Affinage

GRIN2A

Glutamate receptor ionotropic, NMDA 2A · UniProt Q12879

Length
1464 aa
Mass
165.3 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 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

GRIN2A encodes GluN2A (NR2A), a glutamate-binding subunit that co-assembles with the obligate GluN1 subunit to form functional heteromeric NMDA receptor ion channels with binding and biophysical properties matching native adult forebrain receptors (PMID:7904155, PMID:7931566). GluN2A incorporation shortens NMDAR-mediated EPSC duration and underlies the developmental change in synaptic NMDAR kinetics, and GluN2A-containing receptors are more stable at the neuronal surface than GluN2B-containing receptors, contributing to the developmental NR2B-to-NR2A synaptic switch (PMID:9065507, PMID:17124177). GluN1/GluN2A diheteromers and GluN1/GluN2A/GluN2B triheteromers display distinct deactivation kinetics and antagonist/Zn2+ sensitivities (PMID:24607230). Cryo-EM of GluN1/GluN2A defines the allosteric pathway by which zinc binding to the GluN2A amino-terminal domain and protons are transduced through the ligand-binding domain to constrict the channel gate, and shows how competitive antagonists, positive allosteric modulators, and channel blockers engage the LBD and LBD-TMD linker; GluN2A uses long-range allosteric routes mechanistically distinct from GluN2B (PMID:30500536, PMID:34186027, PMID:34354080). Synaptic targeting and trafficking are controlled by phosphorylation and scaffolding: CaMKII associates with GluN2A and phosphorylates it at S1459 to switch SNX27 versus PSD-95 binding (PMID:9751209, PMID:32877683); SAP97 binds GluN2A through its PDZ1 domain, an interaction disrupted by CaMKII phosphorylation of SAP97-S232 (PMID:12933808); Src phosphorylates GluN2A at Tyr1325 to potentiate channel activity and engage DARPP-32 signaling (PMID:19834457); an ER-retention KKK motif limits surface expression (PMID:35484243); and dendritic delivery requires KIF3B-dependent vesicular transport and local CPE-mediated mRNA translation (PMID:31746486, PMID:23678131). GluN2A signaling shapes synaptic plasticity, parvalbumin interneuron maturation, and circuit excitability, with voltage-dependent (Mg2+-block-gated) Ca2+ flux required for normal sensory and associative learning (PMID:20164351, PMID:37723282, PMID:33420383). GRIN2A mutations cause epilepsy-aphasia spectrum and developmental/epileptic encephalopathy disorders: transmembrane/linker variants predominantly produce gain-of-function with severe phenotypes, while ATD/LBD and null variants cause loss-of-function and milder phenotypes (PMID:30544257, PMID:28126851, PMID:20890276, PMID:26312887, PMID:28242877).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    Established that NR2A is a heteromeric partner of NR1, answering whether the subunit forms part of a functional NMDA receptor complex resembling native brain receptors.

    Evidence Co-transfection in HEK293 with [3H]MK801 binding and immunological/deglycosylation characterization; parallel native protein characterization by Western blot and brain fractionation

    PMID:7904155 PMID:8298456

    Open questions at the time
    • Stoichiometry and subunit arrangement not resolved at this stage
    • Channel gating properties not directly measured
  2. 1994 High

    Localized NR2A protein to postsynaptic densities, establishing that the subunit operates at synapses in vivo rather than only in heterologous systems.

    Evidence Subunit-specific immunocytochemistry and electron microscopy of rat brain

    PMID:7931566

    Open questions at the time
    • Did not define functional consequence of synaptic localization
    • No subunit composition of individual PSD receptors
  3. 1997 High

    Linked NR2A expression to faster NMDAR EPSC kinetics, providing the molecular basis for the developmental shortening of synaptic NMDAR responses.

    Evidence Single-cell RT-PCR with whole-cell patch-clamp in postnatal neocortical neurons

    PMID:9065507

    Open questions at the time
    • Mechanism coupling subunit identity to deactivation rate not resolved
    • Trafficking basis of the switch not addressed
  4. 1996 High

    Demonstrated in vivo functional redundancy between NR2A and NR2C in cerebellar transmission and motor coordination using genetic epistasis.

    Evidence Single and double NR2A/NR2C knockout mice with cerebellar slice recordings and behavior

    PMID:8987814

    Open questions at the time
    • Redundancy may be region-specific; forebrain roles not tested here
  5. 2003 High

    Identified phosphorylation-controlled scaffolding interactions (CaMKII-GluN2A, SAP97-PDZ1) as regulators of synaptic targeting, addressing how receptor positioning is dynamically controlled.

    Evidence Co-IP from PSD/synaptosomes, overlay and crosslinking assays, in vitro pull-down with PDZ mutants and phospho-site analysis

    PMID:12933808 PMID:9751209

    Open questions at the time
    • Quantitative impact on synaptic receptor number in vivo not established
    • Interplay of multiple scaffolds not integrated
  6. 2006 High

    Showed GluN2A-containing receptors have lower surface mobility/higher stability than GluN2B, providing a trafficking mechanism for the developmental NR2B-to-NR2A switch.

    Evidence Single-particle tracking with subunit-specific extracellular probes across development in cultured neurons

    PMID:17124177

    Open questions at the time
    • Molecular determinants of differential mobility not identified
    • Relationship to scaffold binding not tested directly
  7. 2009 High

    Defined Src phosphorylation of GluN2A-Tyr1325 as a regulator of channel potentiation and downstream DARPP-32 signaling with behavioral consequences.

    Evidence Y1325F knock-in mice with striatal electrophysiology, phosphorylation analysis, and behavioral tests

    PMID:19834457

    Open questions at the time
    • Upstream signals controlling Src activity at GluN2A not fully defined
    • Generalization beyond striatum not shown
  8. 2010 High

    Dissected the role of GluN2 cytoplasmic tails in LTP, showing the GluN2A C-tail carries inhibitory factors, clarifying subunit-specific contributions to plasticity.

    Evidence RNAi knockdown with chimeric subunit rescue, pharmacology, and recordings in hippocampal slice cultures

    PMID:20164351

    Open questions at the time
    • Identity of the inhibitory C-tail factors not defined
    • In vivo relevance of chimera results not tested
  9. 2013 High

    Established multiple layers of GluN2A regulation—transcriptional (Sp4), translational (dendritic CPE-mediated synthesis), and scaffolding (IQGAP1/ERK)—plus subunit-selective partner binding (Sig1R to GluN1, not GluN2A).

    Evidence Promoter/ChIP/EMSA for Sp4; microfluidic dendrite isolation with local translation and surface insertion assays; IQGAP1 KO co-IP and ERK assays; AFM/co-isolation/PLA for Sig1R

    PMID:21653857 PMID:23678131 PMID:23871830 PMID:24227730

    Open questions at the time
    • IQGAP1 and Sig1R findings are single-lab Medium-confidence (co-IP/PLA without reciprocal in vivo validation)
    • Integration of transcriptional and translational control not unified
  10. 2014 High

    Resolved triheteromeric GluN1/GluN2A/GluN2B pharmacology and kinetics, and uncovered a tumor-suppressive role for GluN2A in melanoma with dominant-negative somatic mutants.

    Evidence Forced triheteromer expression with patch-clamp and antagonist profiling; melanoma functional assays with co-IP, soft-agar growth, migration, and shRNA depletion

    PMID:24607230 PMID:24739903

    Open questions at the time
    • Melanoma role is single-lab Medium-confidence; downstream tumor-suppressive signaling unresolved
    • Native abundance of triheteromers in vivo not quantified
  11. 2015 High

    Characterized the pore N615K variant as gain-of-function (loss of Mg2+ block, reduced blocker sensitivity), advancing genotype-to-channel-phenotype mapping for disease.

    Evidence Two-electrode voltage clamp in oocytes and patch-clamp in primary cortical neurons

    PMID:20890276 PMID:26312887

    Open questions at the time
    • Circuit-level consequences not addressed in these reports
    • Ca2+ permeability versus Mg2+ block effects partly system-dependent
  12. 2017 High

    Systematically linked variant domain location to direction of functional change—linker/TM gain-of-function vs ATD/LBD loss-of-function—and demonstrated pharmacological rescue of loss-of-function mutants.

    Evidence Single-channel and whole-cell electrophysiology with modeling (M817V); calcium flux, trafficking, Western blot, and PAM rescue for LoF mutants

    PMID:28126851 PMID:28242877

    Open questions at the time
    • In vivo validation of rescue not performed in these studies
    • Trafficking deficits not the cause of reduced agonist response, leaving conformational basis incomplete
  13. 2018 High

    Provided the structural mechanism of GluN2A ATD zinc/proton allostery transduced to the channel gate, explaining a hallmark biophysical property of GluN2A-NMDARs.

    Evidence Cryo-EM of GluN1/GluN2A under varying zinc and proton concentrations

    PMID:30500536

    Open questions at the time
    • Dynamics of gating transitions not fully captured
    • Link to specific disease variants not mapped in this study
  14. 2019 High

    Resolved the broad genotype-phenotype architecture across a large cohort and connected GluN2A to interneuron-relevant circuit function, while also defining GluN2A roles in transport, disease toxicity, and a primate-specific isoform.

    Evidence Electrophysiology of recombinant mutants and Grin2a+/- neurons with clinical correlation (248 patients); KIF3B transport imaging; homocysteine/alpha-synuclein toxicity models; isoform RT-PCR/expression

    PMID:30544257 PMID:30927362 PMID:31167782 PMID:31272478 PMID:31746486

    Open questions at the time
    • Several mechanistic links (KIF3B, homocysteine, alpha-synuclein, isoform) are single-lab Medium-confidence
    • How LoF/GoF maps to specific human seizure circuits remains incomplete
  15. 2020 High

    Defined CaMKIIα phosphorylation of GluN2A-S1459 as a trafficking switch (SNX27 vs PSD-95) and validated disease variants (S1459G, S644G) in knock-in mice, connecting molecular regulation to seizures.

    Evidence In vitro kinase assay, co-IP, trafficking and spine/synaptic assays; S644G knock-in mice with slice/MEA recordings and antagonist rescue

    PMID:32577763 PMID:32877683

    Open questions at the time
    • Endogenous stoichiometry of S1459 phosphorylation in vivo not quantified
    • Long-term behavioral outcomes of antagonist rescue not established
  16. 2021 High

    Used high-resolution structures and circuit physiology to define GluN2A-specific allosteric routes, ligand engagement modes, and the requirement of voltage-dependent Ca2+ signaling for sensory and associative function.

    Evidence Cryo-EM of human GluN1-GluN2A with multiple ligands; functional/structural interface mutagenesis; Grin2aN615S knock-in EEG, seizure, and behavioral studies; shRNA knockdown with memory/seizure assays

    PMID:33420383 PMID:33897358 PMID:34186027 PMID:34354080

    Open questions at the time
    • Knockdown study is single-lab Medium-confidence
    • How structural allostery maps onto specific gain-of-function disease variants not fully integrated
  17. 2022 High

    Identified an ER-retention KKK signal whose disruption (K879R) increases surface GluN2A, suppressing GluN2B/AMPA currents and impairing bidirectional plasticity and memory, showing that over-surfacing GluN2A is itself pathogenic.

    Evidence Heterologous surface biotinylation, CA1 patch-clamp, LTP/LTD recordings in knock-in mice, and memory tasks

    PMID:35484243

    Open questions at the time
    • Endogenous regulation of the KKK motif not characterized
    • Mechanism of GluN2B/AMPA suppression by excess GluN2A not fully defined
  18. 2023 High

    Demonstrated that Grin2a loss delays parvalbumin interneuron maturation in a gene-dosage-dependent manner, linking GluN2A to inhibitory circuit development and excitability.

    Evidence Electrophysiology of PV interneurons across developmental timepoints in Grin2a+/+, +/-, and -/- mice

    PMID:37723282

    Open questions at the time
    • Molecular pathway from GluN2A loss to delayed PV maturation not defined
    • Reversibility and therapeutic window not tested
  19. 2024 Medium

    Extended GluN2A genotype-function mapping to schizophrenia and DD/ID variants (including dominant-negative LoF) and revealed RNA-level (m6A) and feedback-phosphorylation mechanisms controlling GluN2A in disease contexts.

    Evidence Co-expression electrophysiology of WT/mutant receptors; METTL14/IGF2BP2 m6A methylation in DRG with pain models; homocysteine-driven Pyk2/Src-Tyr1325 feedback and mitochondrial ROS imaging

    PMID:38307912 PMID:38319733 PMID:38569938

    Open questions at the time
    • m6A and feedback-phosphorylation findings are single-lab Medium-confidence
    • Dominant-negative mechanism at the receptor assembly level not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse regulatory inputs (scaffold phosphorylation, ER retention, transport, local translation, m6A) are integrated to set synaptic GluN2A levels in vivo, and how this quantitatively predicts gain- versus loss-of-function disease outcomes, remains unresolved.
  • No unified quantitative model linking trafficking control to channel-level disease severity
  • Endogenous stoichiometry of key phospho/methylation marks in human neurons unknown
  • In vivo therapeutic windows for PAM/antagonist rescue not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-9609507 Protein localization 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
CAMK2ADLG1DLG4GRIN1IQGAP1KIF3BSNX27SRC
Complex memberships
GluN1/GluN2A NMDA receptorGluN1/GluN2A/GluN2B triheteromeric NMDA receptorpostsynaptic density

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 NR2A subunit expression in cortical neurons shortens NMDA receptor-mediated EPSC duration; even low-level NR2A mRNA expression was sufficient to alter the NMDA receptor time course, providing a molecular basis for the developmental change in NMDAR EPSC duration. Single-cell RT-PCR combined with whole-cell patch-clamp electrophysiology in postnatal neocortical neurons in vivo The Journal of Neuroscience High 9065507
1994 NR2A and NR2B subunits localize to postsynaptic densities in dendrites of cerebral cortex and hippocampus neurons, consistent with assembly into functional NR1/NR2 receptor complexes at synapses in vivo. Immunocytochemistry with subunit-specific antibodies; electron microscopy of rat brain sections The Journal of Neuroscience High 7931566
1993 NMDAR1 and NMDAR2A subunits co-assemble to form a heteromeric complex in HEK293 cells with [3H]MK801 binding properties similar to native adult mammalian forebrain NMDA receptors; co-expression of NR1 and NR2A yields a 10-fold increase in MK801 binding sites over single-subunit expression. Transient co-transfection in HEK293 cells, [3H]MK801 radioligand binding, immunological characterization with anti-NMDAR2A antibody, N-deglycosylation The Biochemical Journal High 7904155
1996 NR2A and NR2C subunits each contribute distinct NMDA receptor-mediated excitatory transmission properties in cerebellar mossy fiber-granule cell synapses; combined knockout of NR2A and NR2C nearly abolishes NMDAR-mediated EPSC components and causes motor discoordination, while single knockouts do not, demonstrating functional redundancy between NR2A and NR2C in motor coordination. Knockout mouse generation (NR2A-/-, NR2C-/-, double knockout), whole-cell recordings from cerebellar slices, motor coordination behavioral assays The Journal of Neuroscience High 8987814
1998 CaMKII physically associates with NR2A and NR2B subunits of NMDA receptors in postsynaptic densities isolated from cortex and hippocampus; this association was confirmed by co-immunoprecipitation, overlay assays with 32P-autophosphorylated CaMKII, and chemical crosslinking. Immunoprecipitation from PSD fractions, overlay assay with 32P-CaMKII, crosslinking with DSS, co-IP with anti-CaMKII and anti-NR2A/B antibodies Journal of Neurochemistry High 9751209
2003 SAP97 directly interacts with the NR2A subunit through its PDZ1 domain; CaMKII-dependent phosphorylation of SAP97 at Ser-232 disrupts the SAP97/NR2A interaction, providing a mechanism for regulation of NMDA receptor synaptic targeting. In vitro pull-down assay, co-immunoprecipitation from hippocampal homogenates and synaptosomes, metabolic labeling, KN-93 CaMKII inhibitor treatment, PDZ domain mutants, CaMKII constitutively active expression in COS-7 cells The Journal of Biological Chemistry High 12933808
2006 NR2A-containing NMDARs are more stable at the neuronal surface than NR2B-containing NMDARs; NR2A subunit overexpression stabilizes surface NR2B-containing NMDARs. The developmental switch in synaptic NMDAR subtype composition depends on regulation of receptor surface trafficking. Single-particle tracking and single-molecule imaging with subunit-specific antibodies against extracellular epitopes of NR2A and NR2B in cultured neurons Proceedings of the National Academy of Sciences High 17124177
2009 NR2A (NMDAR2A) is tyrosine-phosphorylated at Tyr-1325 by Src kinase; knock-in mice with Tyr1325Phe mutation show antidepressant-like behavior, increased DARPP-32 phosphorylation at Thr34 in the striatum, and loss of Src-induced potentiation of NMDA receptor channel activity in the striatum. Knock-in mouse generation (Y1325F), tail suspension and forced swim tests, biochemical phosphorylation analysis, electrophysiology in striatal neurons The EMBO Journal High 19834457
2010 The NR2B cytoplasmic tail (not its channel function) is required for LTP induction; the NR2A cytoplasmic tail carries inhibitory factors for LTP. A chimeric NR2B with NR2A C-tail fails to rescue LTP, while NR2A with NR2B C-tail restores LTP; NR2A lacking its entire C-terminal tail can restore LTP. RNAi knockdown, chimeric subunit overexpression, pharmacological antagonism (Ro25-6981), whole-cell recordings in organotypic hippocampal slice cultures The Journal of Neuroscience High 20164351
2010 The GRIN2A p.N615K mutation in the channel pore causes loss of Mg2+ block and decreased Ca2+ permeability of NR1-NR2A(N615K) receptors, demonstrating gain-of-function NMDAR channel properties linked to epileptic encephalopathy. Heterologous expression in Xenopus oocytes, two-electrode voltage-clamp electrophysiology Nature Genetics High 20890276
2013 IQGAP1 scaffolding protein is a component of NMDAR multiprotein complexes and functionally interacts with NR2A subunits and the ERK1/2 signaling pathway; IQGAP1 knockout neurons show reduced surface NR2A expression and disrupted ERK signaling in response to NR2A-dependent NMDAR stimulation. Co-immunoprecipitation, surface expression assays, NR2A-dependent pharmacological stimulation, ERK phosphorylation assays in hippocampal cultures and brain slices from IQGAP1-/- mice The Journal of Neuroscience Medium 21653857
2013 Activity-induced insertion of GluN2A-containing NMDA receptors into the dendritic membrane requires local dendritic protein synthesis; GluN2A mRNA in dendrites is translationally regulated via a 3' UTR cytoplasmic polyadenylation element (CPE) and its associated translation complex. Microfluidic chamber isolation of dendrites, activity stimulation, surface biotinylation, fluorescence visualization of local GluN2A translation and membrane insertion, CPE mutant analysis The Journal of Neuroscience High 23678131
2013 Sigma-1 receptor (Sig1R) binds directly to GluN1 but not to GluN2A within the GluN1/GluN2A NMDA receptor heterotetramers; the Sig1R C-terminus is extracellular, as shown by in situ proximity ligation assay. Atomic force microscopy imaging of isolated receptors, co-isolation of Sig1R with GluN1 and GluN2A, in situ proximity ligation assay in intact cells The Journal of Neuroscience High 24227730
2014 GluN1/GluN2A/GluN2B triheteromeric NMDA receptors have distinct glutamate deactivation kinetics compared to diheteromers, and show intermediate sensitivity to subunit-selective antagonists (ifenprodil, CP-101,606, TCN-201) and extracellular Zn2+; the ifenprodil binding site geometry is altered in triheteromers relative to GluN1/GluN2B diheteromers. Forced surface expression of recombinant triheteromers in HEK293 cells, whole-cell patch-clamp electrophysiology, pharmacological profiling with selective antagonists Neuron High 24607230
2014 The GRIN2A c.2434C>A (p.L812M) de novo mutation increases charge transfer through GluN2A-L812M-containing NMDARs, and these receptors retain sensitivity to the channel blocker memantine, supporting its use as personalized therapy. In vitro electrophysiology of mutant receptors expressed in heterologous cells, pharmacological screening with NMDAR blockers Annals of Clinical and Translational Neurology Medium 24839611
2018 Cryo-electron microscopy of the GluN1/GluN2A NMDA receptor reveals that zinc binds to the amino-terminal domain (ATD) of GluN2A and elicits structural changes transduced through the ligand-binding domain to constrict the ion channel gate; proton inhibition acts through the same allosteric pathway. Cryo-electron microscopy (cryo-EM) of GluN1/GluN2A receptor under varying zinc and proton concentrations Cell High 30500536
2019 GRIN2A missense variants in transmembrane and linker domains predominantly cause NMDAR gain-of-function and are associated with severe developmental phenotypes, while missense variants in ATD/LBD and null variants cause NMDAR loss-of-function and milder phenotypes; Grin2a+/- cortical neurons show reduced NMDAR function without compensatory GluN2B upregulation. Electrophysiology of recombinant mutant receptors, cortical neuron recordings from Grin2a+/- rats, clinical phenotype-genotype correlation in 248 patients Brain High 30544257
2019 Alpha-synuclein oligomers selectively reduce GluN2A NMDA receptor subunit synaptic localization and GluN2A-mediated synaptic currents in striatal spiny projection neurons; antibodies targeting alpha-synuclein prevent this loss of GluN2A synaptic localization and LTP impairment. Electrophysiology, optogenetics, immunofluorescence, intrastriatal injections of alpha-synuclein, behavioral assays, antibody treatment Brain Medium 30927362
2019 KIF3B kinesin transports vesicles simultaneously containing NR2A and APC complex in dendrites; Kif3b+/- neurons show impaired NR2A dendritic transport and reduced dendritic NR2A levels, leading to decreased NMDAR electrophysiological response and disrupted synaptic plasticity. Co-immunoprecipitation, live imaging of NR2A vesicle transport, electrophysiology in hippocampal slices, rescue experiments in Kif3b+/- neurons The EMBO Journal Medium 31746486
2020 CaMKIIα phosphorylates GluN2A at S1459; this phosphorylation is regulated during development and by synaptic activity (dark rearing model). S1459 phosphorylation promotes SNX27 binding and reduces PSD-95 binding, regulating NMDAR trafficking. The epilepsy-associated GluN2A-S1459G variant shows defective SNX27 and PSD-95 interactions, reduced spine density, and decreased excitatory synaptic transmission. In vitro kinase assay identifying CaMKIIα phosphorylation site, co-immunoprecipitation, surface trafficking assay, spine density measurement, synaptic transmission recording, dark rearing model Cell Reports High 32877683
2021 Cryo-EM structures of the human GluN1-GluN2A receptor reveal: (1) competitive antagonists bind to LBDs of GluN1 and GluN2A; (2) a positive allosteric modulator shortens LBD-to-TMD distance, stretching the channel gate open; (3) the channel blocker 9-aminoacridine binds within the LBD-TMD linker region rather than within the TMD vestibule. Cryo-electron microscopy (cryo-EM) of full-length human GluN1-GluN2A with distinct ligands and modulators at ~4 Å resolution Neuron High 34186027
2021 GluN2A and GluN2B receptors utilize distinct long-range allosteric mechanisms involving different subunit-subunit interfaces and molecular rearrangements between the N-terminal domain and transmembrane domain; GluN2A-NTD allostery is mechanistically distinct from GluN2B-NTD allostery. Functional electrophysiology combined with structural analysis (cryo-EM or X-ray crystallography implied by 'structural interrogation'), mutagenesis of interface residues Nature Communications High 34354080
2013 Sp4 transcription factor functionally regulates transcription of GluN2A (and GluN1, GluN2B, but not GluN2C); Sp1 and Sp3 do not regulate these NMDA receptor subunits. Sp4 acts complementarily and in parallel with NRF-1 and NRF-2 at GluN2A promoter. Promoter-reporter assays, chromatin immunoprecipitation, siRNA knockdown of Sp4 in neurons, electrophoretic mobility shift assay Biochimica et Biophysica Acta Medium 23871830
2019 GluN2A-NMDAR mediates homocysteine-induced sustained low-level Ca2+ influx and ERK MAPK-dependent neuronal death; this is mechanistically distinct from glutamate-induced excitotoxicity mediated by GluN2B-NMDAR. Pharmacological inhibition or genetic deletion of GluN2A attenuates homocysteine-induced Ca2+ increase and neurotoxicity. Pharmacological GluN2A inhibition (NVP-AAM077), GluN2A genetic knockout neurons, Ca2+ imaging, ERK phosphorylation assays, cell viability assays in primary cortical cultures The Journal of Biological Chemistry Medium 31167782
2024 Homocysteine-induced sustained GluN2A-NMDAR Ca2+ influx triggers sequential phosphorylation of Pyk2 and Src family kinases, which phosphorylate GluN2A-Tyr1325 to maintain channel activity in a positive feedback loop; lack of STEP phosphatase activation sustains this cycle. GluN2A-NMDAR-mediated sustained ERK MAPK activation drives mitochondrial ROS generation. Live-cell Ca2+ imaging (Fluo3-AM), Pyk2/Src kinase inhibitors, phosphorylation assays, live-cell mitochondrial ROS imaging with redox-sensitive GFP, pharmacological and genetic GluN2A inhibition The Journal of Biological Chemistry Medium 38569938
2016 GluN2A-containing NMDAR activity mediates an adaptive response to HIV Tat toxin: Tat potentiates NMDARs and activates a GluN2A/Akt/Mdm2 pathway that causes loss of synaptic NMDAR clusters (via PSD-95 degradation); pharmacological inhibition of GluN2A-containing NMDARs prevents this adaptation. Patch-clamp recording, pharmacological inhibition of GluN2A (NVP-AAM077) vs GluN2B, genetic Mdm2 inhibition, GFP-GluN1 puncta imaging, protein synthesis inhibition The Journal of Neuroscience Medium 27810933
2017 GRIN2A epilepsy-associated mutations (P79R, C231Y, G483R, M705V) reduce glutamate and glycine agonist potency and decrease total protein levels and surface trafficking to the plasma membrane; C436R is not trafficked at all; reduced surface expression is not the cause of the reduced agonist response. Treatment with a GluN2A-selective positive allosteric modulator rescues the functional phenotype of these loss-of-function mutants. High-throughput calcium flux assay, patch-clamp electrophysiology, Western blotting, confocal surface trafficking imaging in HEK293 cells, PAM rescue experiments Scientific Reports High 28242877
2017 The GRIN2A de novo mutation p.M817V (pre-M4 linker) causes gain-of-function by enhancing agonist potency, reducing Mg2+/proton/zinc sensitivity, prolonging synaptic-like response time course, increasing single-channel mean open time and open probability; molecular modeling suggests M817V weakens GluN2 M4 interactions with GluN1 transmembrane helices, increasing pre-M1 flexibility. Whole-cell and single-channel electrophysiology in heterologous cells, synaptic-like response recordings, molecular modeling of closed-channel conformation Molecular Pharmacology High 28126851
2020 The GRIN2A p.Ser644Gly mutation causes gain-of-function: enhanced NMDAR agonist potency and slow deactivation after glutamate removal. In heterozygous knock-in mice, NMDAR-mediated synaptic currents in hippocampal slices show prolonged deactivation time course, increased circuit excitability, and altered bursting. NMDAR antagonist treatment delayed lethal seizures in homozygous knock-in pups. Heterologous cell electrophysiology of mutant receptor, hippocampal slice recordings from knock-in mice, multielectrode array recordings, behavioral assays, pharmacological rescue with NMDAR antagonists Brain High 32577763
2023 Loss of Grin2a causes transient, gene dosage-dependent delays in the electrophysiological maturation of parvalbumin (PV) interneurons in CA1, leading to increased circuit excitability and CA1 pyramidal cell output; Grin2a-/- mice do not reach PV cell maturation until adulthood, and Grin2a+/- mice are delayed until preadolescence. Electrophysiological recordings from PV interneurons in Grin2a+/+, +/-, and -/- mice at multiple developmental timepoints, circuit excitability analysis Communications Biology High 37723282
2022 A GluN2A K879R rare variant disrupts a KKK endoplasmic reticulum retention signal, enhancing surface expression of GluN2A-NMDAR; elevated synaptic GluN2A-NMDAR suppresses GluN2B-NMDAR and AMPA receptor-mediated currents, impairs both LTP and LTD, and causes learning and memory deficits in knock-in mice. Heterologous expression, surface biotinylation, whole-cell patch-clamp in hippocampal CA1 neurons, LTP and LTD recordings in knock-in slices, behavioral memory tasks Molecular Psychiatry High 35484243
2021 Voltage-independent GluN2A-containing NMDAR Ca2+ signaling (in Grin2aN615S knock-in mice) causes audiogenic seizures via hyperexcitable midbrain circuits, while hippocampal activity and theta-gamma synchronization are reduced; this demonstrates that voltage-dependent (Mg2+ block-dependent) Ca2+ signaling of GluN2A-NMDARs is essential for appropriate sensory responses and associative learning. Grin2aN615S knock-in mice (voltage-independent Ca2+ influx mutation), EEG/LFP recordings, audiogenic seizure assay, MK-801 c-Fos mapping, behavioral tests Communications Biology High 33420383
2024 SCZ-associated GRIN2A variants are predominantly loss-of-function; two DD/ID-associated LoF variants (M653I and S809R) exert dominant-negative effects on co-expressed wild-type GluN2A, whereas SCZ-linked LoF variants (E58Ter, Y698C) and an epilepsy-linked LoF variant (A727T) do not exhibit dominant-negative effects. Electrophysiology of recombinant GluN1/GluN2A receptors with co-expression of WT and mutant subunits in heterologous cells Scientific Reports Medium 38307912
2024 METTL14-mediated m6A methylation of GluN2A mRNA (read by IGF2BP2) stabilizes GluN2A expression and enhances presynaptic NMDAR activity in DRG neurons, contributing to chemotherapy-induced neuropathic pain; blocking METTL14 reduces m6A methylation and attenuates pain hypersensitivity. Dot blotting, immunofluorescence, gain/loss-of-function AAV experiments, behavioral pain assays in rodent CINP model, human DRG validation The Journal of Clinical Investigation Medium 38319733
2014 Somatic GRIN2A mutations in melanoma cause loss of NMDAR complex formation between GluN1 and mutant GluN2A, functioning as dominant negatives that inhibit the tumor-suppressive phenotype of wild-type GluN2A; GRIN2A depletion in WT melanoma cells increases proliferation and migration. Functional characterization of GRIN2A mutants, NMDAR complex formation assay (co-immunoprecipitation), soft agar anchorage-independent growth, migration assay, shRNA depletion The Journal of Investigative Dermatology Medium 24739903
1993 NR2A protein has a molecular weight of ~175 kDa (162 kDa after N-deglycosylation), is N-glycosylated, and is expressed at high levels in hippocampus and cortex but absent from cerebellum (where NR2C is found); NR2C is 140 kDa (127 kDa deglycosylated). Polyclonal antibody characterization by Western blot, N-deglycosylation, brain region fractionation Protein Science Medium 8298456
2019 A primate-specific short GluN2A isoform (GluN2A-S) is expressed in human and primate but not rodent brain and co-assembles with GluN1 to form functional NMDA receptors. RT-PCR and Western blot of human and primate brain tissue, recombinant expression of GluN2A-S with GluN1, electrophysiological verification of functional NMDA receptor formation Molecular Brain Medium 31272478
2012 Mass spectrometry identified a novel phosphorylation site on NR2A at S511 (in addition to known sites), identified from immunoprecipitated native NMDA receptor complexes from rat hippocampus; phosphorylation was verified by phosphatase treatment and reanalysis. Immunoprecipitation of NR1-containing complexes from rat hippocampus, nano-LC-ESI-MS/MS, phosphatase treatment and reanalysis Journal of Proteome Research Medium 22335236
2015 The de novo GRIN2A p.N615K (pore region) mutation substantially decreases Mg2+ block (from 89% to 5% at -60 mV, 1 mM Mg2+), reduces memantine and amantadine block, and decreases NMDAR current density in primary cortical neurons transfected with mutant GluN2A. Two-electrode voltage clamp in Xenopus oocytes, whole-cell patch-clamp in mouse primary cortical pyramidal neurons Lancet High 26312887
2021 Hippocampal GluN2A-NMDAR reduction (via shRNA) shifts the GluN2A/GluN2B ratio without altering expression of other regulatory subunits, impairs contextual fear-conditioning memory, and increases seizure susceptibility in adult rats. In vitro and in vivo shRNA knockdown, Western blot, fear conditioning, seizure susceptibility assays Frontiers in Neuroscience Medium 33897358

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 499 9065507
1994 The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1. The Journal of neuroscience : the official journal of the Society for Neuroscience 421 7931566
2010 Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature genetics 404 20890276
2006 NMDA receptor surface mobility depends on NR2A-2B subunits. Proceedings of the National Academy of Sciences of the United States of America 295 17124177
2014 Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 260 24607230
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
2014 GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Annals of clinical and translational neurology 207 24839611
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
2019 GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain : a journal of neurology 176 30544257
1996 Motor discoordination results from combined gene disruption of the NMDA receptor NR2A and NR2C subunits, but not from single disruption of the NR2A or NR2C subunit. The Journal of neuroscience : the official journal of the Society for Neuroscience 164 8987814
1998 Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities. Journal of neurochemistry 152 9751209
1994 Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina. The Journal of comparative neurology 142 7836563
2005 Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. American journal of human genetics 141 15830322
2006 Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain research 125 17113057
2010 Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors. The Journal of pharmacology and experimental therapeutics 122 20810618
2008 Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. The international journal of neuropsychopharmacology 116 18570704
2019 Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Research 115 31807283
1996 Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes. Glia 112 8840166
1993 Optimal expression of cloned NMDAR1/NMDAR2A heteromeric glutamate receptors: a biochemical characterization. The Biochemical journal 110 7904155
2018 Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor. Cell 105 30500536
2003 Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. The European journal of neuroscience 101 12956718
2020 Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity. International journal of molecular sciences 98 32102377
2019 Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration. Brain : a journal of neurology 96 30927362
2003 CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction. The Journal of biological chemistry 88 12933808
2003 A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. Pharmacogenetics 87 12724619
2013 The σ-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 84 24227730
2011 IQGAP1 regulates NR2A signaling, spine density, and cognitive processes. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 21653857
2017 Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue. Scientific reports 76 28242877
2009 Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour. The EMBO journal 76 19834457
2017 Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy. Molecular pharmacology 67 28126851
2020 Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice. Brain : a journal of neurology 66 32577763
2023 Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice. Neuron 58 37657442
2021 Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors. Neuron 57 34186027
2015 GRIN2A: an aptly named gene for speech dysfunction. Neurology 56 25596506
2004 Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region. Molecular psychiatry 56 14699423
2013 Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behavioural brain research 55 24029697
1999 Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Experimental neurology 53 10506512
2017 A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. PloS one 52 28182669
2018 The differences between GluN2A and GluN2B signaling in the brain. Journal of neuroscience research 51 29682799
2023 Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients. Translational psychiatry 50 36914641
2019 Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. The EMBO journal 50 31746486
2023 GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia. Molecular psychiatry 49 37736757
2019 Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways. Frontiers in pharmacology 48 31024297
2020 An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking. Cell reports 46 32877683
2013 Dendritic GluN2A synthesis mediates activity-induced NMDA receptor insertion. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 23678131
2019 GluN2A-NMDA receptor-mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death. The Journal of biological chemistry 45 31167782
2018 The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions. Scientific reports 45 29339791
2017 GluN1 and GluN2A NMDA Receptor Subunits Increase in the Hippocampus during Memory Consolidation in the Rat. Frontiers in behavioral neuroscience 45 28133447
2024 METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2. The Journal of clinical investigation 41 38319733
2011 Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 39 21919190
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
1999 Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence. The American journal of physiology 37 10070151
2023 GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases. Pharmaceuticals (Basel, Switzerland) 35 38004401
2019 Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations. Epileptic disorders : international epilepsy journal with videotape 35 31149903
2016 The Functional and Molecular Properties, Physiological Functions, and Pathophysiological Roles of GluN2A in the Central Nervous System. Molecular neurobiology 35 26797520
2021 Knockdown of astrocytic Grin2a aggravates β-amyloid-induced memory and cognitive deficits through regulating nerve growth factor. Aging cell 34 34291567
2016 Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells. Journal of Alzheimer's disease : JAD 33 27497478
1999 NMDA receptor NR1 and NR2A/B subunit expression in trigeminal neurons during early postnatal development. The Journal of comparative neurology 33 10379917
2023 Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons. Communications biology 32 37723282
2022 Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory. Molecular psychiatry 32 35484243
2021 Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Communications biology 32 33420383
2014 Somatic mutation of GRIN2A in malignant melanoma results in loss of tumor suppressor activity via aberrant NMDAR complex formation. The Journal of investigative dermatology 32 24739903
2019 Memory and plasticity impairment after binge drinking in adolescent rat hippocampus: GluN2A/GluN2B NMDA receptor subunits imbalance through HDAC2. Addiction biology 31 31056842
2018 Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. Behavioural brain research 31 30296532
2015 Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation. Psychopharmacology 30 26184010
1993 Characterization of the NR1, NR2A, and NR2C receptor proteins. Protein science : a publication of the Protein Society 30 8298456
2002 Postnatal development of NR2A and NR2B mRNA expression in rat auditory cortex and thalamus. Journal of the Association for Research in Otolaryngology : JARO 29 12486601
2018 A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder. Movement disorders : official journal of the Movement Disorder Society 28 29644724
2015 Association between GRIN2A promoter polymorphism and recovery from concussion. Brain injury 28 26502998
2022 De novo GRIN2A variants associated with epilepsy and autism and literature review. Epilepsy & behavior : E&B 27 35217385
2022 Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A. Communications biology 27 35228668
2024 Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. Physiological research 26 38836461
2013 Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B. Biochimica et biophysica acta 26 23871830
2015 Effect of a GRIN2A de novo mutation associated with epilepsy and intellectual disability on NMDA receptor currents and Mg(2+) block in cultured primary cortical neurons. Lancet (London, England) 25 26312887
2014 Caffeine interaction with glutamate receptor gene GRIN2A: Parkinson's disease in Swedish population. PloS one 25 24915238
2024 Homocysteine-induced sustained GluN2A NMDA receptor stimulation leads to mitochondrial ROS generation and neurotoxicity. The Journal of biological chemistry 24 38569938
2017 GRIN2A mutations in epilepsy-aphasia spectrum disorders. Brain & development 24 29056244
2013 Two patients with a GRIN2A mutation and childhood-onset epilepsy. Pediatric neurology 24 24125812
2015 Correlation of functional GRIN2A gene promoter polymorphisms with schizophrenia and serum D-serine levels. Gene 23 25958346
2015 Different sites of alcohol action in the NMDA receptor GluN2A and GluN2B subunits. Neuropharmacology 23 26051400
2014 Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival. Frontiers in oncology 23 24455489
2021 Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory. Frontiers in neuroscience 22 33897358
2017 Caffeine, creatine, GRIN2A and Parkinson's disease progression. Journal of the neurological sciences 22 28320167
2016 The GRIN2B and GRIN2A Gene Variants Are Associated With Continuous Performance Test Variables in ADHD. Journal of attention disorders 22 27199241
2021 Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms. Life (Basel, Switzerland) 21 34685369
2002 Differential NR2A and NR2B expression between trigeminal neurons during early postnatal development. Synapse (New York, N.Y.) 21 11891879
2012 Mass spectrometrical identification of hippocampal NMDA receptor subunits NR1, NR2A-D and five novel phosphorylation sites on NR2A and NR2B. Journal of proteome research 20 22335236
2024 Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders. Scientific reports 19 38307912
2022 Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches. Biomolecules 19 35204682
2021 GluN2B and GluN2A-containing NMDAR are differentially involved in extinction memory destabilization and restabilization during reconsolidation. Scientific reports 19 33420399
2021 GRIN2A Variants Associated With Idiopathic Generalized Epilepsies. Frontiers in molecular neuroscience 19 34720871
2018 Interaction between caffeine and polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2) on Parkinson's disease risk. Movement disorders : official journal of the Movement Disorder Society 19 29318639
2017 The Role of GluN2A in Cerebral Ischemia: Promoting Neuron Death and Survival in the Early Stage and Thereafter. Molecular neurobiology 19 28102473
2016 NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 27810933
2018 Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children. Environmental research 18 29655037
1994 Expression of NMDAR1-1a (N598Q)/NMDAR2A receptors results in decreased cell mortality. European journal of pharmacology 18 7909752
2019 A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain. Molecular brain 17 31272478
2015 Investigation of GRIN2A in common epilepsy phenotypes. Epilepsy research 17 26220384
2022 GRIN2A-related epilepsy and speech disorders: A comprehensive overview with a focus on the role of precision therapeutics. Epilepsy research 16 36516565

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