Affinage

GRM4

Metabotropic glutamate receptor 4 · UniProt Q14833

Length
912 aa
Mass
101.9 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM4 (mGluR4) is a group III metabotropic glutamate receptor that functions as a presynaptic Gi/o-coupled GPCR to inhibit neurotransmitter release and modulate synaptic plasticity, with additional roles in neural progenitor proliferation and immune regulation of the tumor microenvironment. It is selectively activated by L-AP4, inhibits adenylyl cyclase and cAMP formation, and depresses glutamate release at the cerebellar parallel fiber–Purkinje cell synapse through a PLC/PKC-dependent inhibition of presynaptic Ca²⁺ influx rather than through canonical Gi/cAMP signaling (PMID:8463825, PMID:8815915, PMID:22570379). mGluR4 physically interacts with exocytosis machinery (Munc18-1, synapsins, syntaxin) and with GABAA receptors at presynaptic terminals, and its signaling through MAPK/ERK is regulated by non-catalytic Gβγ sequestration by GRK2 (PMID:22528491, PMID:15102938). Cryo-EM structures reveal that mGluR4 forms asymmetric homodimers and heterodimers (with mGlu2) whose activation involves sequential Venus flytrap domain rearrangements and a unique G-protein coupling interface, while in myeloid cells GRM4 regulates IL-23/IL-12 balance to suppress tumor growth (PMID:34135510, PMID:37286794, PMID:31527131).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    The fundamental signaling mechanism of mGluR4 was established: it couples to Gi/o to inhibit cAMP and is uniquely defined among mGluRs by selective, stereospecific activation by L-AP4.

    Evidence cAMP accumulation assays in stably transfected CHO cells expressing cloned rat mGluR4

    PMID:8463825

    Open questions at the time
    • Downstream effectors beyond cAMP were not identified
    • Native synaptic role was untested
  2. 1995 Medium

    A post-translational modification of mGluR4 was identified: palmitoylation via a thioester bond, which is constitutive and agonist-independent, distinguishing it from mGluR1α.

    Evidence [³H]palmitic acid metabolic labeling and immunoprecipitation in BHK cells

    PMID:7891082

    Open questions at the time
    • Palmitoylation site(s) not mapped
    • Functional consequence of palmitoylation on trafficking or signaling not determined
  3. 1996 High

    The in vivo requirement for mGluR4 in presynaptic function was demonstrated: mGluR4 knockout abolished L-AP4-induced synaptic depression at parallel fiber–Purkinje cell synapses and impaired motor learning without affecting LTD.

    Evidence mGluR4 knockout mice; patch-clamp and field recordings in cerebellar slices; rotating rod behavior

    PMID:8815915

    Open questions at the time
    • Mechanism of presynaptic inhibition (Ca²⁺ channels vs. release machinery) was unknown
    • Contribution at non-cerebellar synapses not tested
  4. 1999 High

    The ligand recognition mechanism was mapped: agonist binding occurs in the extracellular amino-terminal domain, with Arg78, Ser159, and Thr182 identified as critical residues.

    Evidence Truncated soluble ATD construct; [³H]L-AP4 competition binding; site-directed mutagenesis

    PMID:10187777 PMID:10559233

    Open questions at the time
    • No crystal structure of the ATD–ligand complex was available
    • Residue contributions to selectivity over other group III receptors not fully resolved
  5. 2000 High

    Two circuit-level roles for mGluR4 were established: neuroprotection against NMDA excitotoxicity via glutamate homeostasis, and regulation of thalamocortical synchronization relevant to absence seizures.

    Evidence mGluR4 KO mice; cortical cultures and in vivo NMDA infusion; microdialysis; seizure threshold testing and intra-nRT drug infusions

    PMID:10934271 PMID:10964947

    Open questions at the time
    • Whether neuroprotection is cell-autonomous or circuit-mediated was unresolved
    • The downstream signaling pathway for seizure resistance was not identified
  6. 2002 High

    The subcellular localization of mGluR4 was resolved at ultrastructural level: it concentrates at presynaptic active zones throughout the CNS and functions as both an autoreceptor and heteroreceptor depending on synapse type.

    Evidence Pre-embedding immunocytochemistry with electron microscopy; validation in mGluR4 KO mice

    PMID:11906782

    Open questions at the time
    • Molecular determinants of active zone targeting were unknown
    • Heteroreceptor vs. autoreceptor signaling may differ but was not compared
  7. 2003 High

    The first positive allosteric modulator (PAM) of mGluR4, (-)-PHCCC, was characterized and its binding site was localized to the transmembrane domain by chimeric receptor studies, establishing allosteric modulation as a pharmacological strategy.

    Evidence Functional assays in recombinant cells; chimeric mGluR receptor studies; neuroprotection assay

    PMID:14573382

    Open questions at the time
    • Precise PAM binding residues in the TMD were not identified
    • In vivo efficacy in disease models had not yet been tested
  8. 2004 High

    GRK2 was identified as a non-catalytic signaling switch for mGluR4: it selectively attenuates MAPK/ERK activation by sequestering Gβγ while slightly potentiating cAMP inhibition, establishing pathway-selective regulation.

    Evidence GRK2 overexpression, kinase-dead mutants, and C-terminal fragments in HEK293 cells; p-ERK and cAMP readouts; co-immunoprecipitation of GRK2–Gβγ

    PMID:15102938

    Open questions at the time
    • Whether GRK2-mediated regulation occurs at native synapses was not tested
    • Other GRKs beyond GRK2 and GRK4 were not examined
  9. 2006 High

    mGluR4 was positioned as a therapeutic target in two disease contexts: PHCCC-mediated neuroprotection in an MPTP Parkinson's model localized to the globus pallidus, and mGluR4 activation inhibited medulloblastoma proliferation through adenylyl cyclase and PI3K suppression.

    Evidence MPTP mouse model with intrapallidial PHCCC and mGluR4 KO controls; medulloblastoma cell lines with PI3K inhibitor epistasis and xenografts

    PMID:16822979 PMID:16899734

    Open questions at the time
    • Molecular mechanism of neuroprotection in dopaminergic neurons was not delineated
    • Whether PI3K suppression in tumor cells uses the same signaling cascade as neurons was unclear
  10. 2007 High

    A novel effector downstream of mGluR4 was identified: activation of K2P2.1 (TASK-1/TRAAK) potassium channels through PKA-dependent dephosphorylation of Ser333 and Ser300 on the channel C-terminus.

    Evidence Patch-clamp in cells co-expressing mGlu4 and K2P2.1; phosphorylation site mutagenesis; kinase inhibitor pharmacology

    PMID:17916432

    Open questions at the time
    • Physiological relevance at native synapses not demonstrated
    • Whether this pathway operates in parallel with PLC/PKC signaling was not addressed
  11. 2008 High

    At the parallel fiber–Purkinje cell synapse, mGluR4 was shown to be the exclusive group III receptor mediating synaptic depression, ruling out mGluR7 and mGluR8, and was also shown to contribute alongside mGluR8 at the lateral olfactory tract synapse.

    Evidence Cerebellar and piriform cortex slice electrophysiology with subtype-selective agonists and mGluR4 KO mice

    PMID:18266929 PMID:18625254

    Open questions at the time
    • The molecular basis for synapse-specific expression of group III receptor subtypes was unknown
  12. 2012 High

    Multiple aspects of mGluR4 presynaptic signaling were resolved: the Ca²⁺ influx inhibition mechanism at parallel fibers uses PLC/PKC rather than canonical Gi/cAMP; mGluR4 physically interacts with Munc18-1, synapsins, and syntaxin; and mGluR4 co-immunoprecipitates with and functionally interacts with presynaptic GABAA receptors.

    Evidence Systematic pharmacological dissection of presynaptic Ca²⁺ transients; co-IP and mass spectrometry from cerebellar extracts; Munc18-1 affinity chromatography; synaptosome release assays; mGluR4 KO

    PMID:22145864 PMID:22528491 PMID:22570379

    Open questions at the time
    • How PLC/PKC pathway is activated downstream of Gi/o at this synapse was mechanistically unresolved
    • Stoichiometry and structural basis of mGluR4–SNARE interactions not determined
  13. 2012 Medium

    Biased signaling at mGlu4 was demonstrated: co-activation of Gq-coupled H1 histamine receptors enables mGlu4-dependent calcium mobilization without enhancing cAMP inhibition, and PAMs show pathway-biased potentiation.

    Evidence Calcium mobilization and cAMP assays in mGlu4/H1 co-expressing cells

    PMID:22426233

    Open questions at the time
    • Molecular mechanism of Gi-to-calcium signal transduction in H1 co-expression context not identified
    • In vivo relevance of mGlu4 biased signaling not established
  14. 2019 High

    A non-neuronal role for GRM4 was established: in myeloid cells it regulates the IL-23/IL-12 cytokine balance, and GRM4 agonism suppresses osteosarcoma growth through this immune axis.

    Evidence Grm4 KO mice; radiation-induced and transplanted tumor models; osteosarcoma-conditioned media; anti-IL23 antibody rescue

    PMID:31527131

    Open questions at the time
    • The intracellular signaling cascade from GRM4 to IL-23 transcription in myeloid cells was not defined
    • Whether GRM4's immune role extends to other tumor types was untested
  15. 2021 High

    Structural and regulatory insights converged: cryo-EM revealed mGluR4's unique asymmetric homodimer architecture and a novel Gi-coupling interface, while RNA editing at Gln124 by ADAR was shown to selectively reduce heterodimerization with mGlu2 and mGlu7 without affecting homodimer signaling.

    Evidence Cryo-EM structure determination with functional mutagenesis; high-throughput RNA editing quantification; surface heterodimer assays

    PMID:34135510 PMID:34244459

    Open questions at the time
    • Physiological regulation of ADAR-mediated editing at Q124 in vivo was not characterized
    • Whether asymmetric activation differs between homo- and heterodimers functionally was not fully resolved
  16. 2023 High

    The full activation trajectory of mGlu2–mGlu4 heterodimers was structurally resolved, revealing sequential VFT movements, symmetric-to-asymmetric TMD rearrangement, and a PAM binding pocket at the asymmetric dimer interface applicable to both heterodimers and homodimers.

    Evidence Cryo-EM of 12 conformational states of mGlu2–mGlu4 and mGlu2–mGlu3 heterodimers with functional validation

    PMID:37286794

    Open questions at the time
    • How PAM binding at the dimer interface translates to subunit-selective allosteric modulation in vivo is not established
    • Structural basis for biased signaling at heterodimers vs. homodimers not yet addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the molecular mechanism by which mGluR4 activates PLC/PKC independently of canonical Gi signaling at presynaptic terminals; the structural basis and functional consequences of mGluR4 interactions with SNARE/exocytosis machinery; the intracellular pathway linking GRM4 to IL-23 regulation in myeloid cells; and the physiological significance of ADAR-mediated editing in controlling heterodimer composition in vivo.
  • PLC/PKC activation mechanism downstream of Gi/o at presynaptic terminals
  • Structural characterization of mGluR4–Munc18-1/syntaxin complexes
  • Signaling cascade from GRM4 to cytokine transcription in immune cells
  • In vivo functional impact of RNA editing on heterodimer stoichiometry

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 2 GO:0043226 organelle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 1
Partners
CBX4GABRA1GRK2HRH1STX1ASTXBP1SYN1
Complex memberships
mGlu2–mGlu4 heterodimermGlu4 homodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 mGluR4 (and mGluR3) couples to Gi/o proteins to inhibit forskolin-stimulated cAMP accumulation in response to agonist activation; mGluR4 is selectively and potently activated by L-AP4 and L-serine-O-phosphate in a stereoselective manner, a pharmacological profile distinct from all other metabotropic glutamate receptor subtypes. cAMP accumulation assays and ligand pharmacology in stably transfected CHO cells expressing cloned rat mGluR3 and mGluR4 The Journal of neuroscience High 8463825
1996 mGluR4 is required for L-AP4-induced depression of synaptic transmission at the parallel fiber→Purkinje cell synapse and for normal presynaptic short-term plasticity (paired-pulse facilitation and post-tetanic potentiation); loss of mGluR4 impairs motor learning on the rotating rod without abolishing LTD. mGluR4 knockout mice; patch-clamp and extracellular field recordings in cerebellar slices; behavioral motor testing The Journal of neuroscience High 8815915
1999 Ligand binding to mGluR4 is mediated primarily by the extracellular amino-terminal domain (first 548 amino acids); residues Arg78, Ser159, and Thr182 within the predicted binding pocket are critical for agonist binding, with downstream residues modulating affinity but not primary recognition. Truncated epitope-tagged soluble ATD construct; competition radioligand binding with [3H]L-AP4; site-directed mutagenesis of candidate residues; deglycosylation experiments The Journal of biological chemistry High 10187777 10559233
1995 mGluR4 is palmitoylated through a thioester bond (hydroxylamine-sensitive) when expressed in BHK cells, unlike mGluR1α; agonist stimulation does not alter the level of palmitoylation. [3H]palmitic acid metabolic labeling; immunoprecipitation with antipeptide antibodies; hydroxylamine treatment to confirm thioester linkage Journal of neurochemistry Medium 7891082
2002 mGluR4 protein is highly enriched in presynaptic active zones throughout the CNS (cerebellar cortex, basal ganglia, thalamic sensory relay nuclei, hippocampus); in the basal ganglia it acts as a presynaptic heteroreceptor on GABAergic striatal projection neuron terminals of both direct and indirect pathways; in cerebellum and hippocampus it also operates as an autoreceptor. Affinity-purified antibodies; pre-embedding immunocytochemistry (light and electron microscopy); validation in mGluR4 gene-targeted knockout mice Neuroscience High 11906782
2000 mGluR4 is the primary receptor subtype mediating neuroprotection by group III agonists against NMDA excitotoxicity in vitro and in vivo; mGluR4-deficient neurons show greater vulnerability to NMDA and higher extracellular glutamate, indicating mGluR4 is required for maintaining glutamate homeostasis. Cortical cultures and intrastriatal NMDA infusion in mGluR4−/− mice vs. wild-type; neuroprotection assays with (+)-PPG, L-AP4, L-SOP; microdialysis for extracellular glutamate The Journal of neuroscience High 10964947
2000 mGluR4 within the nucleus reticularis thalami (nRT) is critical for GABAergic modulation of thalamocortical synchronization; mGluR4−/− mice are selectively resistant to GABAA receptor antagonist-induced absence seizures, and bilateral intra-nRT injection of mGluR4 antagonist mimics this resistance in wild-type mice. mGluR4 knockout mice; GHB/baclofen and GABAA antagonist seizure threshold testing; bilateral stereotaxic intra-nRT drug infusions in wild-type mice The Journal of neuroscience High 10934271
2003 (-)-PHCCC is a positive allosteric modulator (PAM) of mGluR4 that increases agonist potency and maximal efficacy and can directly activate mGluR4 at higher concentrations with low efficacy; its binding site is localized to the transmembrane domain (demonstrated by chimeric receptor studies); it is inactive at mGluR2, -3, -5a, -6, -7b, -8a but shows partial antagonism at mGluR1b. Functional assays in recombinant cells; chimeric receptor studies mapping binding site; enantioselective comparison; neuroprotection assay in cortical cultures Neuropharmacology High 14573382
2004 GRK2 (but not GRK4) acts as a 'switch molecule' for mGlu4 signaling: it attenuates mGlu4-mediated MAPK/ERK pathway activation by sequestering Gβγ subunits (co-immunoprecipitation showed agonist-dependent GRK2–Gβγ interaction), while slightly potentiating cAMP inhibition; a kinase-dead GRK2 mutant and the C-terminal GRK2 fragment similarly inhibit MAPK signaling, confirming a non-catalytic mechanism; agonist-induced mGlu4 internalization requires dynamin but is not affected by GRK2. GRK2/GRK4 overexpression and kinase-dead mutants in HEK293 cells; Western blot for p-ERK1/2; cAMP assay; co-immunoprecipitation; dominant-negative dynamin; GFP-tagged receptor internalization imaging Molecular pharmacology High 15102938
2006 mGluR4 activation (with PHCCC) reduces nigrostriatal degeneration caused by MPTP in mice; PHCCC protection is absent in mGluR4−/− mice and is reproduced by local infusion into the external globus pallidus, placing mGluR4 in the basal ganglia circuit relevant to Parkinson's disease neuroprotection. MPTP mouse model; striatal dopamine/metabolite HPLC; TH/DAT immunostaining; subcutaneous and intrapallidial PHCCC administration; mGluR4−/− genetic control The Journal of neuroscience High 16822979
2006 mGluR4 receptor activation inhibits adenylyl cyclase and the PI3K pathway (but not MAPK, Sonic Hedgehog, or Wnt pathways) in medulloblastoma cells, reducing DNA synthesis and cell proliferation; PI3K inhibitor LY294002 abolishes this antiproliferative effect. PHCCC treatment of D283med, D341med, DAOY medulloblastoma lines; adenylyl cyclase and PI3K pathway readouts; DNA synthesis assays; LY294002 epistasis; xenograft and Patched-1 heterozygous mouse in vivo experiments The Journal of neuroscience High 16899734
2007 mGlu4 activation increases K2P2.1 (TASK-1/TRAAK) two-pore domain potassium channel activity through a reduction in C-terminal phosphorylation; PKA is involved (not PKC, PKG, or phosphatases); mutational analysis identified Ser333 (~70%) and Ser300 (~30%) as the key phosphorylation sites controlling K2P2.1 activity downstream of mGlu4. Whole-cell patch-clamp recording in cells co-expressing mGlu4 and K2P2.1; pharmacological kinase/phosphatase inhibition; C-terminal phosphorylation site mutagenesis Molecular and cellular neurosciences High 17916432
2008 At the parallel fiber–Purkinje cell synapse in rodent cerebellum, the depression of excitatory transmission by group III mGluR agonists is exclusively mediated by presynaptic mGluR4 autoreceptors; mGluR7 and mGluR8 do not contribute at this synapse, demonstrated with selective agonists and mGluR4 knockout mice. Whole-cell patch-clamp and presynaptic Ca2+ influx measurements in rat and mouse cerebellar slices; selective group III agonists (ACPT-I), mGluR4 PAM PHCCC, mGluR8-selective agonist DCPG; mGluR4 knockout mice Journal of neurochemistry High 18266929
2008 mGluR4 and mGluR8 both contribute to inhibition of synaptic transmission at the lateral olfactory tract–piriform cortex synapse; mGluR4 PAM PHCCC potentiates the inhibitory actions of L-AP4 and the mGluR4-selective agonist Z-cyclopentyl-AP4 at this synapse. Whole-cell patch-clamp of piriform cortex pyramidal cells in brain slices; selective mGluR8 agonist DCPG; mGluR4 PAM PHCCC; concentration-response curves Neuropharmacology Medium 18625254
2012 Native cerebellar mGluR4 physically interacts with exocytosis proteins including Munc18-1, synapsins, and syntaxin; mGluR4 is retained on Munc18-1-Sepharose affinity columns; Munc18-1 and mGluR4 colocalize at the plasma membrane in HEK293 cells; peptides from mGluR4 cytoplasmic domains confirm the interaction, suggesting mGluR4 modulates glutamate release partly through direct interaction with the vesicle release machinery beyond Ca2+ channel inhibition. Co-immunoprecipitation from rat cerebellar extracts (anti-mGluR4 antibodies) followed by mass spectrometry (183 partners identified); Munc18-1 affinity chromatography; immunohistochemistry colocalization; cytoplasmic domain peptide pulldown The Journal of biological chemistry High 22528491
2012 mGluR4 inhibition of presynaptic Ca2+ influx at parallel fiber terminals does not selectively target a specific voltage-gated Ca2+ channel subtype but broadly modulates all classes present; the mechanism does not involve Gi/o (pertussis toxin-insensitive), adenylyl cyclase/PKA, MAPK, PI3K, GIRK channels, or K+ channels, but instead employs a novel signaling pathway involving phospholipase C (PLC) activation and ultimately protein kinase C (PKC). Presynaptic Ca2+ transient measurements and patch-clamp in cerebellar slices; pharmacological inhibition of specific Ca2+ channel types, GIRK, K+ channels, PTX, AC/PKA, MAPK, PI3K, PLC, and PKC The Journal of physiology Medium 22570379
2012 GABAA receptors and mGluR4 are co-localized on glutamatergic parallel fiber axon terminals in cerebellum and co-immunoprecipitate from cerebellar membranes; coincident activation of both receptors increases glutamate release above the level induced by GABAA activation alone; mGluR4 KO mice show reduced GABAA subunit expression and ligand binding in cerebellum. Immunocytochemistry colocalization; co-immunoprecipitation from cerebellar membranes; [3H]glutamate release from cerebellar synaptosomes; [35S]TBPS binding and immunoblot in mGluR4 KO cerebellum Journal of neurochemistry Medium 22145864
2012 Functional selectivity (biased signaling) at mGlu4: co-activation of Gq-coupled H1 histamine receptors induces substantial calcium mobilization downstream of mGlu4 glutamate activation (without chimeric G proteins), while mGlu4-mediated cAMP inhibition is not enhanced; mGlu4 PAM activity is further biased toward calcium signaling when H1 receptors are co-activated. Calcium mobilization and cAMP assays in mGlu4-expressing cells with H1 receptor co-expression; small molecule mGlu4 PAM testing; absence of chimeric G protein controls Neuropharmacology Medium 22426233
2019 GRM4 is expressed in myeloid cells and selectively regulates IL23 (and the related cytokine IL12) expression; osteosarcoma-conditioned media induce myeloid Il23 expression in a GRM4-dependent manner while suppressing Il12; GRM4 agonists suppress osteosarcoma growth in mice through this myeloid IL23/IL12 axis. Grm4 gene-targeted mice; radiation-induced tumor development assays; cytokine expression analysis; osteosarcoma-conditioned media experiments; in vivo tumor growth with GRM4 agonist treatment and anti-IL23 antibody Cancer discovery High 31527131
2019 GRM4 interacts with CBX4 to restrict CBX4's nuclear localization, reducing HIF-1α transcriptional activity, thereby inhibiting osteosarcoma cell proliferation, migration, and invasion. GRM4 overexpression in osteosarcoma cells; colony formation, transwell migration and invasion assays; co-immunoprecipitation demonstrating GRM4–CBX4 interaction; subcellular fractionation/localization of CBX4 Bioscience, biotechnology, and biochemistry Low 31581881
2021 mGlu4 undergoes adenosine-to-inosine (A-to-I) RNA editing by ADAR enzymes converting Gln124 to Arg in the B helix of the amino-terminal domain, a region critical for receptor dimerization; Q124R substitution does not disrupt homodimer G protein activation but decreases mGlu4 propensity to heterodimerize with mGlu2 and mGlu7. High-throughput sequencing to quantify editing; in vitro ADAR editing assay; structural modeling; surface heterodimer assay; G protein activation assay comparing edited vs. unedited receptor RNA Medium 34244459
2021 Cryo-EM structures of human mGlu4 (and mGlu2) bound to heterotrimeric Gi reveal: (1) a G-protein-binding site formed by three intracellular loops and helices III and IV, distinct from all other known GPCR–G protein interfaces; (2) an asymmetric transmembrane domain dimer interface, with functional data confirming asymmetric dimerization is crucial for mGlu4 receptor activation. Cryo-electron microscopy structure determination; functional assays confirming asymmetric signaling; mutagenesis-supported validation Nature High 34135510
2023 Cryo-EM structures of mGlu2–mGlu4 heterodimer in multiple conformational states reveal: sequential VFT conformational changes upon activation; substantial rearrangement of the TMD from a symmetric inactive dimer to an asymmetric active dimer in a conserved mode; stability of inactive conformations and subunit–G protein interaction pattern determine asymmetric signal transduction; a novel binding site for mGlu4 PAMs at the asymmetric TMD dimer interface of both the mGlu2–mGlu4 heterodimer and the mGlu4 homodimer. Cryo-EM of mGlu2–mGlu3 and mGlu2–mGlu4 heterodimers (12 structures); functional assays; PAM binding site identification at dimer interface Cell research High 37286794
2016 OptoGluNAM4.1, a photoswitchable negative allosteric modulator, covalently binds mGlu4 and reversibly inhibits its activity in a blue-light-dependent manner; used in brain slices it demonstrated that mGlu4 receptors are endogenously activated during excitotoxic/ischemic conditions (elevated extracellular glutamate) at parallel fiber–Purkinje cell synapses. Photopharmacology with covalently-attached azobenzene NAM; cerebellar slice electrophysiology; zebrafish behavioral pharmacology; mouse chronic pain model Cell chemical biology Medium 27478159
2013 mGlu4 activation promotes proliferation of rat embryonic neural progenitor cells through activation of ERK1/2 signaling and upregulation of cyclin D1; mGlu4 siRNA knockdown decreases proliferation and p-ERK1/2, and the ERK1/2 inhibitor U0126 abolishes the proliferative effect of mGlu4 agonist VU0155041. mGlu4 agonist VU0155041 and siRNA knockdown in rat NPC cultures; MTT/neurosphere diameter/BrdU proliferation assays; Western blot for p-ERK1/2, p-p38, cyclin D1; U0126 epistasis Cellular and molecular biology Medium 23374450
2016 mGlu4 receptor activation exerts antipsychotic-like effects partly through 5-HT1A receptors operating at the circuit (not single-neuron) level: LSP4-2022-induced reversal of MK-801-elevated dopamine, serotonin, glutamate, and GABA release in the prefrontal cortex is blocked by 5-HT1A antagonist WAY100635, but WAY100635 does not affect mGlu4 modulation of single-neuron sEPSCs. In vivo microdialysis in PFC; behavioral tests (hyperactivity, head twitches, social interaction, FST); whole-cell patch-clamp of sEPSCs in PFC slices; pharmacological dissection with WAY100635 Neuropharmacology Medium 27465045

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4. The Journal of neuroscience : the official journal of the Society for Neuroscience 542 8463825
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
2002 Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience 206 11906782
1996 Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 184 8815915
2003 (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology 166 14573382
2021 Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4. Nature 125 34135510
2006 Pharmacological activation of mGlu4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The Journal of neuroscience : the official journal of the Society for Neuroscience 103 16822979
2014 Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 93 24619243
2000 Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 10964947
2000 Modulation of absence seizures by the GABA(A) receptor: a critical rolefor metabotropic glutamate receptor 4 (mGluR4). The Journal of neuroscience : the official journal of the Society for Neuroscience 84 10934271
2006 Pharmacological activation of mGlu4 metabotropic glutamate receptors inhibits the growth of medulloblastomas. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 16899734
1999 Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor. The Journal of biological chemistry 68 10187777
2009 Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). Journal of medicinal chemistry 67 19469556
1999 Probing the ligand-binding domain of the mGluR4 subtype of metabotropic glutamate receptor. The Journal of biological chemistry 62 10559233
2015 MiR-335 is involved in major depression disorder and antidepressant treatment through targeting GRM4. Neuroscience letters 60 26314506
1994 Expression of mRNAs of L-AP4-sensitive metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7) in the rat retina. Neuroscience letters 60 8084499
2009 mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease. Future medicinal chemistry 59 20161443
2007 Functional role of mGluR1 and mGluR4 in pilocarpine-induced temporal lobe epilepsy. Neurobiology of disease 58 17446080
2000 Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampal neurons with reduced seizure vulnerability. Annals of neurology 58 10632098
2005 Expression patterns of Group III metabotropic glutamate receptors mGluR4 and mGluR8 in multiple sclerosis lesions. Journal of neuroimmunology 56 15589052
1994 Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic subtype (mGluR4) in highly vulnerable rat brain areas. Journal of neurochemistry 56 8035186
2016 OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu4 Receptor Activity. Cell chemical biology 54 27478159
2004 Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2). Molecular pharmacology 53 15102938
1998 Altered spatial learning and memory in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. Behavioral neuroscience 53 9676970
2006 Combined administration of PHCCC, a positive allosteric modulator of mGlu4 receptors and ACPT-I, mGlu III receptor agonist evokes antidepressant-like effects in rats. Amino acids 51 16868652
2018 An mGlu4-Positive Allosteric Modulator Alleviates Parkinsonism in Primates. Movement disorders : official journal of the Movement Disorder Society 50 30216534
2012 Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease. British journal of pharmacology 48 22404342
2011 Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model. Journal of medicinal chemistry 47 21966889
2023 Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. Cell research 45 37286794
2012 Measures of anxiety, sensorimotor function, and memory in male and female mGluR4⁻/⁻ mice. Behavioural brain research 45 22227508
2007 Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology 45 18022649
2009 Association study of polymorphisms in the group III metabotropic glutamate receptor genes, GRM4 and GRM7, with schizophrenia. Psychiatry research 43 19351574
2013 The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents. British journal of pharmacology 42 23714045
2011 Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. Journal of medicinal chemistry 41 21247167
2019 Glutamate metabotropic receptor 4 (GRM4) inhibits cell proliferation, migration and invasion in breast cancer and is regulated by miR-328-3p and miR-370-3p. BMC cancer 40 31492116
2019 Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23. Cancer discovery 39 31527131
2012 Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor. Neuropharmacology 38 22634361
2016 Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4). ACS chemical neuroscience 37 27075300
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