Affinage

GRM4

Metabotropic glutamate receptor 4 · UniProt Q14833

Length
912 aa
Mass
101.9 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM4 (mGluR4) is a presynaptic Group III metabotropic glutamate receptor that suppresses neurotransmitter release by coupling, via agonists such as L-AP4, to Gi/o proteins to inhibit forskolin-stimulated cAMP accumulation (PMID:8463825). Its agonist-binding pocket lies within the extracellular amino-terminal domain, where a soluble truncated ATD recapitulates ligand pharmacology and the residues Arg78, Ser159, and Thr182 form the critical contacts (PMID:10187777, PMID:10559233). Cryo-EM of mGlu4-Gi and of mGlu2-mGlu4 heterodimers established an asymmetric activation mechanism: only one protomer couples to G protein, the transmembrane domains rearrange from symmetric inactive to asymmetric active states, and a positive-allosteric-modulator (PAM) site sits within the transmembrane domain and at the asymmetric dimer interface (PMID:14573382, PMID:34135510, PMID:37286794). The receptor is targeted to presynaptic active zones across cerebellum, basal ganglia, thalamus, and hippocampus, acting as an autoreceptor in cerebellum and as a heteroreceptor on GABAergic and glutamatergic terminals in the basal ganglia (PMID:11906782, PMID:26832920). Genetic and pharmacological dissection at the parallel fiber–Purkinje cell synapse defines mGluR4 as the autoreceptor mediating depression of excitatory transmission and short-term plasticity, acting by inhibiting presynaptic Ca2+ influx through a PLC/PKC pathway that is independent of cAMP, PKA, MAPK, PI3K, and Gi/o-coupled K+ channels at this synapse (PMID:8815915, PMID:18266929, PMID:22570379). mGluR4 signaling is shaped by additional effectors and modulators—GRK2 attenuates mGluR4-driven ERK1/2 activation by sequestering Gβγ rather than by phosphorylating the receptor (PMID:15102938), the receptor potentiates K2P2.1 (TREK-1) channels via PKA-dependent dephosphorylation (PMID:17916432), and it physically associates with the exocytotic machinery (Munc18-1, synapsins, syntaxin) and with GABAA receptors at parallel fiber terminals (PMID:22528491, PMID:22145864). Functionally, mGluR4 maintains presynaptic glutamate homeostasis and confers neuroprotection against NMDA and MPTP toxicity, modulates thalamocortical synchronization underlying absence seizures, and outside the nervous system regulates myeloid IL23/IL12 expression and constrains osteosarcoma growth (PMID:10964947, PMID:10934271, PMID:16822979, PMID:31527131). The receptor is palmitoylated through a thioester bond independent of agonist stimulation (PMID:7891082).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1993 High

    Established the core transduction logic of mGluR4 by showing it is a Gi/o-coupled receptor that lowers cAMP, defining it as an inhibitory glutamate sensor distinct from other mGluR subtypes.

    Evidence Stable CHO expression of cloned rat mGluR4 with cAMP accumulation assay and agonist pharmacology

    PMID:8463825

    Open questions at the time
    • Did not localize the receptor or define its native synaptic role
    • G-protein-binding interface not mapped
  2. 1995 High

    Identified palmitoylation as a covalent post-translational modification of mGluR4, distinguishing it biochemically from mGluR1α.

    Evidence [3H]palmitate metabolic labeling with hydroxylamine cleavage in BHK cells

    PMID:7891082

    Open questions at the time
    • Modified cysteine residue(s) not identified
    • Functional consequence for trafficking or signaling untested
  3. 1996 High

    Demonstrated through knockout that mGluR4 is the presynaptic receptor mediating depression of excitatory transmission and short-term plasticity at the parallel fiber–Purkinje cell synapse.

    Evidence Patch-clamp and field recordings in mGluR4 KO vs WT cerebellar slices with L-AP4 application

    PMID:8815915

    Open questions at the time
    • Downstream presynaptic effector pathway not defined here
    • LTD shown to be unaffected, leaving its receptor unidentified
  4. 1999 High

    Localized the ligand-binding function to the extracellular amino-terminal domain and identified the specific residues (Arg78, Ser159, Thr182) contacting agonists.

    Evidence Soluble truncated ATD binding, deglycosylation, site-directed mutagenesis with [3H]L-AP4 competition, and molecular modeling

    PMID:10187777 PMID:10559233

    Open questions at the time
    • Did not resolve the full activation pathway from ATD to G protein
    • Allosteric/transmembrane sites not addressed
  5. 1999 High

    Used the knockout to establish mGluR4 as the dominant high-affinity L-AP4 binding site across multiple brain regions, anchoring its anatomical distribution.

    Evidence [3H]L-AP4 autoradiography in mGluR4 KO vs WT brain sections

    PMID:9930760

    Open questions at the time
    • Subcellular (presynaptic) localization not resolved at this stage
  6. 2000 High

    Defined physiological roles for mGluR4 in glutamate homeostasis/neuroprotection and in thalamocortical control of absence seizures, linking receptor activity to circuit-level outcomes.

    Evidence mGluR4 KO neurons/mice with NMDA toxicity, microdialysis, and site-specific intra-nRT pharmacology with EEG

    PMID:10934271 PMID:10964947

    Open questions at the time
    • Molecular signaling steps linking receptor to protection/seizure modulation not dissected
    • Cell-type-specific contributions only partially localized
  7. 2002 High

    Resolved the subcellular localization, showing mGluR4 resides at presynaptic active zones and functions as an autoreceptor in cerebellum/hippocampus and a heteroreceptor on GABAergic terminals in basal ganglia.

    Evidence Affinity-purified antibodies, pre-embedding electron microscopy, and KO negative controls across brain regions

    PMID:11906782

    Open questions at the time
    • Did not establish presynaptic effector mechanism
    • Terminal-type specificity in striatum refined only later
  8. 2003 High

    Established a druggable transmembrane allosteric site by showing (-)-PHCCC is a subtype-selective positive allosteric modulator of mGluR4.

    Evidence Chimeric receptor mutagenesis, cAMP functional assay, and selectivity profiling across mGluR subtypes

    PMID:14573382

    Open questions at the time
    • Atomic-level PAM binding pose not resolved until later cryo-EM
  9. 2004 High

    Identified GRK2 as a regulator of mGluR4 signaling acting through Gβγ sequestration rather than receptor phosphorylation, and separated internalization (dynamin-dependent) from desensitization.

    Evidence HEK293 transfection, phospho-ERK and cAMP assays, reciprocal Co-IP, kinase-dead/dominant-negative mutants, and receptor imaging

    PMID:15102938

    Open questions at the time
    • In vivo relevance of GRK2 regulation untested
    • Mechanism couples to ERK in recombinant cells; native pathway not confirmed here
  10. 2006 High

    Extended mGluR4 signaling to growth control and neuroprotection in vivo, placing it upstream of PI3K in tumor cells and confirming target-specific nigrostriatal protection.

    Evidence PHCCC in medulloblastoma lines with PI3K inhibitor epistasis and xenografts; MPTP model with mGluR4 KO validation and site-specific pallidal infusion

    PMID:16822979 PMID:16899734

    Open questions at the time
    • How a Gi/o receptor engages PI3K mechanistically not detailed
    • Anatomical locus identified but circuit mechanism inferred
  11. 2007 High

    Revealed a PKA-dependent effector arm in which mGluR4 potentiates K2P2.1 (TREK-1) channels via dephosphorylation of specific C-terminal serines, and clarified mGluR4 PAM effects on seizure circuits.

    Evidence mGluR4/K2P2.1 co-expression with kinase/phosphatase inhibitors and channel mutagenesis; immuno-EM, in situ hybridization, and EEG in WAG/Rij rats and KO mice

    PMID:17916432 PMID:18022649

    Open questions at the time
    • Whether K2P2.1 modulation operates at native presynaptic terminals not shown
    • Pro- vs anti-epileptic outcomes depend on circuit context not fully resolved
  12. 2008 High

    Pharmacogenetically isolated mGluR4 as the sole Group III autoreceptor mediating cerebellar presynaptic depression and showed broader involvement at olfactory cortical synapses.

    Evidence Whole-cell patch-clamp with selective agonists, PHCCC, and KO slices (cerebellum); slice pharmacology at lateral olfactory tract–piriform synapse

    PMID:18266929 PMID:18625254

    Open questions at the time
    • Olfactory cortex contribution lacks KO validation (Medium-confidence)
    • Effector pathway not yet defined in this work
  13. 2012 High

    Defined the presynaptic effector mechanism and the receptor's interaction network: Ca2+-influx inhibition proceeds via PLC/PKC, and mGluR4 physically associates with exocytotic proteins and GABAA receptors at active zones.

    Evidence Pharmacological dissection of presynaptic Ca2+ transients; Co-IP/affinity chromatography for Munc18-1/synapsins/syntaxin; reciprocal Co-IP and synaptosomal release assays for GABAA receptors; biased Gq co-activation assays

    PMID:22145864 PMID:22426233 PMID:22528491 PMID:22570379

    Open questions at the time
    • Direct effector linking PLC/PKC to Ca2+ channels not identified
    • Functional selectivity via H1/Gq shown only in recombinant cells (Medium-confidence)
  14. 2016 High

    Refined the basal ganglia localization quantitatively, showing mGluR4 predominantly marks glutamatergic terminals onto indirect-pathway spines, providing the anatomical basis for antiparkinsonian action.

    Evidence Quantitative dual-label immuno-electron microscopy for mGluR4, vGluT1, and D1 receptor in mouse striatum

    PMID:26832920

    Open questions at the time
    • Functional confirmation of pathway-selective release control not in this study
  15. 2019 High

    Established non-neuronal and tumor-suppressive roles, with GRM4 controlling myeloid IL23/IL12 balance and restraining osteosarcoma via CBX4/HIF-1α regulation.

    Evidence Grm4 gene-targeted mice with radiation-induced osteosarcoma and cytokine assays; GRM4 overexpression with CBX4 Co-IP, nuclear fractionation, and HIF-1α reporter

    PMID:31527131 PMID:31581881

    Open questions at the time
    • How a GPCR controls cytokine transcription mechanistically not resolved
    • CBX4 interaction shown by single-lab Co-IP (Medium-confidence)
  16. 2021 High

    Provided the structural basis for asymmetric activation, showing only one homodimer protomer couples Gi via a defined intracellular interface.

    Evidence Cryo-EM of human mGlu4-Gi complex with functional validation of asymmetric dimerization

    PMID:34135510

    Open questions at the time
    • Conformational trajectory from ligand binding to coupling not captured in a single state
  17. 2023 High

    Captured the activation trajectory across multiple conformational states and localized the mGlu4 PAM site at the asymmetric dimer interface, unifying ligand binding, dimer rearrangement, and allosteric modulation.

    Evidence Twelve cryo-EM structures of mGlu2-mGlu4 heterodimer in inactive/intermediate/active states with functional validation

    PMID:37286794

    Open questions at the time
    • Functional consequences of mGlu2-mGlu4 heterodimerization in native circuits not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How presynaptic PLC/PKC-dependent Ca2+-channel inhibition, the exocytotic-protein interactome, and the non-neuronal IL23/CBX4 functions are mechanistically connected to the structurally defined asymmetric activation remains unresolved.
  • Molecular link between PLC/PKC and presynaptic Ca2+ channels unidentified
  • Mechanism by which mGluR4 controls myeloid cytokine transcription unknown
  • Physiological role of mGlu2-mGlu4 heterodimers in vivo undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
CBX4GABAA RECEPTORGRK2K2P2.1MUNC18-1SYNTAXIN

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 mGluR4 (GRM4) couples to Gi/o proteins and inhibits forskolin-stimulated intracellular cAMP accumulation in response to agonist binding; the receptor shows high selectivity for L-AP4 and L-serine-O-phosphate as agonists, distinct from other mGluR subtypes. Stable CHO cell expression of cloned rat mGluR4; cAMP accumulation assay; pharmacological characterization The Journal of neuroscience High 8463825
1995 mGluR4 is palmitoylated via a thioester bond when expressed in BHK cells, as demonstrated by [3H]palmitic acid labeling and hydroxylamine cleavage; agonist stimulation with glutamate does not alter the level of palmitoylation. In contrast, mGluR1α is not palmitoylated. [3H]palmitic acid metabolic labeling; immunoprecipitation; hydroxylamine treatment; SDS-PAGE autoradiography in stably transfected BHK cells Journal of neurochemistry High 7891082
1996 mGluR4 knockout mice show impaired presynaptic short-term synaptic plasticity (paired-pulse facilitation and post-tetanic potentiation) at the parallel fiber→Purkinje cell synapse, and L-AP4 (EC50 = 2.5 µM) depresses synaptic responses in wild-type but not knockout mice, establishing mGluR4 as the presynaptic receptor mediating depression of excitatory transmission at this synapse. Long-term depression (LTD) is not impaired. Patch-clamp and extracellular field recordings from cerebellar slices in mGluR4 knockout vs. wild-type mice; pharmacological application of L-AP4 The Journal of neuroscience High 8815915
1999 The primary ligand-binding determinants of mGluR4 reside within the extracellular amino-terminal domain (first 548 amino acids). A soluble truncated ATD binds L-AP4 with similar rank-order pharmacology as the full-length receptor; N-linked glycosylation is not required for agonist binding. Truncated epitope-tagged mGluR4 ATD expressed and secreted from HEK293 cells; competition binding with [3H]L-AP4; deglycosylation experiment; gel electrophoresis The Journal of biological chemistry High 10187777
1999 Site-directed mutagenesis identified Arg78, Ser159, and Thr182 in the mGluR4 ATD as critical residues for agonist binding; mutations to Ala severely impaired binding of [3H]L-AP4. Molecular modeling suggests Ser159 and Thr182 hydrogen-bond with the α-carboxyl and α-amino groups of agonists, while Arg78 forms an electrostatic interaction with the acidic side chain. Site-directed mutagenesis; [3H]L-AP4 competition binding; molecular modeling/docking The Journal of biological chemistry High 10559233
1999 mGluR4 is the predominant contributor to high-affinity [3H]L-AP4 binding in several brain regions including cerebellar cortex, nucleus basalis, thalamus, superior colliculus, substantia nigra, and hippocampal dentate gyrus, as demonstrated by near-complete loss of binding in mGluR4 knockout mice. Autoradiographic binding assay with [3H]L-AP4 in mGluR4 knockout vs. wild-type mouse brain sections Journal of neurochemistry High 9930760
2000 mGluR4 mediates neuroprotection against NMDA excitotoxicity: group III agonists (+)-PPG and L-AP4 protect cortical neurons in wild-type mice but are ineffective in mGluR4−/− neurons. mGluR4−/− neurons are more vulnerable to NMDA and show higher extracellular glutamate, indicating mGluR4 maintains glutamate homeostasis presynaptically. Cortical neuronal cultures from mGluR4 KO and WT mice; NMDA toxicity assay; microdialysis; intrastriatal NMDA infusion in vivo 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 markedly resistant to GABAA receptor antagonist-induced absence seizures, bilateral intra-nRT mGluR4 antagonist injection mimics this resistance in WT mice, and intra-nRT mGluR4 agonist exacerbates absence seizures. mGluR4 KO mice; stereotaxic intra-nRT pharmacological injections; EEG/behavioral seizure monitoring The Journal of neuroscience High 10934271
2002 mGluR4 protein is predominantly localized to presynaptic active zones in multiple brain regions including cerebellar cortex, basal ganglia, thalamus, and hippocampus. In the basal ganglia, mGluR4 is found on GABAergic terminals of striatal projection neurons (both direct and indirect pathways), functioning as a presynaptic heteroreceptor; in cerebellum and hippocampus it functions as an autoreceptor. Affinity-purified antibodies against mGluR4 C-terminal domain; immunohistochemistry; pre-embedding electron microscopy; validation in mGluR4 KO mice (no immunoreactivity) Neuroscience High 11906782
2003 (-)-PHCCC acts as a positive allosteric modulator (PAM) of mGluR4 by binding within the transmembrane domain, increasing agonist potency and maximum efficacy; chimeric receptor studies localized its binding site to the TM region. The compound shows no activity at mGluR2, -3, -5a, -6, -7b, -8a. Recombinant mGluR expression; cAMP assay; chimeric receptor mutagenesis; selectivity profiling across mGluR subtypes Neuropharmacology High 14573382
2004 GRK2 (but not GRK4) regulates mGluR4 signaling: GRK2 overexpression attenuates mGluR4-mediated ERK1/2 (MAPK) activation while slightly potentiating cAMP inhibition. A kinase-dead GRK2 mutant also inhibits MAPK signaling, indicating GRK2 acts by sequestering Gβγ subunits rather than by phosphorylating mGluR4. GRK2 co-immunoprecipitates with Gβγ in an agonist-dependent manner. Agonist-induced internalization of mGluR4 is abolished by dominant-negative dynamin but not affected by GRK2. Transient transfection of HEK293 cells; Western blot for phospho-ERK1/2; cAMP assay; co-immunoprecipitation; GFP-tagged receptor internalization imaging; pertussis toxin treatment Molecular pharmacology High 15102938
2006 Pharmacological activation of mGluR4 (via PHCCC) inhibits adenylyl cyclase and the PI3K pathway in medulloblastoma cells without affecting MAPK, Sonic Hedgehog, or Wnt pathways, and reduces DNA synthesis and cell proliferation; the antiproliferative effect is abolished by the PI3K inhibitor LY294002. mGluR4-expressing medulloblastoma cell lines (D283med, D341med, DAOY); cAMP assay; PI3K pathway analysis; DNA synthesis and proliferation assays; LY294002 pharmacological blockade; xenograft in vivo experiments The Journal of neuroscience High 16899734
2006 mGluR4 activation with PHCCC protects the nigrostriatal pathway against MPTP toxicity in mice; PHCCC is neuroprotective in wild-type but not in mGluR4−/− mice, confirming target specificity. Unilateral infusion of PHCCC into the external globus pallidus is sufficient to protect the ipsilateral nigrostriatal pathway. mGluR4 KO vs. WT C57BL/6 mice; MPTP neurotoxin model; dopamine/metabolite measurements; TH/DAT immunostaining; GFAP immunostaining; stereotaxic drug infusion The Journal of neuroscience High 16822979
2007 mGluR4 activation potentiates K2P2.1 (TREK-1) two-pore domain potassium channel activity via a PKA-dependent reduction in C-terminal phosphorylation; mutational analysis showed that dephosphorylation of S333 accounts for ~70% and S300 for ~30% of the K2P2.1 increase following mGluR4 activation. PKC, PKG, and protein phosphatases are not involved. Co-expression of mGluR4 and K2P2.1 in Xenopus oocytes or HEK cells; pharmacological kinase/phosphatase inhibitors; site-directed mutagenesis of K2P2.1 C-terminal phosphorylation sites; electrophysiological recordings Molecular and cellular neurosciences High 17916432
2007 mGluR4 PAM PHCCC enhances absence seizures in WAG/Rij rats and PTZ-treated mice; mGluR4 expression is elevated in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats. Electron microscopy and in situ hybridization indicate mGluR4 in the RTN is localized on excitatory cortical afferents. PHCCC is inactive in mGluR4 KO mice. Immunoblotting; immunohistochemistry; electron microscopy; in situ hybridization; EEG monitoring in mGluR4 KO and WAG/Rij rats; systemic PHCCC administration Neuropharmacology High 18022649
2008 Depression of excitatory synaptic transmission at parallel fiber–Purkinje cell synapses in the rodent cerebellar cortex by group III mGluRs is mediated exclusively by mGluR4 autoreceptors; neither mGluR7 nor mGluR8 contributes, as demonstrated using selective agonists, the mGluR4 PAM PHCCC, and mGluR4 KO mice. Whole-cell patch-clamp; presynaptic calcium influx measurements; selective agonists (ACPD, LSP4-2022, DCPG); PHCCC; mGluR4 KO cerebellar slices Journal of neurochemistry High 18266929
2008 mGluR4 and mGluR8 both contribute to L-AP4-induced presynaptic inhibition of synaptic transmission at the lateral olfactory tract–piriform cortex synapse; the inhibitory actions of L-AP4 and selective mGluR4 agonist Z-cyclopentyl-AP4 are potentiated by the mGluR4 PAM PHCCC. Whole-cell patch-clamp recordings from piriform cortex pyramidal cells in brain slices; selective agonists (DCPG for mGluR8; Z-cyclopentyl-AP4 for mGluR4); PHCCC potentiation Neuropharmacology Medium 18625254
2012 Native presynaptic mGluR4 in rat cerebellum interacts with exocytosis proteins including Munc18-1, synapsins, and syntaxin; mGluR4 is retained on Munc18-1-conjugated Sepharose, and Munc18-1 co-localizes with mGluR4 at the plasma membrane. Affinity chromatography with peptides from mGluR4 cytoplasmic domains confirmed interactions with multiple exocytosis proteins. Co-immunoprecipitation from cerebellar extracts (mass spectrometry identification of 183 partners); affinity chromatography with recombinant Munc18-1 and mGluR4 cytoplasmic domain peptides; immunohistochemistry co-localization in HEK293 cells The Journal of biological chemistry High 22528491
2012 mGluR4 and GABAA receptors co-localize on cerebellar parallel fiber axon terminals and co-immunoprecipitate from cerebellar membranes. Coincident activation of both receptors increases glutamate release above that of GABAA activation alone. In mGluR4 KO mice, GABAA receptor subunit expression (α1, α6, β2) and [35S]TBPS binding are reduced in the cerebellum. Immunocytochemistry; co-immunoprecipitation from cerebellar membranes; [3H]glutamate release from cerebellar synaptosomes; [35S]TBPS binding; mGluR4 KO mice Journal of neurochemistry High 22145864
2012 mGluR4 inhibition of presynaptic Ca2+ influx at parallel fiber–Purkinje cell synapses does not selectively target a specific voltage-gated Ca2+ channel subtype but modulates all classes present; this inhibition does not involve GIRK channels, TEA-sensitive K+ channels, K2P channels, pertussis toxin-sensitive G proteins, adenylyl cyclase, PKA, MAPK, or PI3K. Instead, it employs a signaling pathway involving phospholipase C (PLC) activation and ultimately protein kinase C. Whole-cell patch-clamp recordings in rat cerebellar slices; presynaptic Ca2+ transient measurements; pharmacological dissection with selective channel/kinase/G-protein inhibitors; pertussis toxin treatment The Journal of physiology High 22570379
2012 Co-activation of Gq-coupled H1 histamine receptors induces substantial calcium mobilization downstream of mGluR4 activation in mGluR4-expressing cells, biasing signaling away from Gi/o-mediated cAMP inhibition toward calcium-dependent pathways. This functional selectivity is further enhanced by mGluR4 PAMs. Calcium mobilization assay in mGluR4-expressing cells; cAMP inhibition assay; pharmacological application of histamine and mGluR4 PAMs; absence of chimeric G proteins confirmed Neuropharmacology Medium 22426233
2013 Activation of mGluR4 in rat neural progenitor cells promotes proliferation via ERK1/2 signaling and upregulation of cyclin D1; mGluR4 siRNA decreases proliferation and p-ERK1/2 levels, and ERK1/2 inhibitor U0126 abolishes the VU0155041-induced proliferative effect. mGluR4 activation also decreases p38 phosphorylation. Rat embryonic NPC culture; mGluR4 siRNA knockdown; VU0155041 agonist treatment; Western blot for p-ERK1/2, p-p38, cyclin D1; neurosphere diameter measurement; U0126 ERK inhibitor epistasis Cellular and molecular biology Medium 23374450
2014 mGluR4 is endogenously activated during simulated cerebellar ischemia (excitotoxic conditions with elevated extracellular glutamate) in rodent cerebellar cortex brain slices; the photoswitchable NAM OptoGluNAM4.1 reversibly inhibits mGluR4 activity in a light-dependent manner, providing direct evidence for endogenous receptor activation under these conditions. OptoGluNAM4.1 photopharmacology in rodent cerebellar slices; parallel fiber–Purkinje cell synaptic recordings; simulated ischemia protocol Frontiers in cellular neuroscience Medium 30542267
2016 mGluR4 presynaptically modulates corticostriatal transmission; immunoelectron microscopy shows >80% mGluR4-immunoreactive structures are unmyelinated axons/terminals in mouse striatum, ~50% of putative glutamatergic terminals (vGluT1+) express mGluR4, and ~70% of mGluR4-positive glutamatergic terminals target D1-receptor-negative (putative indirect pathway) spines, providing anatomical basis for antiparkinsonian actions. Immunoelectron microscopy; dual immunolabeling for mGluR4, vGluT1, and D1 receptor in mouse striatum; quantitative ultrastructural analysis Brain structure & function High 26832920
2019 GRM4 is expressed in myeloid cells and selectively regulates IL23 (and the related cytokine IL12) expression; Grm4 gene-targeted mice show accelerated radiation-induced tumor development. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion while suppressing Il12. GRM4 agonists suppressed osteosarcoma growth in mice. Grm4 gene-targeted mouse model; radiation-induced osteosarcoma; cytokine expression assays; osteosarcoma-conditioned media experiments; in vivo GRM4 agonist treatment Cancer discovery High 31527131
2019 GRM4 overexpression in osteosarcoma cells inhibits proliferation, migration, and invasion by interacting with CBX4 and restricting CBX4 nuclear localization, thereby reducing HIF-1α transcriptional activity. GRM4 overexpression in osteosarcoma cell lines; co-immunoprecipitation of GRM4 and CBX4; nuclear fractionation; colony formation, transwell migration/invasion assays; HIF-1α reporter assay Bioscience, biotechnology, and biochemistry Medium 31581881
2021 cryo-EM structures of human mGlu4 bound to heterotrimeric Gi protein reveal a G-protein-binding site formed by three intracellular loops and helices III and IV; an asymmetric dimer interface of the transmembrane domain is critical for receptor activation and asymmetric signal transduction, with only one subunit of the homodimer coupling to G protein. Cryo-electron microscopy structure determination of mGlu4-Gi complex; functional validation of asymmetric dimerization Nature High 34135510
2023 Twelve cryo-EM structures of the mGlu2-mGlu4 heterodimer in inactive, intermediate, and active conformational states reveal that Venus flytrap domains undergo sequential conformational change upon activation, while transmembrane domains rearrange from symmetric inactive to asymmetric active dimer. A novel binding site for mGlu4 PAMs was identified at the asymmetric dimer interface of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer. Cryo-electron microscopy of mGlu2-mGlu4 heterodimer in multiple states; functional data validating asymmetric signal transduction and PAM binding site Cell research High 37286794

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 128 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 69 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 63 10559233
2015 MiR-335 is involved in major depression disorder and antidepressant treatment through targeting GRM4. Neuroscience letters 61 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
2023 Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. Cell research 50 37286794
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
2007 Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology 46 18022649
2012 Measures of anxiety, sensorimotor function, and memory in male and female mGluR4⁻/⁻ mice. Behavioural brain research 45 22227508
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 40 31527131
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 38 27075300
2012 Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor. Neuropharmacology 38 22634361
2008 Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators. Bioorganic & medicinal chemistry letters 37 18793851
2012 Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders. Expert opinion on drug discovery 34 22468956
2010 An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorganic & medicinal chemistry letters 34 20638279
1995 The metabotropic glutamate receptor mGluR4, but not mGluR1 alpha, is palmitoylated when expressed in BHK cells. Journal of neurochemistry 33 7891082
2012 Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature. Expert opinion on therapeutic patents 32 22506633
2008 Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead. Bioorganic & medicinal chemistry letters 31 19097893
1999 Extended glutamate activates metabotropic receptor types 1, 2 and 4: selective features at mGluR4 binding site. Neuropharmacology 31 10530816
2012 Role of mGluR4 in acquisition of fear learning and memory. Neuropharmacology 30 22884897
2009 Recent progress in the development of mGluR4 positive allosteric modulators for the treatment of Parkinson's disease. Current topics in medicinal chemistry 28 19754407
2008 Depression of excitatory transmission at PF-PC synapse by group III metabotropic glutamate receptors is provided exclusively by mGluR4 in the rodent cerebellar cortex. Journal of neurochemistry 28 18266929
2015 A novel mGlu4 selective agonist LSP4-2022 increases behavioral despair in mouse models of antidepressant action. Neuropharmacology 27 26074092
2009 Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4). Bioorganic & medicinal chemistry letters 27 19640716
2007 mGlu4 potentiation of K(2P)2.1 is dependant on C-terminal dephosphorylation. Molecular and cellular neurosciences 27 17916432
2016 Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022. Current neuropharmacology 26 26769224
2007 Citalopram influences mGlu7, but not mGlu4 receptors' expression in the rat brain hippocampus and cortex. Brain research 26 17976546
2006 Context-dependent regulation of embryonic stem cell differentiation by mGlu4 metabotropic glutamate receptors. Neuropharmacology 24 16806298
2005 Targeting the metabotropic glutamate receptor mGluR4 for the treatment of diseases of the central nervous system. Current topics in medicinal chemistry 24 16178733
1999 Contribution of metabotropic glutamate receptor mGluR4 to L-2-[3H]amino-4-phosphonobutyrate binding in mouse brain. Journal of neurochemistry 24 9930760
2016 Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4 receptor agonist LSP4-2022. Neuropharmacology 23 27465045
2016 A genetic variant in miRNA binding site of glutamate receptor 4, metabotropic (GRM4) is associated with increased risk of major depressive disorder. Journal of affective disorders 22 27792966
2011 Behavioral responses to glutamate receptor agonists and antagonists implicate the involvement of brain-expressed mGluR4 and mGluR1 in taste transduction for umami in mice. Physiology & behavior 22 22008743
1997 Localization of mGluR4 protein in the rat cerebral cortex and hippocampus. Neuroreport 22 9351670
2018 Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents. Psychopharmacology 20 30054675
2008 Metabotropic glutamate receptors mGluR4 and mGluR8 regulate transmission in the lateral olfactory tract-piriform cortex synapse. Neuropharmacology 19 18625254
2018 Discovery, Structure-Activity Relationship, and Biological Characterization of a Novel Series of 6-((1 H-Pyrazolo[4,3- b]pyridin-3-yl)amino)-benzo[ d]isothiazole-3-carboxamides as Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 4 (mGlu4). Journal of medicinal chemistry 18 30247901
2017 Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity. Neuropharmacology 18 28487067
2019 Effects of GRM4, SCN2A and SCN3B polymorphisms on antiepileptic drugs responsiveness and epilepsy susceptibility. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 17 31297029
2014 Distinct effects of mGlu4 receptor positive allosteric modulators at corticostriatal vs. striatopallidal synapses may differentially contribute to their antiparkinsonian action. Neuropharmacology 17 24866785
2014 Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4). Journal of medicinal chemistry 17 25330258
2020 A case study of foliglurax, the first clinical mGluR4 PAM for symptomatic treatment of Parkinson's disease: translational gaps or a failing industry innovation model? Expert opinion on investigational drugs 16 33074728
2020 Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure in male mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 16 33349673
2014 Lu AF21934, a positive allosteric modulator of mGlu4 receptors, reduces the harmaline-induced hyperactivity but not tremor in rats. Neuropharmacology 16 24726309
2013 Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4). Bioorganic & medicinal chemistry 16 23978356
2012 Native presynaptic metabotropic glutamate receptor 4 (mGluR4) interacts with exocytosis proteins in rat cerebellum. The Journal of biological chemistry 16 22528491
2010 Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis. Epilepsy research 16 20338729
2001 Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia. Psychiatric genetics 16 11525421
2019 GRM4 inhibits the proliferation, migration, and invasion of human osteosarcoma cells through interaction with CBX4. Bioscience, biotechnology, and biochemistry 14 31581881
2016 mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice. Brain structure & function 14 26832920
2013 Related functions of mGlu4 and mGlu8. Pharmacology, biochemistry, and behavior 14 23948069
2011 Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator. Bioorganic & medicinal chemistry letters 14 22030026
2003 Changes of mGluR4 and the effects of its specific agonist L-AP4 in a rodent model of diffuse brain injury. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 14 14592619
2001 Localization of the human mGluR4 gene within an epilepsy susceptibility locus(1). Brain research. Molecular brain research 13 11223165
2015 Association of GRM4 gene polymorphisms with susceptibility and clinicopathological characteristics of osteosarcoma in Guangxi Chinese population. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 26276359
2012 Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of Gq coupled receptors. Neuropharmacology 12 22426233
2020 Regulation of the parental gene GRM4 by circGrm4 RNA transcript and glutamate-mediated neurovascular toxicity in eyes. Molecular and cellular biochemistry 11 33074445
2018 A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex. Frontiers in cellular neuroscience 11 30542267
2014 Chemical biology of mGlu4 receptor activation: dogmas, challenges, strategies and opportunities. Current topics in medicinal chemistry 11 25183417
2012 A new signalling pathway for parallel fibre presynaptic type 4 metabotropic glutamate receptors (mGluR4) in the rat cerebellar cortex. The Journal of physiology 11 22570379
2010 mGluR4 positive allosteric modulators with potential for the treatment of Parkinson's disease: WO09010455. Expert opinion on therapeutic patents 11 20180624
2003 Candidate gene analysis of the human metabotropic glutamate receptor type 4 (GRM4) in patients with juvenile myoclonic epilepsy. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 11 14582146
2019 Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates. Molecular imaging and biology 10 30066121
2022 Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain. Pharmacological research 9 36529205
2014 Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats. Pharmacological reports : PR 9 24911071
2012 Modulation of glutamate release from parallel fibers by mGlu4 and pre-synaptic GABA(A) receptors. Journal of neurochemistry 9 22145864
2008 The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors. European journal of pharmacology 9 18593581
2013 Activation of mGluR4 promotes proliferation of rat neural progenitor cells while mediating activation of ERK1/2 signaling pathway. Cellular and molecular biology (Noisy-le-Grand, France) 8 23374450
2021 The role of mGlu4 receptors within the nucleus accumbens in acquisition and expression of morphine-induced conditioned place preference in male rats. BMC neuroscience 7 33743609
2018 To Explore the Mechanism of the GRM4 Gene in Osteosarcoma by RNA Sequencing and Bioinformatics Approach. Medical science monitor basic research 7 29339716
2018 The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate. Bioorganic & medicinal chemistry letters 7 30503632
2015 Co-operative binding assay for the characterization of mGlu4 allosteric modulators. Neuropharmacology 7 26025660
2015 Radiosynthesis and evaluation of 5-methyl-N-(4-[(11)C]methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine ([(11)C]ADX88178) as a novel radioligand for imaging of metabotropic glutamate receptor subtype 4 (mGluR4). Bioorganic & medicinal chemistry letters 7 26707390
2023 The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome. Molecular autism 6 37029391

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