Affinage

GRID2

Glutamate receptor ionotropic, delta-2 · UniProt O43424

Audit flag: wrong gene
Length
1007 aa
Mass
113.4 kDa
Annotated
2026-04-28
79 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRID2 encodes the GluD2 ionotropic glutamate receptor, an essential organizer of parallel fiber–Purkinje cell synapses in the cerebellum that couples trans-synaptic adhesion, ion channel function, and synaptic plasticity through structurally separable domains. The N-terminal domain binds Cbln1 via a flap-loop motif (Arg321/Trp323), nucleating the neurexin–Cbln1–GluD2 trans-synaptic complex that drives presynaptic differentiation, synaptic vesicle accumulation, Purkinje cell dendritic elaboration, and competitive synaptotrophic wiring (PMID:19420242, PMID:20599760, PMID:23141067, PMID:33352118). GluD2 also functions as a bona fide ion channel gated indirectly by mGlu1 receptor activation through the Gαq–PLC–PKC cascade, with D-serine occupying the orthosteric ligand-binding domain whose hinge region tunes binding affinity, while its C-terminal domain independently mediates cerebellar long-term depression (PMID:23564161, PMID:24357660, PMID:27276689, PMID:26661043, PMID:28387240, PMID:33112237). Gain-of-function Lurcher mutations in TM3 render the channel constitutively open, and in the absence of wild-type GluD2 the constitutively active receptor triggers Purkinje cell death through a depolarization-independent GluD2–nPIST–Beclin1 autophagy pathway (PMID:10414327, PMID:12628171, PMID:37944084).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Whether GluD2 had any essential role was unknown; knockout revealed it is required for motor coordination, parallel fiber–Purkinje cell synaptogenesis, and cerebellar LTD, establishing it as a multifunctional cerebellar receptor.

    Evidence Gene-targeted KO mouse with behavioral, electrophysiological, and histological phenotyping

    PMID:7736576

    Open questions at the time
    • Mechanism by which GluD2 mediates synaptogenesis vs. LTD remained unresolved
    • No ligand or channel activity identified
  2. 1999 High

    Whether GluD2 could function as an ion channel was debated; the Lurcher mutation (Ala→Thr in TM3) was shown to generate constitutive inward currents in oocytes, proving GluD2 possesses a functional channel pore.

    Evidence Sequencing of Lurcher allele; electrophysiology in Lc/+ Purkinje cells; reconstitution in Xenopus oocytes

    PMID:10414327

    Open questions at the time
    • Physiological stimulus for wild-type GluD2 channel opening unknown
    • Endogenous ligand unidentified
  3. 2003 High

    The mechanism of Lurcher-induced Purkinje cell death was assumed to be depolarization; genetic epistasis dissociated cell death from depolarization and identified a GluD2–nPIST–Beclin1 autophagy-dependent death pathway.

    Evidence Lurcher/hotfoot heteroallelic mutants; histological and autophagy marker analysis

    PMID:12628171

    Open questions at the time
    • Whether this autophagy pathway operates during normal GluD2 signaling is unclear
    • Upstream triggers of nPIST–Beclin1 engagement not defined
  4. 2009 High

    It was unclear whether GluD2's synaptogenic and plasticity functions shared the same structural basis; domain dissection showed the NTD is necessary and sufficient for synaptogenesis while the CTD mediates LTD, establishing functional modularity.

    Evidence Sindbis virus-mediated expression of NTD-deletion, chimeric GluD2/GluK2, and full-length constructs in GluD2-null mice in vivo and in heterologous cells

    PMID:19420242

    Open questions at the time
    • NTD binding partner not yet identified at this point
    • CTD signaling cascade for LTD not molecularly resolved
  5. 2010 High

    The specific NTD residues mediating trans-synaptic interaction were unknown; mutagenesis pinpointed the flap loop (Arg321, Trp323) as the critical Cbln1-binding interface required for presynaptic differentiation.

    Evidence Alanine-scanning mutagenesis of flap loop; HEK cell coculture synaptogenesis and Cbln1 binding assays

    PMID:20599760

    Open questions at the time
    • Full stoichiometry and structure of the Cbln1–GluD2 complex not resolved
    • In vivo validation of individual point mutants not performed
  6. 2012 High

    How the Nrxn–Cbln1–GluD2 complex promotes synapse maturation was unknown; live imaging showed Cbln1 drives presynaptic protrusion formation that encapsulates Purkinje cell spines, requiring both postsynaptic GluD2 and presynaptic neurexin.

    Evidence Time-lapse imaging in organotypic culture; ultrastructural analysis; genetic manipulation of Cbln1, GluD2, and Nrx

    PMID:23141067

    Open questions at the time
    • Retrograde signals from GluD2 to presynaptic terminals not identified
    • Whether similar mechanisms operate at extracerebellar GluD2 synapses unknown
  7. 2013 High

    Whether GluD2 affected presynaptic function trans-synaptically was unclear; loss of GluD2 impaired presynaptic R-type Ca²⁺ channel function and blocked presynaptic LTP, and GluD2 deletion disrupted microzonal organization by enabling ectopic climbing fiber synapses and diffuse complex spike synchrony.

    Evidence Paired-pulse ratio measurements and VGCC pharmacology in GluD2-KO mice; in vivo two-photon Ca²⁺ imaging and ultrastructural analysis of CF morphology

    PMID:23564161 PMID:23970854

    Open questions at the time
    • Molecular link between postsynaptic GluD2 and presynaptic R-type channel function unresolved
    • Whether microzonal defects are secondary to synaptogenic failure is unclear
  8. 2013 High

    The physiological trigger for wild-type GluD2 channel opening was unknown; co-expression experiments and Purkinje cell recordings demonstrated that mGlu1 activation opens GluD2 channels, resolving GluD2's identity as an mGlu1-coupled ion channel.

    Evidence Whole-cell voltage-clamp in HEK293 cells co-expressing mGlu1 and GluD2; electrophysiology in Purkinje cells

    PMID:24357660

    Open questions at the time
    • Biochemical mechanism linking mGlu1 signaling to GluD2 pore opening not identified
  9. 2015 High

    The identity of the endogenous ligand occupying the GluD2 LBD was uncertain; structural and biophysical analyses confirmed D-serine binding and revealed that 7-CKA induces distinct intermediate cleft closure, establishing the structural pharmacology of the GluD2 LBD.

    Evidence X-ray crystallography of GluD2-LBD with 7-CKA; ITC for D-serine and 7-CKA binding; electrophysiology on GluD2 Lurcher

    PMID:26661043

    Open questions at the time
    • Whether D-serine binding to the LBD directly gates the channel or triggers non-ionotropic signaling was unresolved
  10. 2016 High

    The intracellular cascade linking mGlu1 to GluD2 channel opening was undefined; pharmacological dissection identified the Gαq–PLC–PKC pathway as the required transduction mechanism in both heterologous cells and native PF–Purkinje cell synapses.

    Evidence Whole-cell voltage-clamp with pharmacological blockade of Gαq, PLC, and PKC in HEK293 cells and Purkinje cells

    PMID:27276689

    Open questions at the time
    • Whether PKC directly phosphorylates GluD2 or acts through an intermediate is unknown
    • Stoichiometry of the mGlu1–GluD2 signaling complex not defined
  11. 2017 High

    How GluD2's low D-serine affinity is achieved structurally was unclear; mutagenesis of the LBD hinge region increased D-serine affinity, revealing the hinge as a tuning element, and structural divergence in Cbln1 vs. Cbln4 loop CD was shown to underlie differential GluD2 binding selectivity.

    Evidence Electrophysiology, ITC, and MD simulations on GluD2 hinge mutants; X-ray crystallography of Cbln1/Cbln4 C1q domains with binding assays

    PMID:28387240 PMID:28877468

    Open questions at the time
    • Physiological consequence of hinge-mediated affinity tuning in vivo not tested
    • Whether mixed Cbln heterohexamers show graded GluD2 affinity unknown
  12. 2020 High

    Multiple advances resolved GluD2's full architecture, channel identity, dendritic wiring role, and LBD energetics: cryo-EM revealed a unique non-swapped ATD–LBD architecture; photoswitchable pore blockers confirmed GluD2 as a bona fide mGlu-gated ion channel; MD simulations showed D-serine-driven LBD closure generates free energy exceeding other iGluRs; and sparse KO demonstrated Cbln1–GluD2-dependent competitive dendritic elaboration.

    Evidence Cryo-EM structure; optopharmacology with engineered cysteine-conjugated photoswitchable blocker in HEK cells and neurons; computational free energy calculations; sparse and global conditional GluD2 KO with Cbln1 epistasis and computational modeling

    PMID:32512155 PMID:32735769 PMID:33112237 PMID:33352118

    Open questions at the time
    • Full-length structure with Cbln1 and neurexin bound not yet resolved
    • LBD closure energetics lack direct experimental force measurements
    • Whether D-serine binding drives ionotropic vs. non-ionotropic signaling remains debated
  13. 2024 High

    Whether human GRID2 variants produce constitutive channel activity and could be pharmacologically targeted was unknown; multiple TM3 variants including the Lurcher equivalent were shown to generate constitutive currents, and pentamidine potently inhibited the GluD2-T649A variant.

    Evidence Electrophysiology and co-IP of human GRID2 variants in vitro; pharmacological inhibition assay

    PMID:37944084

    Open questions at the time
    • In vivo efficacy of pentamidine in GluD2 gain-of-function models not tested
    • Structural basis of pentamidine pore block unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full cryo-EM structure of the ternary Nrxn–Cbln1–GluD2 complex, the direct molecular mechanism by which PKC opens the GluD2 pore, and the physiological significance of D-serine binding at wild-type GluD2 (ionotropic vs. non-ionotropic signaling).
  • No structure of the assembled Nrxn–Cbln1–GluD2 complex
  • PKC phosphorylation site(s) on GluD2 not mapped
  • Relative contributions of ionotropic and non-ionotropic GluD2 signaling to cerebellar LTD undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098631 cell adhesion mediator activity 4 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 4 GO:0043226 organelle 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-1500931 Cell-Cell communication 4 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BECN1CBLN1GOPCGRID1GRM1NRXN1
Complex memberships
Nrxn–Cbln1–GluD2 trans-synaptic complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 GluD2 (GRID2) is required for motor coordination, formation of parallel fiber-Purkinje cell synapses, and cerebellar long-term depression (LTD); knockout mice show severe deficits in all three, establishing GluD2 as essential for these cerebellar functions. Gene targeting/knockout mouse with behavioral, electrophysiological, and histological readouts Cell High 7736576
1999 The Lurcher mutation in GRID2 (Ala-to-Thr in transmembrane domain III) converts the delta2 glutamate receptor into a constitutively open, gain-of-function channel causing massive inward current and Purkinje cell depolarization, leading to apoptotic neurodegeneration. Identification of point mutation by sequencing; electrophysiology in Lc/+ Purkinje cells; Xenopus oocyte expression of mutant GluRdelta2Lc confirming constitutive channel opening Annals of the New York Academy of Sciences High 10414327
2003 Lurcher GRID2-induced Purkinje cell death and depolarization can be dissociated: absence of wild-type GRID2 in Lurcher/hotfoot heteroallelic mutants causes early autophagy-dependent Purkinje cell death independent of depolarization, mediated through the GRID2–n-PIST–Beclin1 signaling pathway. Genetic epistasis using Lurcher/hotfoot heteroallelic mutants; histological and autophagy marker analysis Neuron High 12628171
2009 The extracellular N-terminal domain (NTD) of GluD2 is necessary and sufficient for parallel fiber (PF) synaptogenesis in vivo; a chimeric receptor containing the GluD2 NTD grafted onto GluK2 induces synaptogenesis, while the C-terminal domain mediates LTD, showing the two functions are mechanistically separable. Sindbis virus-mediated in vivo expression of wild-type, NTD-deletion, and chimeric GluD2/GluK2 in GluD2-null mice; in vitro synaptogenesis assay in heterologous cells The Journal of neuroscience High 19420242
2010 The flap loop (Arg321–Trp339) in the N-terminal domain of GluD2 is the critical region for binding Cbln1 and inducing presynaptic differentiation; single alanine substitutions at Arg321 or Trp323 abolish both Cbln1 binding and presynaptic differentiation induction in HEK cells. Mutagenesis of flap loop residues; HEK cell coculture synaptogenesis assay; Cbln1 binding assay Biochemical and biophysical research communications High 20599760
2012 Presynaptically released Cbln1 induces dynamic structural changes in parallel fiber axons through a mechanism requiring postsynaptic GluD2 and presynaptic neurexin (Nrx); Nrx–Cbln1–GluD2 signaling drives PF protrusion formation that encapsulates Purkinje cell spines and leads to synaptic vesicle accumulation and mature synapse formation. Time-lapse imaging in organotypic culture; ultrastructural analysis in vivo; genetic manipulation of Cbln1, GluD2, and Nrx Neuron High 23141067
2013 Type 1 metabotropic glutamate receptor (mGlu1) activation triggers opening of GluD2 ion channels both in heterologous cells co-expressing mGlu1 and GluD2 and endogenously in Purkinje cells, establishing that GluD2 functions as a ligand-gated ion channel activated indirectly through mGlu1. Whole-cell voltage-clamp recordings in HEK293 cells co-transfected with mGlu1 and GluD2; electrophysiology in Purkinje cells EMBO reports High 24357660
2015 D-serine binds the orthosteric (ligand-binding) domain of GluD2; the compound 7-chlorokynurenic acid (7-CKA) also binds the GluD2 LBD and induces intermediate cleft closure distinct from D-serine, as shown by crystal structure of GluD2-LBD bound to 7-CKA and thermodynamic measurements. Pharmacological electrophysiology on GluD2 Lurcher mutant; X-ray crystallography of GluD2-LBD; isothermal titration calorimetry Molecular pharmacology High 26661043
2016 mGlu1-induced GluD2 channel opening is mediated by the canonical Gαq–PLC–PKC signaling pathway; inhibition of PLC or PKC strongly reduces DHPG-evoked GluD2 currents in both HEK293 cells and at native PF–Purkinje cell synapses. Whole-cell voltage-clamp in HEK293 cells co-expressing mGlu1 and GluD2; pharmacological blockade of Gαq, PLC, PKC; Purkinje cell recordings Neuropharmacology High 27276689
2016 GluD2 is required for parallel fiber synapse regeneration after axon transection; in wild-type mice PF synapses regenerate via a hypertrophic phase followed by remodeling, but GluD2-KO mice show neither hypertrophic response nor recovery of PF axons or synapses. PF transection surgery in GluD2-KO vs. wild-type mice; electron microscopy and immunohistochemistry at multiple post-lesion time points The Journal of neuroscience High 27122040
2017 The hinge region of the GluD2 ligand-binding domain is responsible for the low affinity of D-serine; GluD2 hinge mutants show increased D-serine affinity, establishing that the hinge fine-tunes ligand binding and gating responses. Electrophysiology, isothermal titration calorimetry, and molecular dynamics on GluD2 hinge mutants Scientific reports High 28387240
2017 Cbln1 and Cbln4 differ in their GluD2-binding capacity due to structural divergence in loop CD of their C1q domain; crystal structures of Cbln1 and Cbln4 C1q homotrimers reveal the molecular basis for differential GluD2 binding. X-ray crystallography of Cbln1 and Cbln4 C1q domains at 2.2 and 2.3 Å; binding assays; negative-stain electron microscopy Cell reports High 28877468
2019 GluD2 and GluD1 form coimmunoprecipitable complexes with each other in HEK293T cells and in the cerebral cortex and hippocampus; GluD2 is localized to PSD-95-positive glutamatergic synapses in extracerebellar regions including retrosplenial cortex. Co-immunoprecipitation from brain tissue and transfected HEK293T cells; SDS-digested freeze-fracture replica labeling; quantitative immunoblotting The Journal of comparative neurology Medium 31625608
2020 Cryo-EM structure of the rat GluD2 receptor reveals a non-swapped architecture at the ATD–LBD interface, with unique organization and arrangement of ATD and LBD domains distinct from GluD1, elucidating the full-length 3D architecture in the presence of calcium and 7-chlorokynurenic acid. Cryo-electron microscopy structural determination Journal of structural biology High 32512155
2020 D-serine binding drives substantial ligand-binding domain (LBD) closure in GluD2 with free energy greater than that for AMPA, NMDA, or kainate receptor LBD closure upon agonist binding, indicating GluD2 LBD closure produces sufficient mechanical force for non-ionotropic signaling rather than pore opening. Computational free energy landscape calculations (molecular dynamics) for GluD2-LBD in apo and D-serine-bound states; comparison with other iGluR subtypes Structure Medium 32735769
2020 GluD2 functions as an ion channel triggered by metabotropic glutamate receptor signaling; using a cysteine mutation above the channel pore conjugated to a photoswitchable blocker, light-reversible current block was demonstrated in constitutively open Lurcher GluD2 and in native GluD2 upon mGlu receptor activation. Chemo-genetic optopharmacology (photoswitchable pore blocker); whole-cell patch-clamp in HEK cells and neurons eLife High 33112237
2020 Sparse knockout of GluD2 causes Purkinje cell dendritic under-elaboration in deep molecular layer and over-elaboration in superficial molecular layer; genetic epistasis and overexpression analyses indicate these defects arise from loss of Cbln1/GluD2-dependent competitive interactions during dendrite development, supporting the synaptotrophic hypothesis. Sparse vs. global conditional GluD2 KO; genetic epistasis with Cbln1; overexpression and structure-function analysis; generative computational model Neuron High 33352118
2013 Deletion of postsynaptic GluD2 impairs presynaptic R-type Ca2+ channel function and reduces glutamate release at PF-Purkinje cell synapses, and prevents presynaptic long-term potentiation (LTP); this trans-synaptic effect is mediated through GluD2's role in presynaptic differentiation via neurexin interaction. Paired-pulse ratio measurements in GluD2-KO mice; pharmacological blockade of specific VGCC subtypes; presynaptic LTP induction protocol Cerebellum Medium 23564161
2013 Loss of GluD2 disrupts cerebellar microzonal organization: GluD2-KO mice show exuberant climbing fiber collaterals that cross microzone boundaries, forming ectopic synapses on distal Purkinje cell dendrites, and this leads to enhanced and spatially diffuse synchrony of complex spike activity across neighboring Purkinje cells. In vivo two-photon calcium imaging of Purkinje cell populations; electron microscopy and immunohistochemistry of CF axonal morphology in GluD2-KO mice Frontiers in neural circuits High 23970854
2024 GRID2 M3 transmembrane domain variants (including GluD2-A654T lurcher and GluD2-T649A) create constitutively active receptors; pentamidine potently inhibits GluD2-T649A constitutive currents (IC50 50 nM); a GRID1 variant disrupts complex formation with Cbln2, perturbing synapse organization. Electrophysiology (constitutive current measurement) and biochemical co-immunoprecipitation assays of GluD2 human variants expressed in vitro; pharmacological inhibition assay Human molecular genetics High 37944084

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Impairment of motor coordination, Purkinje cell synapse formation, and cerebellar long-term depression in GluR delta 2 mutant mice. Cell 482 7736576
2014 Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proceedings of the National Academy of Sciences of the United States of America 90 25225364
2013 Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology 81 24078737
2000 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human glutamate dehydrogenases are regulated by distinct allosteric mechanisms: implications for biologic function. Journal of neurochemistry 79 11032875
2013 Type 1 metabotropic glutamate receptors (mGlu1) trigger the gating of GluD2 delta glutamate receptors. EMBO reports 66 24357660
2003 Lurcher GRID2-induced death and depolarization can be dissociated in cerebellar Purkinje cells. Neuron 66 12628171
2015 GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. Neurology 64 25841024
2013 A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy. Journal of child neurology 62 23611888
2010 Human GLUD2 glutamate dehydrogenase is expressed in neural and testicular supporting cells. The Journal of biological chemistry 58 20194501
2009 The N-terminal domain of GluD2 (GluRdelta2) recruits presynaptic terminals and regulates synaptogenesis in the cerebellum in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 19420242
2003 Study of structure-function relationships in human glutamate dehydrogenases reveals novel molecular mechanisms for the regulation of the nerve tissue-specific (GLUD2) isoenzyme. Neurochemistry international 56 12742085
2011 The human GLUD2 glutamate dehydrogenase and its regulation in health and disease. Neurochemistry international 48 21420458
2012 Presynaptically released Cbln1 induces dynamic axonal structural changes by interacting with GluD2 during cerebellar synapse formation. Neuron 47 23141067
2009 Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mitochondria and endoplasmic reticulum. Biochemistry and cell biology = Biochimie et biologie cellulaire 47 19448744
2009 Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset. European journal of human genetics : EJHG 44 19826450
2020 GluD2- and Cbln1-mediated competitive interactions shape the dendritic arbors of cerebellar Purkinje cells. Neuron 37 33352118
2019 Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain. The Journal of comparative neurology 37 31625608
2012 Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. Neural networks : the official journal of the International Neural Network Society 37 22840919
2013 The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease. Neurochemical research 36 24352816
2014 Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion. Genetics in medicine : official journal of the American College of Medical Genetics 35 25122145
2012 Expression of human GLUD2 glutamate dehydrogenase in human tissues: functional implications. Neurochemistry international 33 22709674
2016 Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development. Proceedings of the National Academy of Sciences of the United States of America 30 27118840
2013 De novo partial deletion in GRID2 presenting with complicated spastic paraplegia. Muscle & nerve 30 24122788
2009 The human GLUD2 glutamate dehydrogenase: localization and functional aspects. Neurochemistry international 30 19428807
2020 The architecture of GluD2 ionotropic delta glutamate receptor elucidated by cryo-EM. Journal of structural biology 27 32512155
2016 GluD2 Endows Parallel Fiber-Purkinje Cell Synapses with a High Regenerative Capacity. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 27122040
2012 The complex regulation of human glud1 and glud2 glutamate dehydrogenases and its implications in nerve tissue biology. Neurochemistry international 27 22658952
2016 mGlu1 receptor canonical signaling pathway contributes to the opening of the orphan GluD2 receptor. Neuropharmacology 26 27276689
2018 Mitochondrial enzyme GLUD2 plays a critical role in glioblastoma progression. EBioMedicine 25 30314897
2015 Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors. Molecular pharmacology 25 26661043
2017 Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features. BMC medical genetics 24 29207948
2007 Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase. Journal of neuroscience research 22 17253646
2015 Expression of human GLUD1 and GLUD2 glutamate dehydrogenases in steroid producing tissues. Molecular and cellular endocrinology 21 26241911
2007 Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase. Journal of neuroscience research 21 17924438
2020 Probing the ionotropic activity of glutamate GluD2 receptor in HEK cells with genetically-engineered photopharmacology. eLife 20 33112237
2008 Discrimination learning in Rora(sg) and Grid2(ho) mutant mice. Neurobiology of learning and memory 20 18583162
1998 The human glutamate receptor delta 2 gene (GRID2) maps to chromosome 4q22. Genomics 20 9465309
2020 Functional validation of a human GLUD2 variant in a murine model of Parkinson's disease. Cell death & disease 19 33093440
2016 Widening Spectrum of Cellular and Subcellular Expression of Human GLUD1 and GLUD2 Glutamate Dehydrogenases Suggests Novel Functions. Neurochemical research 19 27422263
2013 Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse. Frontiers in neural circuits 19 23970854
2003 Motor coordination in mice with hotfoot, Lurcher, and double mutations of the Grid2 gene encoding the delta-2 excitatory amino acid receptor. Physiology & behavior 19 14637233
2017 Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions. Cell reports 17 28877468
1998 Evaluation of two X chromosomal candidate genes for Rett syndrome: glutamate dehydrogenase-2 (GLUD2) and rab GDP-dissociation inhibitor (GDI1). American journal of medical genetics 17 9674910
2020 D-Serine Potently Drives Ligand-Binding Domain Closure in the Ionotropic Glutamate Receptor GluD2. Structure (London, England : 1993) 16 32735769
2017 The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region. Scientific reports 16 28387240
2015 Evolution of GLUD2 Glutamate Dehydrogenase Allows Expression in Human Cortical Neurons. Molecular neurobiology 16 26399640
2014 The effect of genetic background on behavioral manifestation of Grid2(Lc) mutation. Behavioural brain research 16 24937052
2021 Role of Glutamine-Glutamate/GABA cycle and potential target GLUD2 in alleviation of rheumatoid arthritis by Tripterygium hypoglaucum (levl.) Hutch based on metabolomics and molecular pharmacology. Journal of ethnopharmacology 14 34454056
2016 Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism. Neuroscience letters 14 27019035
2022 Differences between the GluD1 and GluD2 receptors revealed by GluD1 X-ray crystallography, binding studies and molecular dynamics. The FEBS journal 13 36128700
1999 GluR delta 2 and the development and death of cerebellar Purkinje neurons in lurcher mice. Annals of the New York Academy of Sciences 13 10414327
2024 Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants. Human molecular genetics 12 37944084
2020 Autosomal recessive spinocerebellar ataxia 18 caused by homozygous exon 14 duplication in GRID2 and review of the literature. Acta neurologica Belgica 12 32170608
2017 A Rare Syndrome of GRID2 Deletion in 2 Siblings. Child neurology open 12 28856174
2012 Alpha helical structures in the leader sequence of human GLUD2 glutamate dehydrogenase responsible for mitochondrial import. Neurochemistry international 12 22709669
2019 Further delineation of the phenotype caused by a novel large homozygous deletion of GRID2 gene in an adult patient. Clinical case reports 11 31183084
2014 GRID2 a novel gene possibly associated with mevalonate kinase deficiency. Rheumatology international 11 25146332
2013 Contribution of postsynaptic GluD2 to presynaptic R-type Ca(2+) channel function, glutamate release and long-term potentiation at parallel fiber to Purkinje cell synapses. Cerebellum (London, England) 11 23564161
2009 Mutations in human GLUD2 glutamate dehydrogenase affecting basal activity and regulation. Journal of neurochemistry 11 19393024
2005 Two reciprocal translocations provide new clues to the high mutability of the Grid2 locus. Mammalian genome : official journal of the International Mammalian Genome Society 10 15674731
2018 Transgenic Mice Carrying GLUD2 as a Tool for Studying the Expressional and the Functional Adaptation of this Positive Selected Gene in Human Brain Evolution. Neurochemical research 9 29777493
2014 Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. Genes 8 25513882
2018 Evidence for generative homology of cerebellum and cerebellum-like structures in an elasmobranch fish based on Pax6, Cbln1 and Grid2 expression. The Journal of comparative neurology 7 29888788
2010 Flap loop of GluD2 binds to Cbln1 and induces presynaptic differentiation. Biochemical and biophysical research communications 7 20599760
2024 Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition. International journal of molecular sciences 6 38791334
2020 Absence of GluD2 Antibodies in Patients With Opsoclonus-Myoclonus Syndrome. Neurology 6 33443132
2012 The ins and outs of GluD2--why and how Purkinje cells use the special glutamate receptor. Cerebellum (London, England) 6 22113500
2022 A heterozygous GRID2 mutation in autosomal dominant cerebellar ataxia. Human genome variation 5 35882834
2020 A case of severe autosomal recessive spinocerebellar ataxia type 18 with a novel nonsense variant in GRID2. European journal of medical genetics 5 32622959
2022 GRID2 aberration leads to disturbance in neuroactive ligand-receptor interactions via changes to the species richness and composition of gut microbes. Biochemical and biophysical research communications 4 36162328
2020 GRID2 Mutation-Related Spinocerebellar Ataxia Type 18: A New Report and Literature Review. Journal of pediatric genetics 4 35769960
2016 Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber-Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex. Biological trace element research 4 27033232
2019 Transgenic expression of the positive selected human GLUD2 gene improves in vivo glucose homeostasis by regulating basic insulin secretion. Metabolism: clinical and experimental 3 31400387
2004 [Fine mapping of Smith-Fineman-Myers syndrome and exclusion of GPC3, GPCR2 MST4 and GLUD2 as candidate genes]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 15192816
2024 De Novo GRID2 Variant as a Cause of Ataxia with Oculomotor Apraxia and Alpha-Fetoprotein Elevation. Cerebellum (London, England) 1 39312122
2016 Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice. PloS one 1 27820843
2025 Integrated ATAC-seq and RNA-seq analysis identifies Grid2 and Reln as potential regulatory genes in migraine pathophysiology. The journal of headache and pain 0 41327020
2025 Peripheral GRID2 DNA methylation as a diagnostic biomarker for adolescent depression: Linking self-compassion to glutamatergic epigenetic changes. Journal of affective disorders 0 41371357
2023 Structural insights into the ligand binding domain of GluD1 and GluD2 receptors. The FEBS journal 0 37345272