Affinage

GRIN2B

Glutamate receptor ionotropic, NMDA 2B · UniProt Q13224

Length
1484 aa
Mass
166.4 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRIN2B encodes the GluN2B subunit of NMDA-type ionotropic glutamate receptors, serving as a critical determinant of receptor gating kinetics, allosteric modulation, and synaptic plasticity signaling. The extended GluN2B C-terminal intracellular domain functions as a signaling scaffold: CaMKII binding to the GluN2B tail (aa 1292–1304) is required for LTP induction, intermediate LTP expression through generation of autonomous CaMKII activity, and maintenance of basal synaptic strength, while competitive DAPK1 binding to the same region during LTD and ischemia phosphorylates S1303 and enhances extrasynaptic receptor conductance to promote neuronal death (PMID:20164351, PMID:39395168, PMID:27246855, PMID:28614711, PMID:20141836). GluN2B surface expression and synaptic versus extrasynaptic localization are dynamically regulated by a phosphorylation code—Y1472 phosphorylation by Src/Fyn blocks AP-2/clathrin-mediated endocytosis, S1480 phosphorylation by CK2 (scaffolded by CaMKII) and dephosphorylation by PP1 control synaptic retention, and S1116 phosphorylation by Cdk5 restricts surface levels—while the PDZ ligand couples GluN2B through PSD-95/nNOS to p38-dependent excitotoxic signaling (PMID:18184784, PMID:23478024, PMID:31291571, PMID:24607229, PMID:18923045). GluN2B-containing receptors additionally anchor synaptic proteasomes to regulate AMPA receptor turnover and negatively regulate developmental AMPA receptor incorporation via TARP-dependent mechanisms (PMID:26041915, PMID:18057203).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1994 High

    Chromosomal assignment of GRIN2B to 12p12 established the genomic location needed for genetic linkage and disease studies.

    Evidence In situ hybridization and somatic cell hybrid analysis in human cells

    PMID:7959773

    Open questions at the time
    • No functional characterization of the gene at this stage
    • No disease association identified
  2. 2007 High

    Identification that Fyn phosphorylates GluN2B at Y1336 to control calpain-mediated cleavage at the plasma membrane established a post-translational mechanism for regulating GluN2B protein turnover independently of endocytosis.

    Evidence Site-directed mutagenesis, siRNA knockdown of Fyn, biochemical cleavage assays, and electrophysiology in HEK cells and neurons

    PMID:17526495

    Open questions at the time
    • Physiological contexts triggering calpain cleavage in vivo not defined
    • Functional consequence of truncated GluN2B at synapses unclear
  3. 2007 High

    Demonstration that GluN2B negatively regulates synaptic AMPA receptor incorporation through TARP expression revealed a developmental gatekeeping role for GluN2B beyond ion channel function.

    Evidence GluN2B genetic knockout, surface biotinylation, electrophysiology, and dominant-negative TARP rescue

    PMID:18057203

    Open questions at the time
    • Direct molecular link between GluN2B and TARP transcription/trafficking not identified
    • Whether this mechanism operates in mature synapses unknown
  4. 2008 High

    The phosphorylation code controlling GluN2B endocytosis was established: Cdk5 inhibition enhances Src-mediated Y1472 phosphorylation, which blocks AP-2/β2-adaptin binding to the YEKL motif and prevents clathrin-mediated internalization, increasing surface GluN2B.

    Evidence Kinase inhibition, co-immunoprecipitation, surface biotinylation, and siRNA knockdown of Fyn/Cdk5

    PMID:18184784

    Open questions at the time
    • How Cdk5 and Src activities are coordinated during plasticity not resolved
    • Role of Y1472 phosphorylation at extrasynaptic versus synaptic pools not distinguished
  5. 2008 High

    The GluN2B PDZ ligand–PSD-95–nNOS pathway was shown to couple NMDAR activation specifically to p38-mediated excitotoxic death without affecting prosurvival CREB/Akt signaling, establishing a bifurcation in downstream death versus survival signaling.

    Evidence PDZ ligand peptide (TAT-NR2B9c), NOS and JNK inhibitors, cell death assays in neuronal/non-neuronal contexts, in vivo stroke model

    PMID:18923045

    Open questions at the time
    • Structural basis of selectivity between p38 and CREB/Akt arms not resolved
    • Whether chronic versus acute activation differentially engages this pathway unknown
  6. 2008 Medium

    Epigenetic regulation of GRIN2B transcription was demonstrated: activity suppression reduces MeCP2 occupancy at the Grin2b promoter and increases transcription through a DNMT-dependent mechanism.

    Evidence TTX treatment of cortical neurons, MeCP2 ChIP, DNMT inhibition, quantitative RT-PCR

    PMID:18952054

    Open questions at the time
    • Specific CpG sites mediating MeCP2 binding not mapped
    • In vivo relevance not tested
    • Single-lab finding
  7. 2010 High

    DAPK1 was identified as a direct GluN2B binding partner and kinase at extrasynaptic sites: DAPK1 binds GluN2B aa 1292–1304, phosphorylates S1303, enhances channel conductance, and mediates ischemic neuronal death—establishing the extrasynaptic GluN2B death-signaling paradigm.

    Evidence Co-immunoprecipitation, direct binding assays, phosphorylation assays, DAPK1 knockout, in vivo uncoupling peptide, electrophysiology, stroke mouse model

    PMID:20141836

    Open questions at the time
    • Whether DAPK1 modulates GluN2B in non-ischemic physiological contexts not fully explored
    • Mechanism of DAPK1 translocation to extrasynaptic sites not defined
  8. 2010 High

    Domain-swap experiments proved that the GluN2B C-terminal tail (not channel properties) is the critical determinant for LTP induction, as an NR2A subunit bearing the NR2B tail rescued LTP after NR2B knockdown.

    Evidence RNAi knockdown with chimeric subunit rescue, electrophysiology in organotypic hippocampal slices

    PMID:20164351

    Open questions at the time
    • Specific binding partners recruited by the GluN2B tail for LTP not fully enumerated
    • Whether this requirement is age-dependent not tested
  9. 2012 High

    The GluN2B–αCaMKII interaction was shown to be the specific pathway coupling NMDAR activation to sustained ERK1/2 phosphorylation, AMPA receptor synaptic insertion, and spine enlargement—distinguishing GluN2B from GluN2A downstream signaling.

    Evidence Subunit-selective pharmacology, co-immunoprecipitation, dominant-negative constructs, ERK phosphorylation assays, spine morphometry, electrophysiology

    PMID:22855824

    Open questions at the time
    • Whether ERK activation requires CaMKII enzymatic activity versus scaffolding not distinguished
    • Role of βCaMKII in modulating this pathway not explored
  10. 2013 High

    CaMKII was found to scaffold CK2 onto GluN2B, forming a trimolecular complex that drives S1480 phosphorylation and controls GluN2B surface expression and synapse density in an activity-dependent manner.

    Evidence Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis, surface expression assays, electrophysiology

    PMID:23478024

    Open questions at the time
    • Whether this trimolecular complex operates at both synaptic and extrasynaptic membranes not tested
    • Structural basis of CaMKII-CK2 co-recruitment unknown
  11. 2014 High

    Two studies established distinct pharmacological properties of GluN1/GluN2A/GluN2B triheteromeric receptors and identified Cdk5 phosphorylation of GluN2B at S1116 as a regulator of surface expression and memory, expanding the phosphorylation code governing GluN2B trafficking.

    Evidence Selective triheteromer expression with electrophysiology [PMID:24607230]; in vitro kinase assay, S1116 mutagenesis, surface biotinylation, in vivo peptide administration with behavioral testing [PMID:24607229]

    PMID:24607229 PMID:24607230

    Open questions at the time
    • How S1116 phosphorylation interacts with other phosphorylation events (Y1472, S1480) not addressed
    • Triheteromer pharmacology not yet linked to specific in vivo plasticity forms
  12. 2015 High

    GluN2B-containing NMDARs were shown to anchor synaptic proteasomes; loss of GluN2B reduces proteasome subunits at PSDs, leading to impaired constitutive AMPA receptor degradation and elevated synaptic AMPAR levels.

    Evidence GluN2B knockout cultures, quantitative PSD proteomics, proteasome activator rescue, surface receptor assays, electrophysiology

    PMID:26041915

    Open questions at the time
    • Direct binding domain on GluN2B for proteasome recruitment not mapped
    • Whether proteasome anchoring is CaMKII-dependent not tested
  13. 2016 High

    Using GluN2B CaMKII-binding-incompetent knock-in mice, CaMKII/GluN2B binding was shown to be required not only for LTP induction but also for maintaining basal synaptic strength, separating constitutive from plasticity-induced roles.

    Evidence Pharmacogenetic GluN2B mutant mice, CaMKII inhibitor tatCN21, electrophysiology

    PMID:27246855

    Open questions at the time
    • Whether basal strength maintenance requires CaMKII enzymatic activity or scaffolding not resolved at this point
  14. 2017 High

    Competitive binding of DAPK1 and CaMKII to the same GluN2B region was demonstrated as a bidirectional switch: calcineurin-dependent DAPK1 activation during LTD displaces CaMKII, while Ca2+/CaM removes DAPK1 during LTP, establishing a molecular toggle for plasticity direction.

    Evidence GluN2B CaMKII-binding mutant mice, biochemical binding assays, LTP/LTD electrophysiology, calcineurin and CaMKII pharmacology

    PMID:28614711

    Open questions at the time
    • Temporal dynamics of the DAPK1–CaMKII switch at single synapses not resolved
    • Whether other kinases modulate this competition unknown
  15. 2017 High

    D-serine was identified as a co-agonist that selectively modulates GluN2B (not GluN2A) membrane dynamics and synaptic content through PDZ-scaffold-dependent mechanisms, revealing co-agonist identity as a subunit-specific regulatory signal.

    Evidence Single-molecule imaging, FRET-FLIM, biochemistry, electrophysiology with co-agonist manipulation

    PMID:28598327

    Open questions at the time
    • Structural mechanism by which D-serine binding transmits conformational change to the GluN2B intracellular domain not resolved
    • In vivo validation of co-agonist-specific trafficking not performed
  16. 2018 High

    SHP2 dephosphorylation of GluN2B at Y1252 was shown to regulate Nck2 binding and NMDAR function; in Noonan syndrome mice with gain-of-function SHP2, dephosphorylation of Y1252 reduces GluN1/GluN2B diheteromer contribution to synaptic currents.

    Evidence In vitro phosphatase assay, phospho-specific immunoprecipitation, Noonan syndrome knock-in mouse electrophysiology, Nck2 co-IP

    PMID:30089263

    Open questions at the time
    • Whether Y1252 phosphorylation affects actin remodeling at spines via Nck2 not directly tested
    • Contribution of other SHP2 substrates to the Noonan syndrome phenotype not excluded
  17. 2019 High

    PP1 was identified as the phosphatase that dephosphorylates GluN2B S1480 in an activity-dependent manner, promoting synaptic NMDAR content; phospho-S1480 maintains NMDARs at extrasynaptic membranes, completing the CK2/PP1 cycle controlling GluN2B localization.

    Evidence Phospho-specific antibodies, co-immunoprecipitation, surface receptor assays, PP1 inhibitors, electrophysiology

    PMID:31291571

    Open questions at the time
    • How PP1 is recruited to GluN2B (direct binding or scaffold-mediated) not fully resolved
    • Whether PP1/S1480 cycle operates during specific plasticity protocols not tested
  18. 2020 High

    Site-specific GluN2B knock-in mutations separating CaMKII from DAPK1 binding demonstrated that CaMKII (not DAPK1) accumulation at synapses via GluN2B mediates ischemic neuronal death after cardiac arrest, resolving which kinase partner drives excitotoxicity through this binding site.

    Evidence GluN2B L1298A/R1300Q knock-in mice, neuronal death assays, immunofluorescence, electrophysiology, cardiac arrest/resuscitation model

    PMID:31914378

    Open questions at the time
    • Downstream CaMKII substrates mediating ischemic death not identified
    • Whether this mechanism is conserved across brain regions not tested
  19. 2021 High

    Structural and functional analysis revealed that GluN2A and GluN2B employ distinct N-terminal domain allosteric pathways and subunit-subunit interfaces to control channel gating, providing a structural basis for subunit-specific pharmacology.

    Evidence Cryo-EM/X-ray structural interrogation combined with functional electrophysiology

    PMID:34354080

    Open questions at the time
    • How N-terminal domain conformational changes propagate through the full-length receptor in a lipid bilayer not resolved
    • Triheteromer allosteric mechanisms not addressed
  20. 2024 High

    The temporal roles of CaMKII enzymatic activity versus structural binding at GluN2B were dissected: GluN2B-generated autonomous CaMKII activity is dispensable for LTP induction but required for an intermediate expression phase (5–15 min), while later maintenance relies on structural (non-enzymatic) functions of GluN2B-bound CaMKII.

    Evidence GluN2B CaMKII-binding mutant mice combined with optogenetic CaMKII tools and temporally resolved electrophysiology

    PMID:39395168

    Open questions at the time
    • Structural basis of non-enzymatic CaMKII function at GluN2B not defined
    • Whether the intermediate phase is synapse-type specific not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: (1) how the multiple phosphorylation sites on GluN2B (Y1252, Y1336, Y1472, S1116, S1303, S1480) are coordinately regulated at individual synapses during plasticity; (2) the structural basis for the CaMKII/DAPK1 competitive switch in the context of full-length receptors; (3) whether GluN2B scaffolding of proteasomes versus CaMKII versus signaling adaptors occurs simultaneously or in mutually exclusive complexes.
  • No integrated model of combinatorial phosphorylation code dynamics at single synapses
  • No full-length receptor structure with intracellular domain resolved
  • Stoichiometry and mutual exclusivity of scaffolded complexes not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 2 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3
Partners
CAMK2ACDK5CSNK2A1DAPK1DLG4DRD2KALRNLRP1
Complex memberships
GluN2B-CaMKII-CK2 trimolecular complexNMDA receptor (GluN1/GluN2A/GluN2B triheteromer)NMDA receptor (GluN1/GluN2B diheteromer)

Evidence

Reading pass · 34 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 phosphorylates GluN2B at Ser-1303, enhancing NR1/NR2B receptor channel conductance; this interaction occurs at extrasynaptic sites and mediates ischemic neuronal death. Co-immunoprecipitation, direct binding assays, phosphorylation assays, genetic deletion of DAPK1, in vivo peptide uncoupling, electrophysiology, stroke mouse model Cell High 20141836
2014 GluN1/GluN2A/GluN2B triheteromeric NMDA receptors have distinct glutamate deactivation kinetics and pharmacological properties (ifenprodil, CP-101,606, TCN-201, Zn2+) compared to diheteromeric GluN1/GluN2A or GluN1/GluN2B receptors. Selective cell-surface expression of recombinant triheteromers, whole-cell electrophysiology, kinetic measurements, pharmacological profiling Neuron High 24607230
2006 Dopamine D2 receptors (D2R) directly interact with GluN2B in striatal postsynaptic densities; cocaine-enhanced D2R-GluN2B interaction disrupts CaMKII association with GluN2B, reduces GluN2B phosphorylation at Ser1303, and inhibits NMDA receptor-mediated currents. Co-immunoprecipitation in vivo, direct binding assays, whole-cell electrophysiology in striatal neurons, behavioral studies Neuron High 17145509
2010 The GluN2B cytoplasmic tail is required for LTP induction: a chimeric NR2B subunit with the NR2A C-terminal tail fails to rescue LTP after NR2B knockdown, while an NR2A subunit with the NR2B tail restores LTP, demonstrating that the NR2B C-terminal domain recruits molecules required for LTP. RNAi knockdown, chimeric subunit rescue experiments, whole-cell electrophysiology in organotypic hippocampal slices The Journal of neuroscience High 20164351
2008 Cdk5 inhibition increases Src binding to PSD-95, which facilitates Src-mediated phosphorylation of GluN2B at Tyr-1472; phospho-Y1472 inhibits AP-2 (beta2-adaptin) binding to the GluN2B YEKL motif, thereby blocking clathrin-mediated endocytosis of NR2B-containing NMDA receptors and increasing their surface expression. Biochemical kinase inhibition, co-immunoprecipitation, surface biotinylation, siRNA knockdown of Fyn/Cdk5, cell-surface receptor assays The Journal of neuroscience High 18184784
2013 Activated CaMKII couples GluN2B and 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; CaMKII/GluN2B association controls synapse density and PSD composition in an activity-dependent manner. Co-immunoprecipitation, phosphorylation assays, site-directed mutagenesis, surface expression assays, electrophysiology Cell reports High 23478024
2014 Cdk5 phosphorylates GluN2B at Ser-1116; Cdk5-dependent phosphorylation regulates GluN2B cell surface expression and synaptic transmission; disrupting GluN2B-Cdk5 interaction via a small interfering peptide increases NR2B surface levels and improves memory formation in vivo. In vitro kinase assay, site-directed mutagenesis, surface biotinylation, electrophysiology, in vivo peptide administration and behavioral testing Neuron High 24607229
2007 Fyn-mediated phosphorylation of GluN2B Tyr-1336 (but not Tyr-1472) controls calpain-mediated cleavage of GluN2B at the plasma membrane; mutation of Tyr-1336 eliminates Fyn's potentiation of calpain cleavage; this regulation is restricted to cell-surface receptors and does not alter basic electrophysiological properties of truncated receptors. Site-directed mutagenesis in HEK cells and neurons, siRNA knockdown of Fyn, Src family kinase inhibitors, biochemical cleavage assays, electrophysiology The Journal of biological chemistry High 17526495
2008 NMDA receptor-dependent pro-death signaling via p38 requires neuronal context and the NR2B PDZ ligand interaction with PSD-95/nNOS; a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c) selectively inhibits p38-mediated ischemic damage without impairing NMDAR-dependent plasticity or prosurvival signaling to CREB or Akt. PDZ ligand peptide competition, NOS inhibitors, JNK inhibitors, cell death assays in neuronal and non-neuronal contexts, in vivo stroke model The Journal of neuroscience High 18923045
2007 NR2B signaling at developing synapses negatively regulates synaptic incorporation of AMPA receptors; genetic removal of NR2B increases surface AMPA receptor expression and synaptic AMPAR-mediated current via increased TARP expression; a dominant-negative TARP blocks AMPAR enrichment caused by NR2B deletion. Genetic knockout, surface biotinylation, electrophysiology, dominant-negative TARP expression The Journal of neuroscience High 18057203
2011 Kalirin-7 binds the juxtamembrane region (preceding the C-terminal domain) of GluN2B via its pleckstrin homology domain; loss of Kalirin-7 reduces NR2B-dependent NMDA receptor currents and GluN2B cell surface expression; Kalirin-7 KO behavioral phenotypes depend on NR2B activity. Co-immunoprecipitation, pulldown, electrophysiology in cortical pyramidal neurons, surface expression assays, NR2B-selective antagonist pharmacology in behavioral tests The Journal of neuroscience High 21880917
2012 GluN2B-containing NMDAR activation (but not GluN2A) leads to long-lasting ERK1/2 phosphorylation through direct interaction between GluN2B and αCaMKII (not βCaMKII); disrupting GluN2B/αCaMKII interaction prevents synaptic activity from inducing ERK-dependent increases in synaptic AMPA receptors and spine volume. Subunit-selective pharmacology, co-immunoprecipitation, dominant-negative constructs, ERK phosphorylation assays, dendritic spine morphometry, electrophysiology The Journal of neuroscience High 22855824
2017 DAPK1 competes with CaMKII for binding to the same region of GluN2B; during LTD, calcineurin-dependent DAPK1 activation blocks CaMKII binding to GluN2B and CaMKII synaptic accumulation; Ca2+/CaM negatively regulates DAPK1/GluN2B binding, resulting in DAPK1 synaptic removal during LTP but retention during LTD. Pharmacogenetic approach (GluN2B CaMKII-binding mutant mice), biochemical binding assays, LTP/LTD electrophysiology, pharmacological manipulation of calcineurin and CaMKII Cell reports High 28614711
2016 CaMKII/GluN2B binding is required not only for LTP induction but also for maintenance of basal synaptic strength; in GluN2B mutant mice with CaMKII-binding-incompetent GluN2B, the persistent reduction of synaptic strength by CaMKII inhibitor tatCN21 is abolished. Pharmacogenetic approach (GluN2B CaMKII-binding mutant mice), electrophysiology, CaMKII inhibitor tatCN21 The Journal of biological chemistry High 27246855
2020 During ischemia, CaMKII accumulates at excitatory synapses via GluN2B binding and mediates ischemic neuronal death; mutating the CaMKII/DAPK1 binding region on GluN2B (L1298A/R1300Q) selectively abolishes CaMKII (but not DAPK1) binding and protects against neuronal death after cardiac arrest/resuscitation. GluN2B binding-region knock-in mice, neuronal death assays, immunofluorescence, electrophysiology, cardiac arrest model Cell reports High 31914378
2019 NMDAR activation recruits protein phosphatase 1 (PP1), which dephosphorylates GluN2B S1480; phospho-S1480 maintains NMDARs at extrasynaptic membranes in a complex with PP1; dephosphorylation of S1480 promotes synaptic NMDAR content in an activity-dependent manner. Phosphorylation-specific antibodies, co-immunoprecipitation, surface receptor assays, PP1 inhibitors, electrophysiology Cell reports High 31291571
2018 NS-associated SHP2 dephosphorylates GluN2B at Y1252 in vitro and in vivo; phospho-Y1252 binds the actin-regulatory adaptor Nck2; this phosphorylation-dependent interaction is required for proper NMDAR function and loss of this regulation in NS mice reduces GluN1:GluN2B diheteromer contribution to synaptic currents. In vitro phosphatase assay, phospho-specific immunoprecipitation, knock-in mouse electrophysiology, Nck2 co-immunoprecipitation, phospho-peptide binding assay Cell reports High 30089263
2021 GluN2A and GluN2B receptors utilize distinct long-distance allosteric mechanisms involving different subunit-subunit interfaces and molecular rearrangements in their N-terminal domains to control ion channel gating. Functional electrophysiology combined with structural interrogation (cryo-EM/X-ray) of N-terminal domain conformations Nature communications High 34354080
2013 LRP1 physically interacts with GluN2B (linked via PSD-95) in a phosphorylation-dependent manner; inactivating the NPxY2 motif of LRP1 increases surface expression of NR2B by reducing endocytosis and alters phosphorylation of NR2B at S1480 (CK2 site) and Y1472 (Src site). LRP1 knock-in mice, co-immunoprecipitation, surface biotinylation, endocytosis assays, behavioral testing Molecular neurodegeneration High 23866919
2015 GluN2B-containing NMDARs anchor synaptic proteasomes; in GluN2B knockout neurons, proteasome subunit levels at PSDs are decreased, leading to increased synaptic AMPA receptor levels and decreased constitutive GluA1 endocytosis; enhancing proteasome activity restores normal AMPAR trafficking. GluN2B knockout cultures, quantitative proteomic analysis of PSDs, proteasome activator treatment, surface receptor assays, electrophysiology The Journal of neuroscience High 26041915
2015 AIDA-1 (encoded by ANKS1B) associates preferentially with GluN2B and with KIF17 kinesin to facilitate transport of GluN2B from the ER to synapses; AIDA-1 conditional knockout reduces GluN2B at synaptic junctions and increases ER-localized GluN2B, impairing NMDAR-dependent plasticity. Conditional knockout mice, co-immunoprecipitation, subcellular fractionation, electrophysiology, immunocytochemistry The Journal of neuroscience High 26085624
2017 D-serine (but not glycine) alters the membrane dynamics and synaptic content of GluN2B-NMDARs (not GluN2A-NMDARs) through a process requiring PDZ-binding scaffold partners; D-serine also induces a conformational change of the GluN1 intracellular C-terminus. Single-molecule imaging, FRET-based FLIM, biochemistry, electrophysiology, ex vivo and in vitro manipulations of co-agonist levels eLife High 28598327
2010 Src-mediated phosphorylation of GluN2B (NR2B) supports NR2B surface expression in amygdala neurons; blocking Src-NMDAR interaction with a Tat-Src peptide reduces NR2B phosphorylation and surface expression, impairs LTP in the lateral-basolateral amygdala pathway, and impairs fear conditioning and social recognition memory. Tat-peptide inhibitor injection in vivo, surface biotinylation, electrophysiology (LTP), behavioral testing (fear conditioning, social recognition) Learning & memory Medium 20660101
2009 Overactivation of GluN2B-containing NMDARs during oxygen-glucose deprivation reduces PINK1 protein expression and inhibits Akt phosphorylation; PINK1 overexpression antagonizes GluN2B-NMDAR-mediated reduction of Akt activity, placing PINK1 downstream of GluN2B in an ischemic survival signaling cascade. NR2B-selective antagonists, PINK1 overexpression in cortical neurons, OGD model, western blotting, neuronal death assays Journal of neurochemistry Medium 19780893
2017 Chronic unpredictable stress increases DAPK1-NR2B interaction and phosphorylated GluN2B at Ser1303, and enhances extrasynaptic GluN2B-mediated NMDA currents in medial PFC; DAPK1 knockdown or pharmacological uncoupling from GluN2B produces rapid antidepressant-like effects and reverses these changes. AAV-mediated shRNA knockdown of DAPK1, pharmacological DAPK1 inhibition, uncoupling peptide, co-IP, electrophysiology, behavioral testing Molecular psychiatry Medium 28439098
2019 TMEM25, localized to late endosomes in neurons, interacts with GluN2B and co-localizes with it on late endosomes; TMEM25 induces lysosomal acidification and accelerates NR2B degradation, thereby reducing neuronal excitability. Co-immunoprecipitation, co-localization by confocal microscopy, lysosomal acidification assay, electrophysiology, overexpression/knockdown The Journal of clinical investigation Medium 31424425
2016 NR4A1 interacts with GluN2B (reciprocal co-IP); NR4A1 knockdown decreases surface NR2B by reducing phospho-NR2B (Tyr1472) and increasing NR2B internalization from the PSD, thereby reducing seizure activity. Reciprocal co-immunoprecipitation, lentiviral shRNA knockdown, immunofluorescence, in vivo seizure model Scientific reports Medium 27876882
2017 GluN2B mutation deleting the C-terminal tail (aa 886-1269) in forebrain neurons effectively disrupts DAPK1-GluN2B interaction and inhibits extrasynaptic (but not synaptic) NMDA receptor currents, providing protection against stroke damage both in vitro and in vivo. Conditional GluN2B C-terminal deletion mice, electrophysiology (synaptic vs extrasynaptic currents), co-IP, in vitro and in vivo stroke models, behavioral testing Molecular neurobiology Medium 28456939
2024 CaMKII binding to GluN2B directly generates Ca2+-independent autonomous CaMKII enzymatic activity; this activity is dispensable for LTP induction but required for an intermediate LTP expression phase (5–15 min after induction); later LTP maintenance may rely on structural functions of GluN2B-bound CaMKII independent of its enzymatic activity. Pharmacogenetic approach (GluN2B CaMKII-binding mutant mice), optogenetic CaMKII tools, electrophysiology with defined temporal resolution Cell reports High 39395168
2016 GluN2B-containing NMDARs are required for extinction memory destabilization during reconsolidation, whereas GluN2A-containing NMDARs are involved in restabilization; intra-hippocampal GluN2B antagonism (RO25-6981) before recall prevents mTOR-dependent memory destabilization. Intra-dorsal CA1 pharmacology with subunit-selective NMDAR antagonists (RO25-6981, TCN201, AP5, rapamycin), behavioral fear conditioning/extinction paradigm in rats Scientific reports Medium 33420399
2008 Activity-dependent NR2B expression is regulated by DNA methylation: suppression of neuronal activity (TTX) decreases MeCP2 association with the NR2B gene, increasing NR2B transcription; DNMT inhibition occludes the TTX-induced NR2B increase, indicating epigenetic control of NR2B expression. In vitro TTX treatment of cortical neurons, MeCP2 chromatin immunoprecipitation, DNMT inhibition, quantitative RT-PCR Biochemical and biophysical research communications Medium 18952054
2014 TBR1 is required for activity-induced upregulation of Grin2b transcription in mature neurons and adult mouse brain; TBR1 binds the Grin2b promoter and its induction by neuronal activation is CaMKII-dependent. Tbr1-deficient neurons, quantitative RT-PCR, CaMKII antagonist (KN-93), luciferase reporter assays, immunostaining Frontiers in cellular neuroscience Medium 25309323
2015 GluN2B F637 residue in the third membrane domain regulates ethanol sensitivity and ion channel gating of NR1/NR2B receptors; substitution mutations at F637 alter ethanol IC50 values and glutamate EC50 values for peak and steady-state currents. Site-directed mutagenesis, two-electrode voltage clamp in Xenopus oocytes Neuropharmacology Medium 26051400
1994 The human GRIN2B gene was mapped to chromosome 12p12 by in situ hybridization and somatic cell hybrid analysis. In situ hybridization, somatic cell hybrid analysis 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
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 226 28945221
2013 GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 220 24298164
2006 Modulation of D2R-NR2B interactions in response to cocaine. Neuron 197 17145509
2010 Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 179 20164351
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
2009 Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Molecular brain 143 19192303
2008 Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 133 18184784
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
2008 Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. The Journal of neuroscience : the official journal of the Society for Neuroscience 126 18923045
2014 Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 113 24607229
2019 Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Research 111 31807283
2006 Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder. Genes, brain, and behavior 100 17010153
2007 NR2B signaling regulates the development of synaptic AMPA receptor current. The Journal of neuroscience : the official journal of the Society for Neuroscience 99 18057203
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
2005 Functional NR2B- and NR2D-containing NMDA receptor channels in rat substantia nigra dopaminergic neurones. The Journal of physiology 88 16141268
2006 Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex. Neuropharmacology 87 16895734
2017 Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Molecular psychiatry 86 28439098
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
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