Affinage

GRM7

Metabotropic glutamate receptor 7 · UniProt Q14831

Length
915 aa
Mass
102.3 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM7 encodes mGluR7, a presynaptic class C G protein-coupled receptor that functions as a central regulator of neurotransmitter release probability and synaptic plasticity at glutamatergic and GABAergic terminals throughout the brain. Canonically coupled to Gi/o, mGluR7 inhibits release by suppressing P/Q-type Ca²⁺ channels and reducing cAMP, but prolonged activation engages an alternative PLC/DAG pathway that recruits Munc13-1 to potentiate release (PMID:8288585, PMID:17650109, PMID:20375012). Surface expression is governed by a convergent regulatory network at Ser862: PKC/PKA/PKG phosphorylation displaces calmodulin to promote PICK1 binding and surface retention, while PP1γ1-mediated dephosphorylation, SUMO conjugation at Lys889, Nedd4/β-arrestin-dependent ubiquitination, and clathrin-independent Arf6-mediated endocytosis dynamically control receptor density (PMID:18549785, PMID:23612982, PMID:26631532, PMID:31373553, PMID:16890965). The postsynaptic organizer Elfn1 recruits mGluR7 in trans to somatostatin-interneuron synapses to constitutively suppress release probability, and pathogenic GRM7 mutations (e.g., I154T) that destabilize protein folding cause neurodevelopmental phenotypes including seizures and impaired motor coordination in knock-in mice (PMID:25047565, PMID:30940718, PMID:33476302).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Establishing the fundamental signaling identity of mGluR7 as a Gi/o-coupled receptor that inhibits cAMP accumulation answered the basic question of which second-messenger pathway this orphan group III mGluR engages.

    Evidence cAMP accumulation assay in mGluR7-transfected CHO cells stimulated with L-AP4

    PMID:8288585

    Open questions at the time
    • Downstream effectors at native synapses unknown
    • No information on splice-variant-specific signaling
  2. 1996 High

    Ultrastructural localization of mGluR7 to presynaptic active zones — and its asymmetric positioning at retinal ribbon synapses — established that this receptor occupies a privileged position to sense synaptically released glutamate as an autoreceptor.

    Evidence Immunoelectron microscopy in spinal cord (with dorsal rhizotomy lesion) and retina

    PMID:8764662 PMID:8787837

    Open questions at the time
    • Mechanism of target-cell-specific presynaptic sorting unknown
    • Functional consequence of asymmetric active-zone positioning not tested
  3. 2000 High

    Identification of PICK1 as a PDZ-domain partner that scaffolds PKCα to mGluR7a and modulates its phosphorylation revealed the first molecular mechanism for regulating mGluR7 signaling at the receptor level.

    Evidence Yeast two-hybrid, GST pulldown, co-IP from brain, in vitro phosphorylation assay

    PMID:11007882

    Open questions at the time
    • In vivo relevance of PICK1-PKCα complex not yet shown
    • Phosphorylation site identity not established
  4. 2002 High

    Mapping the convergent phosphorylation site Ser862 and showing that PKC, PKA, and PKG all phosphorylate this residue to displace calmodulin defined a single molecular switch governing mGluR7 C-terminal protein interactions.

    Evidence In vitro kinase assays, Ser862 mutagenesis, CaM binding assay, GIRK recordings

    PMID:12021391

    Open questions at the time
    • Which kinase acts in vivo at specific synapses unclear
    • Phosphatase identity unknown
  5. 2003 High

    Quantitative ultrastructural demonstration that mGluR7a is selectively concentrated at GABAergic terminals innervating somatostatin interneurons — but absent from terminals on pyramidal cells — established the target-cell-specific expression principle later explained by trans-synaptic recruitment.

    Evidence Immunoelectron microscopy with GAD/cell-type markers in hippocampal stratum oriens

    PMID:12823458

    Open questions at the time
    • Molecular mechanism of target-cell-dependent sorting unknown
    • Whether pattern extends to cortex not tested
  6. 2005 High

    Showing that mGluR7 acts as a metaplastic switch at mossy fiber–interneuron synapses — where its activation induces LTD and subsequent internalization unmasks LTP — linked receptor trafficking to bidirectional synaptic plasticity for the first time.

    Evidence Hippocampal slice electrophysiology with pharmacological manipulation and surface-expression immunofluorescence

    PMID:15820696

    Open questions at the time
    • Internalization pathway not identified
    • Whether metaplastic switch occurs at other synapse types unknown
  7. 2006 High

    Discovery that mGluR7 endocytosis proceeds through a clathrin-independent, Arf6-positive pathway — distinct from classical NMDAR endocytosis — identified an unconventional trafficking route that governs receptor surface levels both constitutively and upon agonist stimulation.

    Evidence Immunofluorescence and pHluorin live imaging in neurons, dominant-negative Arf6

    PMID:16890965 PMID:16914173

    Open questions at the time
    • Recycling vs. degradation fate after Arf6 endocytosis not resolved
    • Adaptor proteins linking mGluR7 to Arf6 pathway unknown
  8. 2007 High

    Pharmacological dissection at hippocampal synaptosomes resolved that the primary mechanism of mGluR7-mediated release inhibition is Gi/o-dependent suppression of P/Q-type Ca²⁺ channels, with cAMP reduction as a secondary modulatory pathway.

    Evidence Glutamate release from rat hippocampal synaptosomes with selective Ca²⁺ channel blockers, pertussis toxin, kinase inhibitors

    PMID:17650109

    Open questions at the time
    • Direct G-protein–Ca²⁺ channel coupling vs. membrane-delimited mechanism not distinguished
    • Contribution at individual synapse types unresolved
  9. 2008 High

    Two contemporaneous studies resolved complementary aspects of mGluR7 regulation: Ser862 phosphorylation by PKC controls a competitive switch between calmodulin and PICK1 binding to govern surface expression (validated in PICK1-KO mice), while intracellular Ca²⁺ potentiates mGluR7 signaling, establishing a coincidence-detection mechanism for glutamate and Ca²⁺ influx.

    Evidence Phospho-specific antibodies, Ser862 mutagenesis, PICK1-KO slice physiology; Xenopus oocyte GIRK readout with channelrhodopsin-controlled Ca²⁺

    PMID:18549785 PMID:18599484

    Open questions at the time
    • Whether CaM mediates the Ca²⁺ coincidence detection in vivo not proven
    • Relative contributions of CaM vs. PICK1 binding states at native synapses unknown
  10. 2010 High

    The demonstration that prolonged mGlu7 activation switches from inhibitory Gi/o coupling to a PLC/DAG pathway that translocates Munc13-1 and potentiates release revealed a dual-mode signaling capacity unprecedented for group III mGluRs.

    Evidence Cortical synaptosomal release assay with PLC inhibitors, calphostin C, Munc13-1 subcellular fractionation

    PMID:20375012

    Open questions at the time
    • G-protein identity for the PLC pathway not identified
    • Duration threshold for pathway switching not defined
    • In vivo relevance at specific circuit level unknown
  11. 2013 High

    Identification of PP1γ1 as the phosphatase that dephosphorylates Ser862 completed the kinase–phosphatase cycle controlling mGluR7 surface expression, while parallel work delineated biased GRK2/GRK4 and β-arrestin1/2 signaling through ERK and JNK pathways.

    Evidence PP1 isoform-specific knockdown and inhibitors in neurons with phospho-Ser862 readout; GRK/arrestin overexpression/knockdown with pathway-selective signaling assays

    PMID:23612982 PMID:24148810

    Open questions at the time
    • Activity-dependent regulation of PP1γ1 at mGluR7-containing synapses not explored
    • GRK/arrestin findings from recombinant system only
  12. 2014 High

    Discovery that the postsynaptic adhesion molecule Elfn1 recruits mGluR7 in trans to somatostatin-interneuron synapses provided the molecular explanation for the long-observed target-cell-specific presynaptic expression of mGluR7 and linked it to synapse-type-specific plasticity rules.

    Evidence Elfn1-KO mice, electrophysiology of SOM interneuron synapses, immunocytochemistry, human mutation analysis

    PMID:25047565

    Open questions at the time
    • Direct biophysical interaction interface not mapped
    • Whether other postsynaptic organizers contribute unknown
  13. 2015 High

    SUMOylation at Lys889 was identified as a novel post-translational modification stabilizing mGluR7 surface expression, with Ser862 phosphorylation facilitating SUMO conjugation, revealing crosstalk between phosphorylation and SUMOylation in receptor trafficking.

    Evidence SUMO assay in HEK293T cells and brain tissue, Lys889 mutagenesis, SENP1 overexpression, neuronal internalization assay

    PMID:26631532

    Open questions at the time
    • SUMO E3 ligase identity unknown
    • Functional consequence at synaptic level not tested
  14. 2019 High

    Two key advances solidified the mGluR7 trafficking and signaling framework: Nedd4/β-arrestin-mediated ubiquitination was shown to drive both constitutive and agonist-induced endocytosis and degradation, while Elfn1 was demonstrated to produce constitutive (glutamate-independent) mGluR7 activation that tonically reduces release probability at somatostatin-interneuron synapses.

    Evidence Ubiquitination assays and trafficking in neurons with Nedd4/β-arrestin manipulation; cortical slice electrophysiology in Elfn1/mGluR7-manipulated mice

    PMID:30940718 PMID:31373553

    Open questions at the time
    • Ubiquitin chain type (K48 vs K63) on mGluR7 not determined
    • Relative contribution of proteasomal vs. lysosomal degradation in vivo unclear
  15. 2020 High

    N-glycosylation at four asparagine residues was shown to be essential for ER export and surface expression of mGlu7, with deglycosylated receptor shunted to autophagolysosomal degradation; glycosylation also facilitates trans-synaptic Elfn1 interaction.

    Evidence Glycosylation-site mutagenesis, surface biotinylation, ER retention assay, co-IP with Elfn1, autophagolysosome inhibitors

    PMID:32931036

    Open questions at the time
    • Specific glycan structures not characterized
    • Whether glycosylation defects contribute to disease mutations unknown
  16. 2021 High

    Cryo-EM structures of mGlu7 homodimers and mGlu2/mGlu7 heterodimers revealed a subtype-specific dimerization mode and demonstrated that the mGlu7 subunit dominantly controls G-protein activation in heterodimers, providing the first atomic-level framework for understanding mGluR7 function and heterodimer pharmacology.

    Evidence Cryo-EM structure determination with chimeric receptor and G-protein activation assays

    PMID:34135509

    Open questions at the time
    • No structure of mGlu7/mGlu8 heterodimer, the predominant form at SC-CA1 synapses
    • Agonist-bound active-state structure not yet available
  17. 2021 High

    Pathogenic GRM7 mutations (I154T, R658W/T675K) were shown to cause mGlu7 protein destabilization and loss of surface expression, impairing MAPK-cAMP-PKA signaling and axon outgrowth; I154T knock-in mice recapitulate neurodevelopmental phenotypes including seizures, establishing GRM7 as a neurodevelopmental disease gene.

    Evidence Patient mutation identification, functional studies in HEK293A and neurons, knock-in mouse behavioral phenotyping, pharmacological rescue

    PMID:33476302 PMID:33500274

    Open questions at the time
    • Full allelic series and genotype-phenotype correlation in humans incomplete
    • Whether pharmacological chaperones can rescue folding-deficient mutants unknown
  18. 2022 Medium

    Detection of functional mGlu7/mGlu8 heterodimers at Schaffer collateral-CA1 synapses with pharmacology distinct from homodimers raised the possibility that heterodimeric assemblies are the physiologically predominant signaling species at major hippocampal synapses.

    Evidence CADET FRET-based heterodimer detection in vitro, SC-CA1 slice electrophysiology with NAM pharmacology

    PMID:36063995

    Open questions at the time
    • Heterodimer stoichiometry at native synapses not quantified
    • Selective genetic tools to dissect heterodimer vs. homodimer function in vivo lacking
    • Finding from single lab awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how the dual-mode Gi/o-inhibitory versus PLC-facilitatory signaling switch is temporally and spatially regulated at individual synapses in vivo; the structural basis for mGlu7/mGlu8 heterodimer signaling; and whether pharmacological chaperones or allosteric modulators can rescue pathogenic folding-deficient GRM7 mutants for therapeutic purposes.
  • No in vivo signaling-mode switching data at single-synapse resolution
  • No mGlu7/mGlu8 heterodimer structure
  • No pharmacological rescue strategy for loss-of-function mutations tested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-112316 Neuronal System 4 R-HSA-9609507 Protein localization 3
Partners
ARRB1ARRB2CALM1ELFN1GRM8NEDD4PICK1PPP1CC
Complex memberships
mGlu2/mGlu7 heterodimermGlu7/mGlu7 homodimermGlu7/mGlu8 heterodimer

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 mGluR7 (metabotropic glutamate receptor) is a G protein-coupled receptor that inhibits forskolin-stimulated cAMP accumulation in response to agonist interaction (L-AP4, L-serine-O-phosphate), demonstrating Gi/o-coupled inhibitory signaling. Functional assay in transfected CHO cells (cAMP accumulation assay) The Journal of biological chemistry High 8288585
2000 PICK1 binds via its PDZ domain to the C-terminus of mGluR7a, forming a complex with PKCα, and PICK1 reduces PKCα-evoked phosphorylation of mGluR7a in vitro, identifying PICK1 as a regulator of mGluR7 phosphorylation. Yeast two-hybrid, GST pulldown, co-immunoprecipitation from COS-7 cells and rat brain tissue, confocal microscopy in hippocampal neurons, in vitro phosphorylation assay The Journal of neuroscience High 11007882
2005 mGluR7 acts as a metaplastic switch at hippocampal mossy fiber-stratum lucidum interneuron (MF-SLIN) synapses: activation during high-frequency stimulation induces LTD via a PKC-dependent mechanism suppressing presynaptic release; subsequent mGluR7 internalization unmasks the ability of these synapses to undergo LTP with the same stimulus. Hippocampal slice electrophysiology, pharmacological manipulation, immunofluorescence for receptor surface expression Neuron High 15820696
2006 mGluR7 undergoes rapid agonist-induced internalization via a clathrin-independent, Arf6-positive endosomal pathway, distinct from NMDAR clathrin-mediated endocytosis, determining the steady-state amount of receptor on the plasma membrane. Immunofluorescence internalization assay, live imaging with pHluorin-tagged mGluR7 in hippocampal neurons, dominant-negative Arf6 experiments Neuropharmacology High 16890965 16914173
2006 Constitutive endocytosis of mGluR7 in neurons proceeds via a clathrin-independent, Arf6-positive pathway (similar to MHC I and GPI-anchored proteins), not through the clathrin pathway used by NMDARs. Biochemical endocytosis assay in heterologous cells and neurons, dominant-negative constructs for clathrin pathway vs. Arf6 pathway Neuropharmacology High 16890965
2008 PKC phosphorylation of mGluR7 at Ser862 inhibits calmodulin (CaM) binding, thereby increasing mGluR7 surface expression and PICK1 binding; in PICK1 knockout mice, PKC-dependent increases in mGluR7 phosphorylation and surface expression are diminished, and mGluR7-dependent plasticity at MF-interneuron synapses is impaired. Phosphorylation-specific antibodies, mutagenesis of Ser862, PICK1 knockout mice, hippocampal slice electrophysiology, surface biotinylation Neuron High 18549785
2002 PKC, PKA, and PKG each phosphorylate mGluR7 at a single serine residue (Ser862) in the C-terminus, which inhibits calmodulin binding; however, PKC-mediated inhibition of mGluR7-coupled GIRK currents is independent of Ser862 phosphorylation and CaM binding. In vitro phosphorylation assays, site-directed mutagenesis of Ser862, CaM binding assay, GIRK current recordings in heterologous expression system Molecular pharmacology High 12021391
2007 mGluR7 inhibits glutamate release at hippocampal nerve terminals primarily by inhibiting P/Q-type (but not N-type) Ca2+ channels via pertussis toxin-sensitive (Gi/o) G-proteins; a secondary pathway involving cAMP reduction is revealed when cAMP levels are elevated. The mechanism is PKC- and PKA-independent. Glutamate release assay from rat hippocampal synaptosomes, selective Ca2+ channel blockers (omega-conotoxin-GVIA), pertussis toxin, cAMP measurement, PKC/PKA inhibitors The European journal of neuroscience High 17650109
2010 Prolonged activation of mGlu7 receptor with L-AP4 at cerebrocortical nerve terminals activates a second signaling pathway (phospholipase C/PIP2 hydrolysis/DAG) that potentiates glutamate release via translocation of the active zone priming protein Munc13-1 from soluble to particulate fractions; this is distinct from the canonical Gi/o-mediated inhibitory pathway. Glutamate release assay from cortical synaptosomes, pertussis toxin, PLC inhibitors, calphostin C (DAG-binding site antagonist), subcellular fractionation for Munc13-1 The Journal of biological chemistry High 20375012
2008 Intracellular Ca2+ elevation potentiates mGluR7a signaling: physiological levels of [Ca2+]i enhance L-AP4-induced GIRK channel activation via mGluR7a, consistent with mGluR7a acting as a coincidence detector of Ca2+ influx and glutamate release at presynaptic terminals. Xenopus oocyte expression system with channelrhodopsin-2 (ChR2) for controlled Ca2+ influx, GIRK3.1/3.2 concatemer as readout, Ca2+ chelator controls The Journal of biological chemistry High 18599484
2013 PP1 (serine/threonine protein phosphatase 1), specifically the PP1γ1 isoform, dephosphorylates mGluR7 at Ser862 and regulates agonist-induced (but not NMDA-activity-induced) dephosphorylation, thereby controlling mGluR7 surface expression. PP1 inhibitors in neurons, phospho-specific antibody for Ser862, surface biotinylation, isoform-specific knockdown The Journal of biological chemistry High 23612982
2013 GRK4 regulates mGluR7 signaling through the adenylyl cyclase and JNK pathways, while GRK2 selectively regulates the ERK1/2 pathway; β-arrestin1 positively modulates ERK1/2 and inhibits JNK, while β-arrestin2 does the opposite; β-arrestin1 amplifies mGluR7-dependent ERK1/2 activation in response to orthosteric agonist L-AP4 but not the allosteric agonist AMN082. Recombinant mGluR7 expression, GRK/arrestin overexpression and knockdown, signaling pathway assays (adenylyl cyclase, ERK1/2, JNK) Neuropharmacology Medium 24148810
2014 Elfn1 (extracellular leucine-rich repeat and fibronectin type III domain-containing 1) recruits mGluR7 in trans to presynaptic sites on somatostatin interneuron synapses; loss of Elfn1 leads to deficits in mGluR7 recruitment and impaired presynaptic plasticity, with missense mutations in ELFN1 clustering in the region required for mGluR7 recruitment. Immunocytochemistry/immunofluorescence, Elfn1 KO mice, electrophysiology of SOM interneuron synapses, patient mutation analysis Nature communications High 25047565
2019 Elfn1 produces glutamate-independent (constitutive) activation of mGluR7 via presynaptic clustering at synapses onto cortical somatostatin neurons, reducing initial release probability and generating synaptic facilitation; this represents a deviation from the canonical autoreceptor role of group III mGluRs. Electrophysiology in cortical slices from WT and mGluR7/Elfn1 manipulated mice, pharmacological dissection with mGluR7 agonist/antagonist The Journal of neuroscience High 30940718
2015 mGluR7 SUMOylation at Lys889 is required for stable surface expression; agonist treatment reduces SUMOylation; SENP1 (SUMO isopeptidase) reverses SUMOylation and increases mGluR7 internalization; Ser862 phosphorylation facilitates SUMO conjugation of mGluR7. SUMOylation assay in HEK293T cells, identification of SUMOylated mGluR7 in brain and cortical neurons, site-directed mutagenesis (Lys889), SENP1 overexpression, internalization assay in hippocampal neurons Neuropharmacology High 26631532
2019 Nedd4 E3 ubiquitin ligase and β-arrestins cooperate to ubiquitinate mGluR7 upon agonist stimulation: β-arrestins recruit Nedd4 to mGluR7, facilitating ubiquitination; Nedd4 and β-arrestins regulate constitutive and agonist-induced mGluR7 endocytosis, are required for mGluR7-dependent MAPK signaling in neurons, and Nedd4-mediated ubiquitination leads to mGluR7 degradation via both the proteasome and lysosomal pathways. Co-immunoprecipitation, ubiquitination assays in heterologous cells and rat neurons, KD/KO with defined trafficking phenotypes, MAPK signaling readout eLife High 31373553
2020 N-glycosylation of mGlu7 at four asparagine residues is essential for forward trafficking and surface expression; deglycosylated mGlu7 is retained in the ER and degraded via the autophagolysosomal pathway; N-glycosylation of mGlu7 also promotes its trans-synaptic interaction with Elfn1. Site-directed mutagenesis of glycosylation sites, ER retention assay, surface biotinylation, co-immunoprecipitation with Elfn1, autophagolysosomal pathway inhibitors FASEB journal High 32931036
2021 Cryo-EM structures of human mGlu2 and mGlu7 homo- and heterodimers revealed: a subtype-dependent dimerization mode with a unique helix IV-mediated dimer interface in inactive mGlu2 important for limiting receptor activity; the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the mGlu2-mGlu7 heterodimer. Cryo-electron microscopy structure determination, functional validation with chimeric receptor studies and G-protein activation assays Nature High 34135509
2021 The GRM7 I154T mutation (within the mGlu7 ligand-binding domain) causes significant loss of mGlu7 protein expression at the posttranscriptional level due to impaired protein folding/trafficking; mGlu7-I154T knock-in mice recapitulate mGlu7-KO phenotypes including reduced motor coordination, deficits in contextual fear learning, and seizures. Patient mutation identification, functional studies in HEK293A cells and knock-in mice, surface expression analysis, behavioral phenotyping JCI insight High 33476302
2021 Pathogenic GRM7 mutations (I154T and R658W/T675K) lead to mGlu7 protein degradation; R658W/T675K abolishes mGlu7 surface expression; pathogenic mutations impair axon outgrowth through the MAPK-cAMP-PKA signaling pathway during early neuronal development, subsequently reducing presynaptic terminal number. Mutagenesis in heterologous cells and primary neurons, surface expression assay, axon outgrowth assay, MAPK/PKA pathway pharmacology, presynaptic terminal counting The Journal of neuroscience High 33500274
2014 mGlu7 activation decreases NMDAR-mediated currents and NR1 surface expression in basal forebrain cholinergic neurons via a mechanism involving cofilin-regulated actin dynamics; Aβ selectively impairs this mGlu7 regulation by increasing p21-activated kinase activity and decreasing cofilin-mediated actin depolymerization through a p75NTR-dependent mechanism. Whole-cell patch clamp, surface biotinylation, pharmacological dissection (p21-activated kinase inhibitors, cofilin pathway), p75NTR-selective inhibition, actin polymerization assays The Journal of neuroscience High 25297090
2015 mGluR7 regulates embryonic neurogenesis by directly interacting with calmodulin (CaM), modulating CREB phosphorylation and YAP expression; GRM7 knockdown increases neural progenitor cell proliferation and decreases neuronal differentiation via CyclinD1 regulation; these defects are rescued by Creb or Yap knockdown. In utero electroporation (gain/loss of function), co-immunoprecipitation of GRM7 with CaM, Western blot for pCREB/YAP/CyclinD1, cortical progenitor proliferation assays Stem cell reports Medium 25921811
2012 Presynaptic mGlu7 receptors exist as heteroreceptors on GABAergic terminals in the mouse hippocampus; their activation (by AMN082 or L-AP4) inhibits GABA release via an adenylyl cyclase-dependent mechanism and they colocalize with syntaxin-1A and VGAT, but do not functionally cross-talk with co-localized GABAB autoreceptors. Synaptosomal superfusion assay, AMN082/MMPIP pharmacology, confocal microscopy colocalization, cAMP pathway inhibitors Neuropharmacology Medium 22564442
2014 The mGlu7 antagonist XAP044 binds within mGlu7's extracellular Venus flytrap domain (not the seven-transmembrane region) and blocks lateral amygdala LTP in an mGlu7-dependent manner; this was demonstrated by chimeric receptor studies showing XAP044's binding site is in the VFTD. Chimeric receptor studies in recombinant cells, LTP recordings in amygdala brain slices from WT and mGlu7-KO mice The Journal of biological chemistry High 24596089
2022 mGlu7 forms heterodimers with mGlu8 at hippocampal Schaffer collateral-CA1 synapses; mGlu7/8 heterodimers display distinct pharmacology from mGlu7/7 homodimers — ADX71743 blocks both, while MMPIP only antagonizes the homodimer — providing evidence that mGlu7/8 heterodimers are the functionally predominant form at SC-CA1 synapses. Complemented donor acceptor-resonance energy transfer (CADET) for heterodimer detection in vitro, SC-CA1 electrophysiology in brain slices, pharmacological dissection with selective NAMs The Journal of biological chemistry Medium 36063995
1995 mGluR7 is localized presynaptically in axon terminals of primary afferent fibers in laminae I and II of the spinal dorsal horn, where it functions as an autoreceptor; dorsal rhizotomy reduces immunoreactivity in these laminae, confirming the presynaptic location on afferent terminals. Immunohistochemistry with specific anti-mGluR7 antibody, dorsal rhizotomy lesion experiment, electron microscopy Neuroscience letters High 8787837
1996 In the rat retina, mGluR7 is localized both presynaptically (as an autoreceptor at cone bipolar cell ribbon synapses) and postsynaptically in amacrine cells; the presynaptic mGluR7 is restricted to one half of the active zone, facing only one of two postsynaptic processes. Immunofluorescence with specific antiserum, electron microscopy, double-labeling The Journal of neuroscience Medium 8764662
2003 mGluR7a is expressed at high levels in the presynaptic active zones of GABAergic terminals that innervate somatostatin/mGluR1α-positive interneurons in the hippocampal stratum oriens; VIP-positive GABAergic terminals on these cells express mGluR7a at >90%; GABAergic terminals on pyramidal cells are mGluR7a-negative, demonstrating target-cell-specific expression. Immunocytochemistry (electron microscopy), double-labeling with GAD/GABA and cell-type markers, quantitative analysis The European journal of neuroscience High 12823458
2005 The C-terminal splice variant GluR7a is highly expressed at the plasma membrane through a stretch of positively charged amino acids, while GluR7b is mostly retained in the ER; GluR7a promotes surface expression of ER-retained splice variants when assembled into heteromeric kainate receptors. Trafficking studies in hippocampal neurons from WT and KAR mutant mice, surface biotinylation, confocal microscopy, mutagenesis The Journal of biological chemistry Medium 15805114
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 at these synapses; MECP2 mutations reduce mGlu7 protein expression, and positive allosteric modulation of mGlu7 restores LTP and improves learning/memory phenotypes in RTT model mice. Western blot of RTT patient and mouse tissue, hippocampal slice LTP recordings, PAM pharmacology, behavioral tests Science translational medicine High 28814546

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
2005 mGluR7 is a metaplastic switch controlling bidirectional plasticity of feedforward inhibition. Neuron 156 15820696
2008 GRM7 variants confer susceptibility to age-related hearing impairment. Human molecular genetics 154 19047183
1997 Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate receptor subunits with a low sensitivity to glutamate. Neuron 151 9390526
1998 Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: evidence on reversible up-regulation by typical neuroleptics. Journal of neurochemistry 145 9832144
1993 Expression of glutamate receptor genes in the mammalian retina: the localization of GluR1 through GluR7 mRNAs. The Journal of neuroscience : the official journal of the Society for Neuroscience 137 8478682
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 129 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 126 8764662
2007 Activation of the mGlu7 receptor elicits antidepressant-like effects in mice. Psychopharmacology 124 17622518
2007 GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proceedings of the National Academy of Sciences of the United States of America 119 17620617
2021 Structures of human mGlu2 and mGlu7 homo- and heterodimers. Nature 114 34135509
1999 Heteromeric kainate receptors formed by the coassembly of GluR5, GluR6, and GluR7. The Journal of neuroscience : the official journal of the Society for Neuroscience 113 10493729
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 92 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 80 9080455
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
2017 mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science translational medicine 69 28814546
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
2007 Association of the human kainate receptor GluR7 gene (GRIK3) with recurrent major depressive disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 62 16958029
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
2015 Activation of a Temporal Memory in Purkinje Cells by the mGluR7 Receptor. Cell reports 57 26655894
2008 A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia. Schizophrenia research 57 18329248
2002 Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7. TheScientificWorldJournal 56 12805997
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