Affinage

GRIN2B

Glutamate receptor ionotropic, NMDA 2B · UniProt Q13224

Length
1484 aa
Mass
166.4 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 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

GRIN2B encodes GluN2B, the glutamate-binding regulatory subunit of NMDA-type glutamate receptors that assemble as GluN1/GluN2B diheteromers and GluN1/GluN2A/GluN2B triheteromers, the latter exhibiting distinct deactivation kinetics and pharmacology (ifenprodil, Zn2+) from either diheteromer (PMID:24607230), with GluN2A and GluN2B receptors using divergent long-distance allosteric coupling between N-terminal domains and the channel pore (PMID:34354080). The GluN2B C-terminal tail is a signaling and trafficking hub: it directly binds αCaMKII, an interaction that drives CaMKII synaptic accumulation, Thr286 autophosphorylation, GluR1 phosphorylation, ERK1/2 signaling, spine growth, hippocampal LTP, basal synaptic strength, and spatial learning, and additionally generates Ca2+-independent autonomous CaMKII activity required for an intermediary LTP phase (PMID:18077696, PMID:22855824, PMID:27246855, PMID:39395168). DAPK1 competes with CaMKII for the same C-terminal region; calcineurin-dependent DAPK1 activation displaces CaMKII during LTD, while DAPK1 recruited to extrasynaptic GluN2B phosphorylates Ser-1303 to enhance channel conductance and drive excitotoxic Ca2+ influx in ischemia, chronic stress, and depression-related signaling (PMID:20141836, PMID:28614711, PMID:28439098, PMID:28456939). Phosphorylation toggles control receptor localization: CaMKII couples GluN2B to CK2 to phosphorylate S1480 and retain receptors extrasynaptically, PP1 dephosphorylates S1480 to promote synaptic recruitment, and Src/Fyn-mediated Tyr-1472 phosphorylation (downstream of m1-Gαq-PKC-PYK2 and leptin receptor signaling) controls surface expression, anxiety behavior, fear memory, and synaptogenesis (PMID:23478024, PMID:31291571, PMID:20660101, PMID:31840160, PMID:25114227), while SHP2 dephosphorylates Tyr-1252 to govern Nck2 binding and receptor function (PMID:30089263). GluN2B levels are further set by degradation via the E3 ligase HECTD4 and TMEM25-driven lysosomal turnover, and by anchoring of the synaptic proteasome that controls AMPA receptor endocytosis (PMID:26041915, PMID:31424425, PMID:36527595). GRIN2B transcription is regulated by the PKA-dependent CASK–Tbr-1–CINAP complex and by activity-dependent DNA methylation/MeCP2 binding (PMID:20067577, PMID:19275891, PMID:18952054). GluN2B-containing receptors mediate distinct cellular roles including somatosensory map refinement, extinction-memory destabilization, and responses to drugs of abuse, and a truncating ASD-associated mutation abolishes surface trafficking and Ca2+ influx and disrupts dendritic morphology (PMID:31548203, PMID:33420399, PMID:27976681, PMID:25164652).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    Establishing the chromosomal location of the human gene encoding the NMDAR2B subunit provided the genomic foundation for studying GRIN2B in human disease.

    Evidence FISH and somatic cell hybrid mapping to 12p12

    PMID:7959773

    Open questions at the time
    • No functional or regulatory information
    • Does not address protein function or interactions
  2. 2007 High

    Defining the requirement of direct CaMKII binding to the GluN2B C-terminal tail answered how NMDAR activation is transduced into synaptic plasticity and memory.

    Evidence Transgenic CaMKII-sequestering GluN2B fragment with LTP and Morris water maze readouts; co-expression Ca2+ imaging with PSD-95

    PMID:17506933 PMID:18077696

    Open questions at the time
    • Did not resolve the temporal phases of CaMKII-dependent LTP
    • Competition with other C-tail binders not yet addressed
  3. 2010 High

    Identifying DAPK1 as a direct GluN2B partner that phosphorylates Ser-1303 at extrasynaptic sites revealed the molecular route from receptor to excitotoxic Ca2+ influx in stroke.

    Evidence Co-IP, in vitro kinase assay, DAPK1 KO mice, competing peptide in a stroke model

    PMID:20141836

    Open questions at the time
    • Did not yet establish DAPK1/CaMKII mutual exclusivity
    • Synaptic vs extrasynaptic substrate selectivity mechanism unresolved
  4. 2010 High

    Linking Src/Fyn-dependent Tyr-1472 phosphorylation to GluN2B surface expression connected tyrosine signaling to anxiety and fear-related behaviors.

    Evidence Y1472F knock-in mice, Tat-Src inhibitory peptide, surface biotinylation, LTP and behavioral assays in amygdala

    PMID:20660101 PMID:21118530

    Open questions at the time
    • Upstream kinase activation signals not fully mapped
    • Phosphatase counteracting Y1472 not identified here
  5. 2013 High

    Showing that activated CaMKII recruits CK2 to phosphorylate S1480 explained how a plasticity signal controls synaptic versus extrasynaptic receptor distribution.

    Evidence Co-IP, phospho-site mutagenesis, surface biotinylation, imaging

    PMID:23478024

    Open questions at the time
    • Phosphatase reversing S1480 not yet identified
    • In vivo relevance of the trimolecular complex untested
  6. 2014 High

    Engineered triheteromeric receptors and subunit-localization studies resolved that GluN2B confers distinct kinetics, pharmacology, and developmental/circuit roles separable from GluN2A and GluN2D.

    Evidence Forced triheteromer surface expression with electrophysiology/pharmacology; GluN2B+/- and GluN2D-/- mice with immuno-EM and critical-period assays; cholinergic m1-PKC-PYK2-Src pathway dissection

    PMID:24607230 PMID:25114227 PMID:25164652

    Open questions at the time
    • Native triheteromer stoichiometry in vivo not quantified
    • Structural basis of altered ifenprodil site not yet resolved
  7. 2015 High

    Mapping a transmembrane determinant (F637) of ethanol and gating, plus a proteasome-anchoring role, expanded GluN2B function beyond ligand binding into channel pharmacology and protein turnover at synapses.

    Evidence F637 mutagenesis with two-electrode voltage clamp; GluN2B-/- neurons with PSD proteomics and proteasome activator rescue; PKC-Tyr1472 pain model

    PMID:26041915 PMID:26051400 PMID:26515544

    Open questions at the time
    • F637 ethanol mechanism is structure-function only, no in vivo behavior
    • How GluN2B physically anchors the proteasome unresolved
  8. 2017 High

    Demonstrating DAPK1/CaMKII mutual competition for GluN2B unified bidirectional plasticity, showing the same C-tail site switches between LTP and LTD depending on calcium signaling.

    Evidence Pharmacogenetic GluN2B knock-in mice, LTP/LTD electrophysiology, biochemical competition; D-serine single-molecule and FRET-FLIM trafficking study

    PMID:27246855 PMID:28598327 PMID:28614711

    Open questions at the time
    • Timing of calcineurin-DAPK1 versus Ca2+/CaM signals not fully resolved
    • Coactivator selectivity (D-serine vs glycine) mechanism partial
  9. 2019 High

    Identifying PP1-mediated S1480 dephosphorylation and TMEM25/lysosomal degradation defined the bidirectional control of GluN2B synaptic recruitment and abundance, while an ASD truncation linked trafficking failure to morphological disease phenotypes.

    Evidence Co-IP/phospho-mutant electrophysiology (PP1); Co-IP, lysosomal acidification and epilepsy model (TMEM25); Ca2+ imaging and dendritic morphology of ASD truncation

    PMID:31291571 PMID:31424425 PMID:31548203

    Open questions at the time
    • How global NMDAR activity selectively activates PP1 at S1480 unknown
    • Disease-mutation dominant-negative mechanism on WT receptors not fully defined
  10. 2020 High

    Connecting leptin receptor–Fyn–Tyr1472 signaling and Syt7-driven peripheral glutamate release placed GluN2B activity within metabolic and presynaptic release contexts relevant to synaptogenesis and mood.

    Evidence Co-IP, dominant-negative Fyn, synaptogenesis (leptin); super-resolution imaging, Syt7 KO mice and iPSC rescue (Syt7)

    PMID:31840160 PMID:33229564

    Open questions at the time
    • Spatial organization of the LepRb-GluN2B-Fyn complex unresolved
    • Direct vs indirect Syt7-GluN2B coupling not biochemically defined
  11. 2022 Medium

    Establishing HECTD4-mediated ubiquitination and CK2-driven extrasynaptic mislocalization tied GluN2B degradation and distribution to ischemic injury and Alzheimer's tau pathology.

    Evidence Interactome MS, Co-IP, ubiquitination and Ca2+ imaging in ischemia (HECTD4); human AD brain plus CK2 inhibitor and memantine rescue (CK2)

    PMID:35246269 PMID:36527595

    Open questions at the time
    • HECTD4 ubiquitination sites on GluN2B not mapped
    • Causality between CK2-driven mislocalization and tau accumulation is correlative in human tissue
  12. 2024 High

    Resolving that GluN2B-induced autonomous CaMKII activity is dispensable for LTP induction but required for an intermediary expression phase gave a temporal mechanistic definition to CaMKII-dependent plasticity.

    Evidence Pharmacogenetic and optogenetic (CRY2) CaMKII activation with electrophysiology and biochemistry

    PMID:39395168

    Open questions at the time
    • Downstream effectors of the autonomous activity in the 15-min phase not identified
    • Relation to late-phase consolidation not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the competing C-terminal interactions (CaMKII, DAPK1, CK2, PP1, Src/Fyn, SHP2, HECTD4) are spatially and temporally coordinated into a single integrated decision about GluN2B localization, conductance, and degradation remains unresolved.
  • No unified model of competitive C-tail occupancy in vivo
  • Stoichiometry of native synaptic vs extrasynaptic complexes unknown
  • Quantitative cross-regulation among phospho-sites not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CAMK2ACSNK2A1DAPK1FYNHECTD4PPP1CAPTPN11TMEM25
Complex memberships
CASK-Tbr-1-CINAP transcription complexGluN1/GluN2A/GluN2B triheteromeric NMDA receptorGluN1/GluN2B NMDA receptor

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 DAPK1 directly binds the NMDA receptor GluN2B C-terminal tail (amino acids 1292–1304) and, when constitutively active, phosphorylates GluN2B at Ser-1303, enhancing NR1/NR2B receptor channel conductance. Cerebral ischemia recruits DAPK1 into the GluN2B complex at extrasynaptic sites; genetic deletion of DAPK1 or a competing peptide (NR2B-CT) blocks injurious Ca2+ influx and is neuroprotective in mice. Co-immunoprecipitation, in vitro kinase assay, peptide competition, DAPK1 knockout mice, electrophysiology, stroke model Cell High 20141836
2007 Dopamine D2 receptors (D2R) directly interact with the GluN2B subunit within the postsynaptic density of striatal neurons. Cocaine enhances this D2R–GluN2B complex formation, which disrupts CaMKII association with GluN2B, reduces GluN2B phosphorylation at Ser-1303, and inhibits NMDA receptor-mediated currents in striatal neurons. Co-immunoprecipitation, GST pulldown, electrophysiology, behavioral cocaine model Neuron High 17145509
2013 Activated CaMKII couples GluN2B and casein kinase 2 (CK2) into a trimolecular complex, increasing CK2-mediated phosphorylation of GluN2B at S1480. A GluN2B mutant unable to bind CaMKII shows reduced S1480 phosphorylation and increased surface expression. Disrupting GluN2B/CaMKII binding reduces synapse number but increases synaptic GluN2B content. Co-immunoprecipitation, phospho-site mutagenesis, surface biotinylation, confocal imaging Cell reports High 23478024
2007 CaMKII binding to the GluN2B C-terminal tail is required for CaMKII synaptic accumulation, Thr286 autophosphorylation, GluR1 phosphorylation, hippocampal LTP, and spatial learning. Transgenic expression of a C-terminal GluN2B fragment that sequesters endogenous CaMKII disrupts these interactions and impairs plasticity and memory. Transgenic mouse (ligand-inducible NR2B fragment), immunoprecipitation, electrophysiology (LTP), Morris water maze The Journal of neuroscience High 18077696
2012 Direct interaction between GluN2B and αCaMKII (but not βCaMKII) is required for GluN2B-dependent, long-lasting ERK1/2 phosphorylation following synaptic NMDAR activation. Disrupting this interaction prevents activity-induced increases in synaptic AMPA receptors and spine volume. Co-immunoprecipitation, pharmacological disruption of GluN2B/CaMKII binding, ERK phosphorylation assay, dendritic spine imaging The Journal of neuroscience High 22855824
2017 DAPK1 competes with CaMKII for binding to GluN2B. During LTD, calcineurin-dependent DAPK1 activation blocks CaMKII binding to GluN2B, preventing CaMKII synaptic accumulation. During LTP, Ca2+/CaM inhibits DAPK1/GluN2B binding, allowing CaMKII accumulation. A pharmacogenetic approach confirmed that suppression of CaMKII/GluN2B binding is a DAPK1-specific function required for LTD. Pharmacogenetic approach (GluN2B knock-in mice), electrophysiology (LTP/LTD), biochemical competition assays Cell reports High 28614711
2019 GluN2B S1480 phosphorylation maintains NMDARs at extrasynaptic membranes within a complex containing protein phosphatase 1 (PP1). Global NMDAR activation leads to PP1 activation, which dephosphorylates GluN2B S1480 and promotes increased synaptic NMDAR content. Co-immunoprecipitation, phospho-site mutagenesis, surface biotinylation, electrophysiology Cell reports High 31291571
2016 CaMKII/GluN2B interaction is required not only for LTP induction but also for the maintenance of basal synaptic strength, as shown by pharmacogenetic disruption using a CaMKII-binding-incompetent GluN2B knock-in mouse. Pharmacogenetic mouse (GluN2B CaMKII-binding mutant knock-in), electrophysiology, CaMKII inhibitor tatCN21 The Journal of biological chemistry High 27246855
2024 GluN2B binding to CaMKII directly generates Ca2+-independent autonomous CaMKII activity. This enzymatic activity is dispensable for LTP induction (within 5 min) but required for an intermediary LTP expression phase (within 15 min), providing an objective temporal definition for this LTP phase. Pharmacogenetic approach, electrophysiology, optogenetic CaMKII activation (CRY2 constructs), biochemical assays Cell reports High 39395168
2014 GluN1/GluN2A/GluN2B triheteromeric NMDA receptors have distinct glutamate deactivation kinetics compared with GluN1/GluN2A and GluN1/GluN2B diheteromers, and show unique modulation by ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. The ifenprodil binding site of triheteromers differs kinetically from that of GluN1/GluN2B diheteromers. Engineered forced-expression system for exclusive triheteromeric surface expression, whole-cell electrophysiology, pharmacological profiling Neuron High 24607230
2021 GluN2A and GluN2B receptors utilize distinct long-distance allosteric mechanisms involving different subunit–subunit interfaces and molecular rearrangements between their N-terminal domains (NTDs) and transmembrane channel pore. Functional electrophysiology combined with structural analysis (cryo-EM/X-ray), mutagenesis of subunit interfaces Nature communications High 34354080
2017 DAPK1 interaction with GluN2B at extrasynaptic sites is enhanced by chronic stress (CUS) in the rat prefrontal cortex, increasing GluN2B-mediated NMDA currents and extrasynaptic responses. Uncoupling DAPK1 from GluN2B (via DAPK1 knockdown, pharmacological inhibition, or competing peptide) produces rapid antidepressant-like effects and reverses CUS-induced synaptic deficits. AAV-shRNA knockdown, pharmacological inhibition, competing peptide, electrophysiology, behavioral tests Molecular psychiatry High 28439098
2010 Tyrosine phosphorylation of GluN2B at Tyr-1472 (the major phosphorylation site) negatively regulates anxiety-like behavior and CRF expression in the amygdala. Knock-in mice expressing GluN2B Y1472F (phosphorylation-deficient) show enhanced anxiety and elevated amygdalar CRF expression; CRF receptor antagonism attenuates this enhanced anxiety. Knock-in mice (Y1472F GluN2B), elevated plus-maze, CRF immunoassay, CRF receptor antagonist injection Molecular brain High 21118530
2010 Src tyrosine kinase regulates GluN2B surface expression in amygdala neurons. A cell-permeable Src inhibitory peptide (Tat-Src 40-58) reduces GluN2B tyrosine phosphorylation and surface expression in amygdala neurons, blocks amygdalar LTP, and impairs amygdala-dependent fear conditioning and social recognition memory. Cell-permeable peptide, surface biotinylation, electrophysiology (LTP), fear conditioning behavioral assay Learning & memory High 20660101
2015 GluN2B-containing NMDARs anchor the synaptic proteasome, regulating constitutive AMPA receptor endocytosis. In GluN2B-knockout neurons, synaptic proteasome subunit levels decrease, GluA1-AMPA receptor constitutive endocytosis is reduced, and synaptic AMPA receptor levels increase. Pharmacological enhancement of proteasome activity rescues these phenotypes. GluN2B-/- neuronal cultures, quantitative postsynaptic density proteomics, surface biotinylation, proteasome activator treatment The Journal of neuroscience High 26041915
2018 Noonan syndrome-associated SHP2 dephosphorylates GluN2B at Y1252 (identified as an SHP2 substrate in vitro and in vivo). Phospho-Y1252 binds the actin-regulatory adaptor protein Nck2, and this interaction is required for proper NMDAR function. NS mice show selectively reduced GluN1:GluN2B diheteromer contribution to NMDAR currents. In vitro phosphatase assay, mass spectrometry, Co-immunoprecipitation, electrophysiology, NS knock-in mice Cell reports High 30089263
2015 PKC activation in the arcuate nucleus enhances phosphorylation of GluN2B at Tyr-1472 without altering total GluN2B expression. Intra-ARC injection of the PKC inhibitor chelerythrine reverses CFA-induced upregulation of phospho-GluN2B(Tyr1472) and attenuates inflammatory hyperalgesia. In vivo microinjection, western blotting, in vivo extracellular electrophysiology, inflammatory pain model Scientific reports Medium 26515544
2017 D-serine (but not glycine) alters the membrane dynamics and synaptic content of GluN2B-NMDARs (but not GluN2A-NMDARs) through a process requiring PDZ-binding scaffold partners. D-serine also rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain, detected by FRET-FLIM. Single-molecule tracking, surface biotinylation, FRET-FLIM, electrophysiology, ex vivo and in vitro pharmacology eLife High 28598327
2019 An ASD-associated truncating mutation in GluN2B (within the extracellular loop) abolishes NMDA-dependent Ca2+ influx. Mutant GluN2B co-assembles with GluN1 but is not trafficked to the cell surface or dendrites, and when expressed in developing cortical neurons causes shorter, fewer dendritic branches and dysmorphic filopodial-like structures even on a wild-type background. Calcium imaging, surface biotinylation, immunocytochemistry, dendritic morphology analysis in primary cortical neurons, HEK293 expression Journal of cell science High 31548203
2019 TMEM25 interacts with GluN2B and co-localizes with it in late endosomes. TMEM25 induces lysosomal acidification and accelerates GluN2B degradation. Loss of TMEM25 increases GluN2B levels and neuronal excitability, while TMEM25 overexpression attenuates epileptic seizure phenotypes. Co-immunoprecipitation, confocal co-localization, lysosomal acidification assay, electrophysiology, overexpression/knockdown in mice, epilepsy model The Journal of clinical investigation High 31424425
2020 Leptin receptor (LepRb) forms a complex with GluN2B and Fyn kinase. Leptin stimulates Fyn-dependent phosphorylation of GluN2B at Tyr-1472, increasing surface expression of NR2B-containing NMDARs. Blocking Y1472 phosphorylation (via dominant-negative Fyn or NR2B-Y1472F mutant) prevents leptin-stimulated glutamatergic synaptogenesis in hippocampal neurons. Co-immunoprecipitation, surface biotinylation, phospho-site mutagenesis, synapse morphometry, dominant-negative Fyn Endocrinology High 31840160
2014 Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors converge on the m1 muscarinic receptor–Gαq–PKC–PYK2–Src signaling pathway to selectively enhance GluN2B-NMDAR responses in hippocampal CA1 pyramidal cells. In vivo cholinergic drug exposure occludes in vitro m1 and Src potentiation of NMDAR responses. In vivo drug administration, in vitro electrophysiology (whole-cell patch clamp), pharmacological dissection Proceedings of the National Academy of Sciences of the United States of America High 25114227
2010 PKA phosphorylation of CASK at Thr-724 in the guanylate kinase domain upregulates the CASK–Tbr-1 interaction. This complex activates the NMDAR2B promoter, and T724A CASK mutation abolishes cAMP-stimulated NMDAR2B expression in cortical neurons. In vitro PKA kinase assay, site-directed mutagenesis, Co-immunoprecipitation, NMDAR2B promoter-reporter assay, cortical neuron culture Journal of neurochemistry High 20067577
2009 CASK Thr-724 point mutation in the GK domain selectively reduces CASK interactions with Tbr-1 and CINAP without affecting CASK dimerization, and diminishes NMDAR2B (NR2b) promoter activity, confirming that the CASK–Tbr-1–CINAP complex is required for NMDAR2B transcriptional regulation. Site-directed mutagenesis, Co-immunoprecipitation, promoter-reporter assay Biochemical and biophysical research communications Medium 19275891
2008 Activity suppression (TTX treatment) increases GluN2B mRNA expression in cortical neurons, and this upregulation is occluded by DNMT inhibition. MeCP2 binds to the NR2B gene, and TTX reduces MeCP2 association with the NR2B locus, indicating that DNA methylation and MeCP2 binding mediate activity-dependent regulation of NR2B expression. TTX treatment of cortical neurons, RT-qPCR, chromatin immunoprecipitation (ChIP), DNMT inhibitor treatment, dark-rearing model Biochemical and biophysical research communications Medium 18952054
2015 GluN2B(F637) in the third membrane-associated domain regulates ethanol sensitivity and ion channel gating. Substitution mutations at F637 significantly alter ethanol IC50 values and glutamate EC50 values for peak and steady-state current, demonstrating this residue as a functional determinant of alcohol action on GluN2B-containing NMDARs. Site-directed mutagenesis, two-electrode voltage clamp in Xenopus oocytes, ethanol concentration–response analysis Neuropharmacology High 26051400
2022 HECTD4 (an E3 ubiquitin ligase) interacts with GluN2B and ubiquitinates it. Ischemic stroke weakens this HECTD4–GluN2B interaction and reduces GluN2B ubiquitination. HECTD4 knockdown exacerbates NMDA/hypoxia-induced injury with increased GluN2B phosphorylation and Ca2+ overload, while MALT1 acts downstream of HECTD4 to regulate STEP61 and GluN2B phosphorylation. Nano-LC-MS/MS (interactome), Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, Ca2+ imaging, ischemia rat model Molecular neurobiology Medium 36527595
2020 Synaptotagmin-7 (Syt7) and GluN2B-NMDARs co-localize at the peripheral synaptic region in hippocampal neurons. Syt7 triggers multiple forms of glutamate release to activate juxtaposed GluN2B-NMDARs. Syt7 deficiency causes GluN2B-NMDAR hypoactivity and mania-like behavior in mice; this hypoactivity was rescued by Syt7 overexpression in patient iPSC-derived neurons. Super-resolution imaging, iPSC-derived neuron electrophysiology, Syt7 KO mice, lentiviral overexpression, behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 33229564
2022 CK2 is aberrantly elevated in Alzheimer's disease (AD) brains, causing GluN2B to mislocalize from synaptic to extrasynaptic sites. CK2 inhibition corrects this NR2B synaptic distribution, reduces tau accumulation in vitro, and inhibiting excessive extrasynaptic GluN2B with memantine also mitigates tau pathology. Human AD brain immunohistochemistry, hippocampal neuron culture (AD-tau treatment), CK2 inhibitor treatment, synaptic fractionation, tau immunoassay Acta neuropathologica communications Medium 35246269
2017 Conditional deletion of the GluN2B C-terminal tail (amino acids 886–1269) in forebrain excitatory neurons disrupts DAPK1–GluN2B interaction and inhibits extrasynaptic but not synaptic NMDAR currents. This genetic manipulation protects neurons against ischemic stroke damage and improves behavioral outcomes in vivo. Conditional knockout mice, whole-cell electrophysiology, infarct volume measurement, behavioral tests Molecular neurobiology High 28456939
2021 GluN2B-containing NMDARs are required for extinction memory destabilization upon recall (shown by GluN2B antagonist RO25-6981 blocking reconsolidation-mediated memory recovery), whereas GluN2A-containing NMDARs are involved in restabilization (shown by GluN2A antagonist TCN201 impairment of retention). Intra-hippocampal drug microinfusion, inhibitory avoidance behavioral paradigm, pharmacological dissection Scientific reports Medium 33420399
2016 Amphetamine and methamphetamine increase GluN2B-NMDAR synaptic currents in midbrain dopamine neurons dependent on dopamine transporter-mediated drug entry. EAAT3 internalization caused by AMPH increases extracellular glutamate to activate GluN2B-containing NMDARs. GluN2B inhibitors reduce MA-stimulated locomotor activity without affecting basal activity. Whole-cell patch clamp in midbrain slices, selective GluN2B antagonists, MK-801 use-dependent block, dopamine transporter inhibition, behavioral locomotor assay Neuropsychopharmacology High 27976681
2014 GluN2B and GluN2D play counteractive roles in the temporal development of somatosensory maps: GluN2B is expressed at asymmetric synapses of glutamatergic projection neurons and facilitates refinement of ascending pathway synapses, while GluN2D is expressed at asymmetric synapses of GABAergic interneurons and delays it indirectly. GluN2B+/- and GluN2D-/- mice, unilateral infraorbital nerve transection (critical period assay), immunoelectron microscopy for subunit localization The Journal of neuroscience High 25164652
2007 PSD-95 is required for dopamine D1 receptor modulation of GluN1a/GluN2B receptor function. D1R stimulation increases NMDA-mediated Ca2+ influx only when PSD-95 is co-expressed; this modulation is blocked by PKA and PKC inhibitors. HEK293 cell co-expression, Ca2+ imaging, pharmacological inhibition of PKA and PKC Acta pharmacologica Sinica Medium 17506933
1994 The human GRIN2B gene, encoding the NMDAR2B receptor subunit, was mapped to chromosome 12p12 by in situ hybridization and somatic cell hybrid analysis. Fluorescence in situ hybridization, somatic cell hybrid panel Genomics High 7959773

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 420 20141836
2010 Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature genetics 404 20890276
2014 Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 260 24607230
2017 α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B. Nature neuroscience 229 28945221
2013 GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 224 24298164
2006 Modulation of D2R-NR2B interactions in response to cocaine. Neuron 198 17145509
2016 Human GRIN2B variants in neurodevelopmental disorders. Journal of pharmacological sciences 193 27818011
2009 Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 155 19789073
2005 Glutamate-based therapeutic approaches: NR2B receptor antagonists. Current opinion in pharmacology 148 16376149
2007 Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning. The Journal of neuroscience : the official journal of the Society for Neuroscience 145 18077696
2009 Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Molecular brain 144 19192303
2009 Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 130 19562769
2019 Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Research 115 31807283
2006 N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels. Schizophrenia research 100 16549338
2006 Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder. Genes, brain, and behavior 100 17010153
2002 NR2B selective NMDA receptor antagonists. Current pharmaceutical design 94 11945135
2013 Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors. Cell reports 93 23478024
2017 Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Molecular psychiatry 88 28439098
2005 Functional NR2B- and NR2D-containing NMDA receptor channels in rat substantia nigra dopaminergic neurones. The Journal of physiology 88 16141268
2009 Effects of chronic noise exposure on spatial learning and memory of rats in relation to neurotransmitters and NMDAR2B alteration in the hippocampus. Journal of occupational health 86 19225220
2017 Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. eLife 85 28598327
2001 Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Molecular psychiatry 81 11317224
2017 DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific. Cell reports 74 28614711
2013 A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology 73 24114429
2016 The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength. The Journal of biological chemistry 69 27246855
2007 Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: a HuGE review and meta-analysis. Genetics in medicine : official journal of the American College of Medical Genetics 60 17224684
2012 Interaction between αCaMKII and GluN2B controls ERK-dependent plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 22855824
2012 Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors. Brain research bulletin 55 23085545
2007 Quantitative hypermethylation of NMDAR2B in human gastric cancer. International journal of cancer 54 17620329
2018 The differences between GluN2A and GluN2B signaling in the brain. Journal of neuroscience research 51 29682799
2018 Disruption of GRIN2B Impairs Differentiation in Human Neurons. Stem cell reports 51 29937144
2014 Opposing role of NMDA receptor GluN2B and GluN2D in somatosensory development and maturation. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 25164652
2012 Glutamatergic GRIN2B and polyaminergic ODC1 genes in suicide attempts: associations and gene-environment interactions with childhood/adolescent physical assault. Molecular psychiatry 48 22850629
2023 GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms. Frontiers in synaptic neuroscience 47 36704660
2018 Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans. Scientific reports 44 30054528
2012 Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder. Journal of psychiatry & neuroscience : JPN 42 22433450
2019 Ginger extract and its compound, 6-shogaol, attenuates painful diabetic neuropathy in mice via reducing TRPV1 and NMDAR2B expressions in the spinal cord. Journal of ethnopharmacology 41 31743763
2013 Metabolism studies of ifenprodil, a potent GluN2B receptor antagonist. Journal of pharmaceutical and biomedical analysis 41 24042122
2010 Src inhibition reduces NR2B surface expression and synaptic plasticity in the amygdala. Learning & memory (Cold Spring Harbor, N.Y.) 41 20660101
2015 GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 26041915
2013 GluN2A versus GluN2B: twins, but quite different. Neuroscience bulletin 38 23604599
2021 GluN2A and GluN2B NMDA receptors use distinct allosteric routes. Nature communications 37 34354080
2019 An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth. Journal of cell science 37 31548203
2016 Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment. Behavioural brain research 37 27180168
2016 Amphetamine and Methamphetamine Increase NMDAR-GluN2B Synaptic Currents in Midbrain Dopamine Neurons. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36 27976681
2013 Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer's disease. Journal of neural transmission (Vienna, Austria : 1996) 36 24292895
2023 GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology. Frontiers in molecular neuroscience 35 37324591
2019 GRIN2B promoter methylation deficits in early-onset schizophrenia and its association with cognitive function. Epigenomics 35 30785307
2011 Aberrant methylation of N-methyl-D-aspartate receptor type 2B (NMDAR2B) in non-small cell carcinoma. BMC cancer 34 21639937
2016 Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells. Journal of Alzheimer's disease : JAD 33 27497478
2015 Phosphorylation of NR2B NMDA subunits by protein kinase C in arcuate nucleus contributes to inflammatory pain in rats. Scientific reports 33 26515544
2014 Overexpression of NMDAR2B in an inflammatory model of Alzheimer's disease: modulation by NOS inhibitors. Brain research bulletin 33 25454121
2019 NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content. Cell reports 32 31291571
2010 NMDAR2B tyrosine phosphorylation regulates anxiety-like behavior and CRF expression in the amygdala. Molecular brain 32 21118530
2008 Association between NR2B subunit gene (GRIN2B) promoter polymorphisms and sporadic Alzheimer's disease in the North Chinese population. Neuroscience letters 31 18983893
2018 Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell reports 30 30089263
2000 Transient expression of NMDA receptor subunit NR2B in the developing rat heart. Journal of neurochemistry 30 11080199
2015 Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance. Psychological medicine 29 26690829
2022 Inhibition of CK2 mitigates Alzheimer's tau pathology by preventing NR2B synaptic mislocalization. Acta neuropathologica communications 27 35246269
2015 Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure. Neurochemistry international 27 25846226
2009 Different expression of NR2B and PSD-95 in rat hippocampal subregions during postnatal development. Microscopy research and technique 27 19306263
2024 Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. Physiological research 26 38836461
2019 TMEM25 modulates neuronal excitability and NMDA receptor subunit NR2B degradation. The Journal of clinical investigation 26 31424425
2022 Modulation of KIF17/NR2B crosstalk by tozasertib attenuates inflammatory pain in rats. Inflammopharmacology 25 35243557
2016 Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. Scientific reports 25 27616045
2015 Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology. Neuroscience 25 26211447
2010 CASK phosphorylation by PKA regulates the protein-protein interactions of CASK and expression of the NMDAR2b gene. Journal of neurochemistry 25 20067577
2023 A decrease in NR2B expression mediated by DNA hypermethylation induces perioperative neurocognitive disorder in aged mice. CNS neuroscience & therapeutics 24 36694341
2022 Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish. Molecular autism 24 36138431
2017 Genetic Mutation of GluN2B Protects Brain Cells Against Stroke Damages. Molecular neurobiology 24 28456939
2010 Psychosis and relapse in bipolar disorder are related to GRM3, DAOA, and GRIN2B genotype. African journal of psychiatry 24 20957330
2020 Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats. International journal of molecular sciences 23 33348808
2018 The effects of GRIN2B and DRD4 gene variants on local functional connectivity in attention-deficit/hyperactivity disorder. Brain imaging and behavior 23 28258362
2016 Association of GRIN2B gene polymorphism and Obsessive Compulsive disorder and symptom dimensions: A pilot study. Psychiatry research 23 27394963
2015 Different sites of alcohol action in the NMDA receptor GluN2A and GluN2B subunits. Neuropharmacology 23 26051400
1994 Mapping of the human NMDAR2B receptor subunit gene (GRIN2B) to chromosome 12p12. Genomics 23 7959773
2018 Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists. ChemMedChem 22 29806151
2016 The GRIN2B and GRIN2A Gene Variants Are Associated With Continuous Performance Test Variables in ADHD. Journal of attention disorders 22 27199241
2014 Nicotinic and muscarinic agonists and acetylcholinesterase inhibitors stimulate a common pathway to enhance GluN2B-NMDAR responses. Proceedings of the National Academy of Sciences of the United States of America 22 25114227
2024 LTP expression mediated by autonomous activity of GluN2B-bound CaMKII. Cell reports 21 39395168
2021 Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms. Life (Basel, Switzerland) 21 34685369
2020 Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity. Proceedings of the National Academy of Sciences of the United States of America 21 33229564
2015 Association Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population. PloS one 21 26020650
2008 Activity-dependent NR2B expression is mediated by MeCP2-dependent epigenetic regulation. Biochemical and biophysical research communications 21 18952054
2002 Differential NR2A and NR2B expression between trigeminal neurons during early postnatal development. Synapse (New York, N.Y.) 21 11891879
2014 Promising targets of cell death signaling of NR2B receptor subunit in stroke pathogenesis. Regenerative medicine research 20 25984336
2009 CASK point mutation regulates protein-protein interactions and NR2b promoter activity. Biochemical and biophysical research communications 20 19275891
2022 Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b. British journal of anaesthesia 19 35697546
2022 Molecular Insights into the Role of Pathogenic nsSNPs in GRIN2B Gene Provoking Neurodevelopmental Disorders. Genes 19 35893069
2021 GluN2B and GluN2A-containing NMDAR are differentially involved in extinction memory destabilization and restabilization during reconsolidation. Scientific reports 19 33420399
2016 Further evidence for GRIN2B mutation as the cause of severe epileptic encephalopathy. American journal of medical genetics. Part A 19 27605359
2007 Requirement of PSD-95 for dopamine D1 receptor modulating glutamate NR1a/NR2B receptor function. Acta pharmacologica Sinica 19 17506933
2022 The Weakened Interaction Between HECTD4 and GluN2B in Ischemic Stroke Promotes Calcium Overload and Brain Injury Through a Mechanism Involving the Decrease of GluN2B and MALT1 Ubiquitination. Molecular neurobiology 18 36527595
2021 An Autism-Associated de novo Mutation in GluN2B Destabilizes Growing Dendrites by Promoting Retraction and Pruning. Frontiers in cellular neuroscience 18 34393725
2020 Leptin Controls Glutamatergic Synaptogenesis and NMDA-Receptor Trafficking via Fyn Kinase Regulation of NR2B. Endocrinology 18 31840160
2020 Childhood adversity increases methylation in the GRIN2B gene. Journal of psychiatric research 18 33038564
2018 GluN2B Subunit of the NMDA Receptor: The Keystone of the Effects of Alcohol During Neurodevelopment. Neurochemical research 18 29307084
2024 Long-term plasticity of NMDA GluN2B (NR2B) receptor in anterior cingulate cortical synapses. Molecular pain 17 38246915
2022 Carnosic Acid Attenuates AβOs-Induced Apoptosis and Synaptic Impairment via Regulating NMDAR2B and Its Downstream Cascades in SH-SY5Y Cells. Molecular neurobiology 16 36224322
2019 NR2B receptor- and calpain-mediated KCC2 cleavage resulted in cognitive deficiency exposure to isoflurane. Neurotoxicology 16 31672664

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