor. Heterologous expression in CHO cells with cAMP accumulation assay The Journal of biological chemistry High 8288585
1995 mGluR7 protein is localized presynaptically in axon terminals of primary afferent fibers projecting to laminae I and II of the spinal dorsal horn, as demonstrated by immunoreactivity reduced after dorsal rhizotomy. Immunohistochemistry with dorsal rhizotomy lesion; electron microscopy Neuroscience letters High 8787837
1996 mGluR7 is localized both presynaptically as an autoreceptor at cone bipolar cell ribbon synapses and postsynaptically in amacrine cells in the rat retina, with the presynaptic pool restricted to one half of the active zone. Electron microscopy immunohistochemistry with double-labeling in rat retina The Journal of neuroscience High 8764662
1998 Alternative splicing of mGluR7 produces a 'b' isoform (mGluR7b) with a different C-terminal sequence; both mGluR7a and mGluR7b show identical pharmacological profiles when expressed in heterologous systems, indicating the C-terminal differences do not alter agonist pharmacology. RT-PCR cloning, expression in HEK293 cells and Xenopus oocytes with pharmacological profiling The European journal of neuroscience High 9875342
1999 mGluR7-like receptor activation by high concentrations of L-AP4 inhibits NMDA-induced glutamate release and excitotoxicity in cerebellar granule neurons via a pertussis toxin-sensitive Gi/o protein, suggesting a presynaptic neuroprotective mechanism. Cell culture excitotoxicity assay with pertussis toxin, glutamate release measurement, immunocytochemistry for mGluR7 protein The European journal of neuroscience Medium 10051767
2000 PICK1 binds to the extreme C-terminus (PDZ-binding motif) of mGluR7a via its PDZ domain, forms a trimeric complex with PKCα, and reduces PKCα-evoked phosphorylation of mGluR7a in vitro. Yeast two-hybrid, GST pulldown, co-immunoprecipitation from COS-7 cells and rat brain tissue, confocal colocalization in hippocampal neurons, in vitro phosphorylation assay The Journal of neuroscience High 11007882
2002 PKC, PKA, and PKG all inhibit calmodulin (CaM) binding to mGluR7 by phosphorylating a single serine residue, Ser862, in the C-terminal tail; however, PKC-mediated inhibition of mGluR7-coupled GIRK currents is independent of Ser862 phosphorylation and CaM binding. Site-directed mutagenesis of Ser862, in vitro kinase assays, CaM binding assays, GIRK current recordings in heterologous expression system Molecular pharmacology High 12021391
2002 mGluR7 knockout mice display attenuated short-term potentiation (STP), reduced frequency facilitation during high-frequency trains, and decreased post-tetanic potentiation at hippocampal Schaffer collateral-CA1 synapses, while long-term potentiation is preserved. Electrophysiological field recordings in hippocampal slices from mGluR7-/- knockout mice TheScientificWorldJournal Medium 12805997
2003 mGluR7a is highly enriched in the presynaptic active zones of GABAergic terminals (particularly VIP-positive interneurons) that innervate somatostatin- and mGluR1α-positive interneurons in the hippocampus, demonstrating target-cell-specific expression of mGluR7 in GABAergic terminals. Quantitative immunocytochemistry and electron microscopy with multiple antibody markers in rat hippocampus The European journal of neuroscience High 12823458
2004 mGluR7, but not mGluR8, mediates presynaptic inhibition at medial perforant path synapses in the dentate gyrus, and this mGluR7-mediated inhibition is significantly reduced 3–9 days after pilocarpine-induced status epilepticus. Field EPSP recordings in hippocampal slices from wild-type, mGluR8-KO, and mGluR4/8 double-KO mice with selective pharmacological agonists Journal of neurophysiology High 15152022
2005 mGluR7 acts as a metaplastic switch at mossy fiber–stratum lucidum interneuron (MF-SLIN) synapses: its activation during high-frequency stimulation induces LTD through a PKC-dependent reduction in presynaptic release, and subsequent agonist-induced internalization of mGluR7 unmasks the ability of the same stimulation to induce LTP. Hippocampal slice electrophysiology, pharmacological activation/blockade of mGluR7, PKC inhibitors, immunofluorescence for receptor surface expression Neuron High 15820696
2006 mGluR7 constitutively internalizes via a clathrin-independent, Arf6-positive endosomal pathway in both heterologous cells and neurons. Immunofluorescence internalization assay, dominant-negative Arf6 and clathrin inhibition, co-localization with Arf6 endosomes in heterologous cells and neurons Neuropharmacology Medium 16890965
2006 The allosteric agonist AMN082 induces rapid mGluR7 internalization in hippocampal neurons, resistant to competitive orthosteric antagonists, as confirmed by pHluorin-tagged live imaging of surface receptor loss. Immunofluorescence internalization assay and live imaging with N-terminal pHluorin-tagged mGluR7 in dissociated hippocampal neurons Neuropharmacology Medium 16914173
2007 mGluR7 inhibits glutamate release at hippocampal nerve terminals primarily by inhibiting P/Q-type Ca2+ channels through a pertussis toxin-sensitive (Gi/o) PKC-independent mechanism; a separate pathway decreases cAMP when cAMP is elevated by forskolin. Glutamate release assays in rat hippocampal synaptosomes with selective Ca2+ channel blockers (ω-conotoxin), pertussis toxin, PKC inhibitors, PKA inhibitors, cAMP measurements The European journal of neuroscience High 17650109
2007 mGluR7 activation blocks LTP acquisition in the lateral amygdala and facilitates extinction of aversive memories; siRNA knockdown of mGluR7 attenuates extinction, demonstrating a required role for mGluR7 in amygdala plasticity and fear memory extinction. AMN082 pharmacological activation, siRNA knockdown in vivo, fear conditioning behavioral assays, lateral amygdala LTP electrophysiology in mice Molecular psychiatry High 17712315
2008 mGluR7 surface expression requires both PKC phosphorylation at Ser862 (which inhibits CaM binding) and PICK1 binding; in PICK1 knockout mice, PKC-dependent increases in mGluR7 phosphorylation and surface expression are diminished, and mGluR7-dependent plasticity at mossy fiber–interneuron synapses is impaired. Site-directed mutagenesis of Ser862, surface biotinylation assays, co-immunoprecipitation, CaM binding assays, hippocampal slice electrophysiology in PICK1-/- mice Neuron High 18549785
2008 mGluR7a signaling (GIRK channel activation) is potentiated by physiological increases in intracellular Ca2+, mediated through calmodulin binding to the C-terminal tail; light-gated Ca2+ influx via ChR2 markedly enhanced L-AP4-dependent GIRK currents, an effect attenuated by intracellular Ca2+ chelation. Xenopus oocyte electrophysiology with ChR2-mediated Ca2+ influx, BAPTA chelation, GIRK3.1/3.2 concatemer reporter The Journal of biological chemistry High 18599484
2010 Prolonged activation of mGlu7 receptors at cerebrocortical nerve terminals switches signaling from inhibition to potentiation of glutamate release; this potentiation involves phospholipase C activation, PIP2 hydrolysis, a pertussis toxin-insensitive G protein, and translocation of Munc13-1 from soluble to particulate fractions, independent of PKC. Glutamate release assays in synaptosomes with pertussis toxin, PLC inhibitors, calphostin C (DAG-binding site inhibitor), Ca2+ ionophore ionomycin, Munc13-1 subcellular fractionation The Journal of biological chemistry High 20375012
2012 Presynaptic mGlu7 receptors on hippocampal GABAergic terminals inhibit GABA release via an adenylyl cyclase-dependent (cAMP-mediated) mechanism; these mGlu7 heteroreceptors colocalize with syntaxin-1A, VGAT, and GABAB receptor subunits but do not functionally cross-talk with GABAB autoreceptors. [3H]GABA release from hippocampal synaptosomes with selective pharmacological tools (AMN082, MMPIP, cAMP pathway modulators, GABAB antagonists), confocal colocalization Neuropharmacology High 22564442
2013 GRK4 regulates mGluR7-dependent adenylyl cyclase and JNK pathways, while GRK2 selectively regulates the ERK1/2 pathway; β-arrestin1 and β-arrestin2 exert reciprocally opposite effects on ERK1/2 and JNK signaling downstream of mGluR7, with β-arrestin1 amplifying ERK1/2 activation by the orthosteric agonist L-AP4 but not by the allosteric agonist AMN082. Overexpression of GRK subtypes and β-arrestin isoforms in recombinant cells expressing mGluR7, with adenylyl cyclase, ERK1/2, and JNK pathway readouts Neuropharmacology Medium 24148810
2013 PP1γ1 dephosphorylates Ser862 on mGluR7 and regulates agonist-induced (but not NMDA-induced) dephosphorylation and surface expression of mGluR7; PP1 inhibitors increase Ser862 phosphorylation and mGluR7 surface expression in neurons. Phospho-specific immunoblotting, surface biotinylation, PP1 inhibitor pharmacology, and PP1γ1 overexpression/knockdown in neurons The Journal of biological chemistry High 23612982
2014 Elfn1 recruits mGluR7 to presynaptic sites of excitatory synapses onto somatostatin interneurons via a transsynaptic interaction; Elfn1 knockout mice show deficits in mGluR7 recruitment to these synapses and impaired presynaptic plasticity. Immunohistochemistry, co-immunoprecipitation, electrophysiology in Elfn1-KO mice, identification of damaging ELFN1 mutations in epilepsy/ADHD patients Nature communications High 25047565
2014 The mGlu7-selective antagonist XAP044 acts via a binding pocket in the extracellular Venus flytrap domain (VFTD), not the transmembrane region; this was demonstrated by chimeric receptor studies in which the VFTD of mGlu7 conferred XAP044 sensitivity. Chimeric receptor construction and functional assays in recombinant cell lines; lateral amygdala LTP electrophysiology in wild-type and mGlu7-KO mice The Journal of biological chemistry High 24596089
2014 mGluR7 activation decreases NMDAR-mediated currents and NR1 surface expression in basal forebrain cholinergic neurons via cofilin-regulated actin dynamics; Aβ selectively impairs this mGluR7 regulation by increasing PAK activity and decreasing cofilin-mediated actin depolymerization through a p75NTR-dependent mechanism. Whole-cell patch-clamp recordings, surface biotinylation, actin dynamics assays (cofilin phosphorylation), PAK activity assays, p75NTR neutralization in rodent BF neurons The Journal of neuroscience High 25297090
2015 mGlu7 receptor activation on cerebellar Purkinje cells mediates adaptively timed pauses in firing that constitute intrinsic cellular temporal memory; antagonists of mGlu7 but not other glutamate receptor subtypes abolished these learned responses in vivo. In vivo single-unit recordings in rat cerebellum with pharmacological blockade of mGlu7 and GABA receptors during conditioned stimulus presentation Cell reports Medium 26655894
2015 GRM7 knockdown reduces neural progenitor cell proliferation and promotes neuronal differentiation during cortical development; mGlu7 regulates CREB phosphorylation and YAP expression by directly interacting with calmodulin, controlling CyclinD1 expression. In utero electroporation knockdown/overexpression, immunofluorescence, co-immunoprecipitation (mGlu7-CaM interaction), Western blot in mouse cortex Stem cell reports Medium 25921811
2015 mGluR7 is SUMOylated at Lys889; this SUMOylation is reversed by SENP1 and is reduced by agonist (L-AP4) treatment. DeSUMOylation or SENP1 overexpression markedly increases mGluR7 internalization in hippocampal neurons, and Ser862 phosphorylation facilitates SUMO conjugation. SUMO conjugation assays in HEK293T cells, identification of SUMOylated mGluR7 in brain and cortical neurons by immunoprecipitation, SENP1 overexpression, mGluR7 internalization assays in hippocampal neurons Neuropharmacology Medium 26631532
2016 mGlu7 receptors are functionally expressed at both glutamatergic and GABAergic thalamic synapses where they inhibit neurotransmission and regulate short-term plasticity in a PDZ-ligand-dependent manner; constitutive (tonic) mGlu7 activity prevents pathological thalamocortical synchrony, as in vivo NAM application induces absence-like seizures. Thalamic slice electrophysiology, optogenetics, pharmacology with NAM ADX71743, and in vivo EEG in mice with PDZ-domain mutant mGlu7 Frontiers in neural circuits High 27199672
2017 mGlu7 is the predominant mGlu receptor expressed presynaptically at Schaffer collateral–CA1 synapses in adult mice; its activation on GABAergic interneurons is necessary for LTP induction; MECP2 mutations reduce mGlu7 protein expression, and positive allosteric modulation of mGlu7 restores LTP and improves cognitive and social behaviors in RTT mouse models. Immunohistochemistry, hippocampal slice LTP recordings, behavioral testing (fear learning, novel object recognition, social memory), in vivo pharmacology in Mecp2 mutant mice Science translational medicine High 28814546
2019 Nedd4 E3 ubiquitin ligase ubiquitinates mGluR7 upon agonist stimulation; β-arrestins recruit Nedd4 to mGluR7 and facilitate ubiquitination; Nedd4 and β-arrestins are required for constitutive and agonist-induced endocytosis of mGluR7 and for mGluR7-dependent MAPK signaling; Nedd4-mediated ubiquitination leads to mGluR7 degradation via both the ubiquitin-proteasome system and lysosomal pathway. Co-immunoprecipitation, ubiquitination assays in heterologous cells and rat neurons, endocytosis assays, MAPK signaling assays, proteasome/lysosome inhibitors eLife High 31373553
2019 Elfn1 produces glutamate-independent (constitutive) activation of mGluR7 through presynaptic clustering, tonically suppressing initial release probability at synapses onto somatostatin interneurons, which is distinct from canonical autoreceptor function. Electrophysiology in cortical slices from Elfn1-KO mice, pharmacological mGluR7 activation/blockade, assessment of short-term synaptic facilitation in Layer 2/3 and Layer 5 The Journal of neuroscience High 30940718
2020 mGluR7 is N-glycosylated at four asparagine residues; N-glycosylation is essential for ER exit and forward trafficking to the plasma membrane; deglycosylated mGluR7 is retained in the ER and degraded via the autophagolysosomal pathway; N-glycosylation also promotes the mGluR7–Elfn1 transsynaptic interaction. Glycosylation-deficient mutagenesis, surface biotinylation, ER retention assays, co-immunoprecipitation with Elfn1, autophagy/lysosome inhibitor studies in heterologous cells and neurons FASEB journal High 32931036
2021 mGluR7 neddylation is required for presynaptic clustering and stabilization of mGluR7 protein; agonist treatment reduces neddylation; neddylation facilitates ubiquitination of mGluR7 and is necessary for maturation of excitatory presynaptic terminals. Neddylation assays in heterologous cells and primary neurons, neddylation inhibitor (MLN4924), presynaptic clustering immunostaining, synaptosome fractionation Experimental & molecular medicine Medium 33767338
2021 Pathogenic GRM7 mutations I154T and R658W/T675K cause degradation and loss of surface expression of mGluR7 protein; I154T and R658W/T675K mutations impair axon outgrowth and reduce presynaptic terminal number through the MAPK-cAMP-PKA signaling pathway; mGluR7 agonist treatment rescues I154T (which retains partial surface expression) but not R658W/T675K phenotypes. Expression of mutant constructs in HEK293A cells and rat primary neurons, surface biotinylation, axon outgrowth measurements, presynaptic terminal counting, MAPK/cAMP/PKA pathway assays, pharmacological rescue The Journal of neuroscience High 33500274
2021 Cryo-EM structures of mGlu2 and mGlu7 homo- and heterodimers reveal that mGlu7 forms a distinct homodimer interface and a heterodimer with mGlu2; in the mGlu2–mGlu7 heterodimer, the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation. Cryo-electron microscopy structure determination; functional studies of mGlu2–mGlu7 heterodimer G-protein activation Nature High 34135509
2022 mGlu7/8 heterodimers modulate Schaffer collateral–CA1 synaptic transmission and LTP; ADX71743 (mGlu7 NAM) blocks responses of both mGlu7/7 homodimers and mGlu7/8 heterodimers, whereas MMPIP only antagonizes mGlu7/7 homodimers, explaining the differential pharmacology observed at SC-CA1 synapses. complemented donor-acceptor FRET (CODA-RET) to study heterodimer activation in vitro; hippocampal slice electrophysiology with differential NAM pharmacology The Journal of biological chemistry High 36063995

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. The Journal of biological chemistry 419 8288585
1995 Distributions of the mRNAs for L-2-amino-4-phosphonobutyrate-sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain. The Journal of comparative neurology 254 8801249
2003 Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. The European journal of neuroscience 222 12814372
2008 GRM7 variants confer susceptibility to age-related hearing impairment. Human molecular genetics 156 19047183
2005 mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 156 15820696
2000 PICK1 interacts with and regulates PKC phosphorylation of mGLUR7. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 11007882
1995 Presynaptic localization of a metabotropic glutamate receptor, mGluR7, in the primary afferent neurons: an immunohistochemical study in the rat. Neuroscience letters 130 8787837
1996 Compartmental localization of a metabotropic glutamate receptor (mGluR7): two different active sites at a retinal synapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 127 8764662
2007 Activation of the mGlu7 receptor elicits antidepressant-like effects in mice. Psychopharmacology 124 17622518
2021 Structures of human mGlu2 and mGlu7 homo- and heterodimers. Nature 115 34135509
2007 mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity. Molecular psychiatry 112 17712315
1998 Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8. The European journal of neuroscience 108 9875342
2006 mGluR7 undergoes rapid internalization in response to activation by the allosteric agonist AMN082. Neuropharmacology 99 16914173
2014 Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures. Nature communications 98 25047565
2003 High level of mGluR7 in the presynaptic active zones of select populations of GABAergic terminals innervating interneurons in the rat hippocampus. The European journal of neuroscience 93 12823458
1997 Localization of a metabotropic glutamate receptor, mGluR7, in axon terminals of presumed nociceptive, primary afferent fibers in the superficial layers of the spinal dorsal horn: an electron microscope study in the rat. Neuroscience letters 81 9080455
2017 mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science translational medicine 70 28814546
2014 Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior. The Journal of biological chemistry 70 24596089
2008 Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7. Neuron 67 18549785
2012 GRM7 variants associated with age-related hearing loss based on auditory perception. Hearing research 64 23102807
2008 Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice. Neurobiology of learning and memory 60 18289889
1994 Expression of mRNAs of L-AP4-sensitive metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7) in the rat retina. Neuroscience letters 60 8084499
2015 MMPIP, an mGluR7-selective negative allosteric modulator, alleviates pain and normalizes affective and cognitive behavior in neuropathic mice. Pain 58 25760470
2013 Association between the GRM7 rs3792452 polymorphism and attention deficit hyperacitiveity disorder in a Korean sample. Behavioral and brain functions : BBF 58 23295062
2010 The metabotropic glutamate receptor mGlu7 activates phospholipase C, translocates munc-13-1 protein, and potentiates glutamate release at cerebrocortical nerve terminals. The Journal of biological chemistry 58 20375012
2008 A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia. Schizophrenia research 58 18329248
2015 Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor. Cell reports 57 26655894
2002 Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. TheScientificWorldJournal 56 12805997
1999 mGluR7-like metabotropic glutamate receptors inhibit NMDA-mediated excitotoxicity in cultured mouse cerebellar granule neurons. The European journal of neuroscience 56 10051767
2007 A novel connection between rods and ON cone bipolar cells revealed by ectopic metabotropic glutamate receptor 7 (mGluR7) in mGluR6-deficient mouse retinas. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 17553999
2019 Elfn1-Induced Constitutive Activation of mGluR7 Determines Frequency-Dependent Recruitment of Somatostatin Interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 30940718
2012 Presynaptic mGlu7 receptors control GABA release in mouse hippocampus. Neuropharmacology 53 22564442
2007 The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats. Neuropharmacology 51 18155073
2011 The mGluR7 allosteric agonist AMN082 produces antidepressant-like effects by modulating glutamatergic signaling. Pharmacology, biochemistry, and behavior 50 22138407
2001 Regulation of mglu(7) receptors by proteins that interact with the intracellular C-terminus. Trends in pharmacological sciences 49 11431030
2015 GRM7 regulates embryonic neurogenesis via CREB and YAP. Stem cell reports 48 25921811
2019 Nedd4 E3 ligase and beta-arrestins regulate ubiquitination, trafficking, and stability of the mGlu7 receptor. eLife 46 31373553
1996 Immunohistochemical localization of a metabotropic glutamate receptor, mGluR7, in ganglion neurons of the rat; with special reference to the presence in glutamatergic ganglion neurons. Neuroscience letters 44 8929965
2009 Association study of polymorphisms in the group III metabotropic glutamate receptor genes, GRM4 and GRM7, with schizophrenia. Psychiatry research 43 19351574
2011 Pharmacological modulation of mGluR7 with AMN082 and MMPIP exerts specific influences on alcohol consumption and preference in rats. Addiction biology 41 21392179
2016 Glutamate receptor, metabotropic 7 (GRM7) gene variations and susceptibility to autism: A case-control study. Autism research : official journal of the International Society for Autism Research 40 27312574
2014 Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats. Neuropharmacology 40 24631968
2007 mGluR7 inhibits glutamate release through a PKC-independent decrease in the activity of P/Q-type Ca2+ channels and by diminishing cAMP in hippocampal nerve terminals. The European journal of neuroscience 40 17650109
2014 Aβ selectively impairs mGluR7 modulation of NMDA signaling in basal forebrain cholinergic neurons: implication in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 25297090
2015 Significant association of GRM7 and GRM8 genes with schizophrenia and major depressive disorder in the Han Chinese population. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 35 26655190
2014 Allelic association, DNA resequencing and copy number variation at the metabotropic glutamate receptor GRM7 gene locus in bipolar disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 35 24804643
2009 A family-based association study of DNA sequence variants in GRM7 with schizophrenia in an Indonesian population. The international journal of neuropsychopharmacology 34 19638256
2020 Phenotypic profiling of mGlu7 knockout mice reveals new implications for neurodevelopmental disorders. Genes, brain, and behavior 32 32248644
2015 Regulation of mGluR7 trafficking by SUMOylation in neurons. Neuropharmacology 32 26631532
2013 Differential roles of mGlu(7) and mGlu(8) in amygdala-dependent behavior and physiology. Neuropharmacology 32 23664812
2021 A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes. JCI insight 31 33476302
2006 Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent. Neuropharmacology 31 16890965
1998 Immunohistochemical localisation of mGluR7 protein in the rodent and human cerebellar cortex using subtype specific antibodies. Brain research. Molecular brain research 31 9630572
2016 Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network. Frontiers in neural circuits 30 27199672
2015 Rare de novo deletion of metabotropic glutamate receptor 7 (GRM7) gene in a patient with autism spectrum disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 30 25921429
2013 Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse. Neuropharmacology 30 23603202
1999 mGluR7-like receptor and GABA(B) receptor activation enhance neurotoxic effects of N-methyl-D-aspartate in cultured mouse striatal GABAergic neurones. Neuropharmacology 30 10530824
2021 Pathogenic GRM7 Mutations Associated with Neurodevelopmental Disorders Impair Axon Outgrowth and Presynaptic Terminal Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 33500274
2011 mGluR7 genetics and alcohol: intersection yields clues for addiction. Neurochemical research 28 21448595
2012 Viral-mediated knockdown of mGluR7 in the nucleus accumbens mediates excessive alcohol drinking and increased ethanol-elicited conditioned place preference in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 27 22781839
2019 Discovery of an Orally Bioavailable and Central Nervous System (CNS) Penetrant mGlu7 Negative Allosteric Modulator (NAM) in Vivo Tool Compound: N-(2-(1 H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)-4-(cyclopropylmethoxy)-3-methoxybenzamide (VU6012962). Journal of medicinal chemistry 26 30608678
2007 Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex. Brain research 26 17976546
2002 Characterization of three novel isoforms of the metabotrobic glutamate receptor 7 (GRM7). Neuroscience letters 26 12052533
2018 Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs. Frontiers in molecular neuroscience 25 30294258
2002 Dissociation of protein kinase-mediated regulation of metabotropic glutamate receptor 7 (mGluR7) interactions with calmodulin and regulation of mGluR7 function. Molecular pharmacology 25 12021391
2013 The effects of mGlu₇ receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains. Behavioural pharmacology 24 23455446
2013 Regulation of metabotropic glutamate receptor 7 (mGluR7) internalization and surface expression by Ser/Thr protein phosphatase 1. The Journal of biological chemistry 24 23612982
2013 Selective regulation of recombinantly expressed mGlu7 metabotropic glutamate receptors by G protein-coupled receptor kinases and arrestins. Neuropharmacology 23 24148810
2012 A selective mGlu7 receptor antagonist MMPIP reversed antidepressant-like effects of AMN082 in rats. Behavioural brain research 23 23085340
2020 Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy. Annals of clinical and translational neurology 22 32286009
2020 N-linked glycosylation of the mGlu7 receptor regulates the forward trafficking and transsynaptic interaction with Elfn1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 32931036
2013 Contribution of the mGluR7 receptor to antiparkinsonian-like effects in rats: a behavioral study with the selective agonist AMN082. Pharmacological reports : PR 22 24399715
2008 AMN082, an allosteric mGluR7 agonist that inhibits afferent glutamatergic transmission in rat basolateral amygdala. Neuropharmacology 22 18533198
2020 Variants of GRM7 as risk factor and response to antipsychotic therapy in schizophrenia. Translational psychiatry 21 32127521
2019 The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures. Neurobiology of disease 21 31051234
2019 Glutamate receptor metabotropic 7 (GRM7) gene polymorphisms in mood disorders and attention deficit hyperactive disorder. Neurochemistry international 21 31170425
2013 Association of GRM7 variants with different phenotype patterns of age-related hearing impairment in an elderly male Han Chinese population. PloS one 21 24146964
2018 Role of mGlu7 receptor in morphine rewarding effects is uncovered by a novel orthosteric agonist. Neuropharmacology 20 29307544
2018 Effect of GRM7 polymorphisms on the development of noise-induced hearing loss in Chinese Han workers: a nested case-control study. BMC medical genetics 19 29301492
2023 GRM7 gene mutations and consequences for neurodevelopment. Pharmacology, biochemistry, and behavior 18 37003303
2018 New evidences for a role of mGluR7 in astrocyte survival: Possible implications for neuroprotection. Neuropharmacology 18 30170084
2012 Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence. Neuropharmacology 18 22546614
2004 Medial perforant path inhibition mediated by mGluR7 is reduced after status epilepticus. Journal of neurophysiology 18 15152022
2022 Differential activity of mGlu7 allosteric modulators provides evidence for mGlu7/8 heterodimers at hippocampal Schaffer collateral-CA1 synapses. The Journal of biological chemistry 17 36063995
2018 The potential antidepressant action and adverse effects profile of scopolamine co-administered with the mGlu7 receptor allosteric agonist AMN082 in mice. Neuropharmacology 17 30145321
2010 GABAergic dysfunction in mGlu7 receptor-deficient mice as reflected by decreased levels of glutamic acid decarboxylase 65 and 67kDa and increased reelin proteins in the hippocampus. Brain research 17 20353761
2008 Increases in intracellular calcium triggered by channelrhodopsin-2 potentiate the response of metabotropic glutamate receptor mGluR7. The Journal of biological chemistry 17 18599484
2000 No association found between polymorphisms in genes encoding mGluR7 and mGluR8 and idiopathic generalised epilepsy in a case control study. Epilepsy research 16 10690750
2019 Surveying heterocycles as amide bioisosteres within a series of mGlu7 NAMs: Discovery of VU6019278. Bioorganic & medicinal chemistry letters 15 30910459
2015 Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain. Neurobiology of stress 15 26844237
2011 Non-additive potentiation of glutamate release by phorbol esters and metabotropic mGlu7 receptor in cerebrocortical nerve terminals. Journal of neurochemistry 15 21143597
2002 No association between metabotropic glutamate receptors 7 and 8 (mGlur7 and mGlur8) gene polymorphisms and withdrawal seizures and delirium tremens in alcohol-dependent individuals. Alcohol and alcoholism (Oxford, Oxfordshire) 15 11912074
2017 The influence of AMN082, metabotropic glutamate receptor 7 (mGlu7) allosteric agonist on the acute and chronic antinociceptive effects of morphine in the tail-immersion test in mice: Comparison with mGlu5 and mGlu2/3 ligands. Physiology & behavior 14 29294304
2010 Comparison of hippocampal metabotropic glutamate receptor 7 (mGlu7) mRNA levels in two animal models of depression. Neuroscience letters 14 20638442
2008 The inhibition of release by mGlu7 receptors is independent of the Ca2+ channel type but associated to GABAB and adenosine A1 receptors. Neuropharmacology 14 18514236
2021 Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals. Experimental & molecular medicine 13 33767338
2000 Development of a functional reporter gene HTS assay for the identification of mGluR7 modulators. Journal of biomolecular screening 13 10992046
2021 A large consanguineous family with a homozygous Metabotropic Glutamate Receptor 7 (mGlu7) variant and developmental epileptic encephalopathy: Effect on protein structure and ligand affinity. Orphanet journal of rare diseases 12 34273994
2021 Overexpression of mGluR7 in the Prefrontal Cortex Attenuates Autistic Behaviors in Mice. Frontiers in cellular neuroscience 12 34335187
2016 Off-target potential of AMN082 on sleep EEG and related physiological variables: Evidence from mGluR7 (-/-) mice. Behavioural brain research 11 27211063

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