{"gene":"GRIN2A","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1997,"finding":"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.","method":"Single-cell RT-PCR combined with whole-cell patch-clamp electrophysiology in postnatal neocortical neurons in vivo","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct correlation of NR2A mRNA expression with EPSC kinetics in identified single neurons across multiple postnatal ages, replicated across many cells","pmids":["9065507"],"is_preprint":false},{"year":1994,"finding":"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.","method":"Immunocytochemistry with subunit-specific antibodies; electron microscopy of rat brain sections","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ultrastructural localization by EM with specific antibodies, replicated across brain regions","pmids":["7931566"],"is_preprint":false},{"year":1993,"finding":"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.","method":"Transient co-transfection in HEK293 cells, [3H]MK801 radioligand binding, immunological characterization with anti-NMDAR2A antibody, N-deglycosylation","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of heteromeric complex with functional readout, multiple orthogonal methods","pmids":["7904155"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Knockout mouse generation (NR2A-/-, NR2C-/-, double knockout), whole-cell recordings from cerebellar slices, motor coordination behavioral assays","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo with direct electrophysiological readout, multiple genotypes compared","pmids":["8987814"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Immunoprecipitation from PSD fractions, overlay assay with 32P-CaMKII, crosslinking with DSS, co-IP with anti-CaMKII and anti-NR2A/B antibodies","journal":"Journal of Neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus multiple orthogonal biochemical methods (overlay, crosslinking) from native brain tissue","pmids":["9751209"],"is_preprint":false},{"year":2003,"finding":"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.","method":"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","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro pull-down plus co-IP from native tissue plus phosphorylation site mutagenesis, multiple orthogonal methods","pmids":["12933808"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Single-particle tracking and single-molecule imaging with subunit-specific antibodies against extracellular epitopes of NR2A and NR2B in cultured neurons","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct single-molecule surface mobility measurements with subunit-specific probes, developmental time series","pmids":["17124177"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Knock-in mouse generation (Y1325F), tail suspension and forced swim tests, biochemical phosphorylation analysis, electrophysiology in striatal neurons","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo phosphorylation site knock-in with electrophysiological and behavioral readouts, multiple methods","pmids":["19834457"],"is_preprint":false},{"year":2010,"finding":"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.","method":"RNAi knockdown, chimeric subunit overexpression, pharmacological antagonism (Ro25-6981), whole-cell recordings in organotypic hippocampal slice cultures","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection with chimeric constructs plus pharmacology plus electrophysiology, multiple rescue experiments","pmids":["20164351"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Heterologous expression in Xenopus oocytes, two-electrode voltage-clamp electrophysiology","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiological reconstitution of mutant receptor, single lab but rigorous functional assay","pmids":["20890276"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, surface expression assays, NR2A-dependent pharmacological stimulation, ERK phosphorylation assays in hippocampal cultures and brain slices from IQGAP1-/- mice","journal":"The Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and KO neuron phenotyping with specific pharmacological dissection, single lab","pmids":["21653857"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Microfluidic chamber isolation of dendrites, activity stimulation, surface biotinylation, fluorescence visualization of local GluN2A translation and membrane insertion, CPE mutant analysis","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct visualization of local translation with functional surface insertion assay, multiple orthogonal methods including genetic CPE mutation","pmids":["23678131"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Atomic force microscopy imaging of isolated receptors, co-isolation of Sig1R with GluN1 and GluN2A, in situ proximity ligation assay in intact cells","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — AFM structural imaging plus biochemical co-isolation plus in situ PLA, multiple orthogonal methods","pmids":["24227730"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Forced surface expression of recombinant triheteromers in HEK293 cells, whole-cell patch-clamp electrophysiology, pharmacological profiling with selective antagonists","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of defined triheteromeric receptor with rigorous pharmacological and kinetic characterization","pmids":["24607230"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro electrophysiology of mutant receptors expressed in heterologous cells, pharmacological screening with NMDAR blockers","journal":"Annals of Clinical and Translational Neurology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and pharmacological characterization, single lab","pmids":["24839611"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Cryo-electron microscopy (cryo-EM) of GluN1/GluN2A receptor under varying zinc and proton concentrations","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural determination by cryo-EM with multiple conformational states under physiologically relevant conditions","pmids":["30500536"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Electrophysiology of recombinant mutant receptors, cortical neuron recordings from Grin2a+/- rats, clinical phenotype-genotype correlation in 248 patients","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional electrophysiology correlated with genotype across large clinical cohort plus neuronal recordings, replicated across labs","pmids":["30544257"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Electrophysiology, optogenetics, immunofluorescence, intrastriatal injections of alpha-synuclein, behavioral assays, antibody treatment","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab, direct rescue with anti-alpha-synuclein antibody","pmids":["30927362"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, live imaging of NR2A vesicle transport, electrophysiology in hippocampal slices, rescue experiments in Kif3b+/- neurons","journal":"The EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of transport complex plus live imaging plus functional electrophysiology, single lab","pmids":["31746486"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro kinase assay identifying CaMKIIα phosphorylation site, co-immunoprecipitation, surface trafficking assay, spine density measurement, synaptic transmission recording, dark rearing model","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identified kinase, phosphorylation site, downstream binding partners, trafficking outcome, and disease variant functional consequences with multiple orthogonal methods","pmids":["32877683"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Cryo-electron microscopy (cryo-EM) of full-length human GluN1-GluN2A with distinct ligands and modulators at ~4 Å resolution","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structural determination with multiple ligand-bound states directly showing allosteric mechanisms","pmids":["34186027"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Functional electrophysiology combined with structural analysis (cryo-EM or X-ray crystallography implied by 'structural interrogation'), mutagenesis of interface residues","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — combined functional and structural interrogation with mutagenesis demonstrating distinct allosteric routes","pmids":["34354080"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Promoter-reporter assays, chromatin immunoprecipitation, siRNA knockdown of Sp4 in neurons, electrophoretic mobility shift assay","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular methods for transcriptional regulation, single lab","pmids":["23871830"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Pharmacological GluN2A inhibition (NVP-AAM077), GluN2A genetic knockout neurons, Ca2+ imaging, ERK phosphorylation assays, cell viability assays in primary cortical cultures","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus genetic loss-of-function with multiple readouts, single lab","pmids":["31167782"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus biochemical pathway dissection, single lab with multiple orthogonal readouts","pmids":["38569938"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Patch-clamp recording, pharmacological inhibition of GluN2A (NVP-AAM077) vs GluN2B, genetic Mdm2 inhibition, GFP-GluN1 puncta imaging, protein synthesis inhibition","journal":"The Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological plus genetic dissection with electrophysiology and imaging, single lab","pmids":["27810933"],"is_preprint":false},{"year":2017,"finding":"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.","method":"High-throughput calcium flux assay, patch-clamp electrophysiology, Western blotting, confocal surface trafficking imaging in HEK293 cells, PAM rescue experiments","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple mutations characterized by orthogonal functional, expression and trafficking assays with pharmacological rescue","pmids":["28242877"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Whole-cell and single-channel electrophysiology in heterologous cells, synaptic-like response recordings, molecular modeling of closed-channel conformation","journal":"Molecular Pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous in vitro reconstitution with single-channel analysis, pharmacological profiling, and structural modeling","pmids":["28126851"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Heterologous cell electrophysiology of mutant receptor, hippocampal slice recordings from knock-in mice, multielectrode array recordings, behavioral assays, pharmacological rescue with NMDAR antagonists","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution confirmed in native neuronal preparation (knock-in mice), multiple readouts including pharmacological rescue","pmids":["32577763"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Electrophysiological recordings from PV interneurons in Grin2a+/+, +/-, and -/- mice at multiple developmental timepoints, circuit excitability analysis","journal":"Communications Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene dosage series with direct electrophysiological phenotyping across multiple developmental stages","pmids":["37723282"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Heterologous expression, surface biotinylation, whole-cell patch-clamp in hippocampal CA1 neurons, LTP and LTD recordings in knock-in slices, behavioral memory tasks","journal":"Molecular Psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ER retention signal identified and validated with surface expression assay, knock-in mouse with synaptic plasticity and memory phenotype","pmids":["35484243"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Grin2aN615S knock-in mice (voltage-independent Ca2+ influx mutation), EEG/LFP recordings, audiogenic seizure assay, MK-801 c-Fos mapping, behavioral tests","journal":"Communications Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific knock-in mutation removing voltage-dependence, with multiple circuit-level and behavioral readouts","pmids":["33420383"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Electrophysiology of recombinant GluN1/GluN2A receptors with co-expression of WT and mutant subunits in heterologous cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro electrophysiology, single lab","pmids":["38307912"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Dot blotting, immunofluorescence, gain/loss-of-function AAV experiments, behavioral pain assays in rodent CINP model, human DRG validation","journal":"The Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with multiple readouts, single lab, translational validation in human DRG","pmids":["38319733"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Functional characterization of GRIN2A mutants, NMDAR complex formation assay (co-immunoprecipitation), soft agar anchorage-independent growth, migration assay, shRNA depletion","journal":"The Journal of Investigative Dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of complex formation, loss-of-function with specific cellular phenotype, single lab","pmids":["24739903"],"is_preprint":false},{"year":1993,"finding":"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).","method":"Polyclonal antibody characterization by Western blot, N-deglycosylation, brain region fractionation","journal":"Protein Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of native protein with antibodies and enzymatic deglycosylation, basic characterization","pmids":["8298456"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Molecular Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression confirmed in human tissue, functional reconstitution of novel isoform with GluN1, single lab","pmids":["31272478"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Immunoprecipitation of NR1-containing complexes from rat hippocampus, nano-LC-ESI-MS/MS, phosphatase treatment and reanalysis","journal":"Journal of Proteome Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification from native brain tissue with phosphatase verification, novel site identification","pmids":["22335236"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Two-electrode voltage clamp in Xenopus oocytes, whole-cell patch-clamp in mouse primary cortical pyramidal neurons","journal":"Lancet","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous electrophysiology in two separate experimental systems (oocytes and primary neurons) with quantitative pharmacological characterization","pmids":["26312887"],"is_preprint":false},{"year":2021,"finding":"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.","method":"In vitro and in vivo shRNA knockdown, Western blot, fear conditioning, seizure susceptibility assays","journal":"Frontiers in Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo specific knockdown with behavioral and seizure readouts, single lab","pmids":["33897358"],"is_preprint":false}],"current_model":"GluN2A (GRIN2A/NR2A) is a glutamate-binding regulatory subunit that co-assembles with obligate GluN1 subunits to form functional heterotetrameric NMDA receptor ion channels with distinct biophysical properties (faster deactivation, higher Mg2+ sensitivity, and nanomolar Zn2+ inhibition through allosteric ATD mechanisms) compared to GluN2B-containing receptors; its synaptic targeting is regulated by CaMKII-dependent phosphorylation at S1459 (controlling SNX27/PSD-95 binding and trafficking), SAP97 PDZ1-domain interaction (disrupted by CaMKII phosphorylation of SAP97-S232), Src kinase phosphorylation at Tyr1325 (regulating channel potentiation and downstream DARPP-32 signaling), and local dendritic mRNA translation via CPE-mediated polyadenylation; its surface mobility is lower than GluN2B, contributing to the developmental NR2B-to-NR2A synaptic switch; disease-causing mutations cause gain- or loss-of-function depending on their domain location, with transmembrane/linker domain mutations predominantly causing gain-of-function linked to severe epileptic encephalopathy and ATD/LBD mutations causing loss-of-function linked to milder epilepsy-aphasia spectrum disorders."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1993,"claim":"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","pmids":["7904155","8298456"],"confidence":"High","gaps":["Stoichiometry and subunit arrangement not resolved at this stage","Channel gating properties not directly measured"]},{"year":1994,"claim":"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","pmids":["7931566"],"confidence":"High","gaps":["Did not define functional consequence of synaptic localization","No subunit composition of individual PSD receptors"]},{"year":1997,"claim":"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","pmids":["9065507"],"confidence":"High","gaps":["Mechanism coupling subunit identity to deactivation rate not resolved","Trafficking basis of the switch not addressed"]},{"year":1996,"claim":"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","pmids":["8987814"],"confidence":"High","gaps":["Redundancy may be region-specific; forebrain roles not tested here"]},{"year":2003,"claim":"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","pmids":["9751209","12933808"],"confidence":"High","gaps":["Quantitative impact on synaptic receptor number in vivo not established","Interplay of multiple scaffolds not integrated"]},{"year":2006,"claim":"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","pmids":["17124177"],"confidence":"High","gaps":["Molecular determinants of differential mobility not identified","Relationship to scaffold binding not tested directly"]},{"year":2009,"claim":"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","pmids":["19834457"],"confidence":"High","gaps":["Upstream signals controlling Src activity at GluN2A not fully defined","Generalization beyond striatum not shown"]},{"year":2010,"claim":"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","pmids":["20164351"],"confidence":"High","gaps":["Identity of the inhibitory C-tail factors not defined","In vivo relevance of chimera results not tested"]},{"year":2013,"claim":"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","pmids":["23871830","23678131","21653857","24227730"],"confidence":"High","gaps":["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"]},{"year":2014,"claim":"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","pmids":["24607230","24739903"],"confidence":"High","gaps":["Melanoma role is single-lab Medium-confidence; downstream tumor-suppressive signaling unresolved","Native abundance of triheteromers in vivo not quantified"]},{"year":2015,"claim":"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","pmids":["26312887","20890276"],"confidence":"High","gaps":["Circuit-level consequences not addressed in these reports","Ca2+ permeability versus Mg2+ block effects partly system-dependent"]},{"year":2017,"claim":"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","pmids":["28126851","28242877"],"confidence":"High","gaps":["In vivo validation of rescue not performed in these studies","Trafficking deficits not the cause of reduced agonist response, leaving conformational basis incomplete"]},{"year":2018,"claim":"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","pmids":["30500536"],"confidence":"High","gaps":["Dynamics of gating transitions not fully captured","Link to specific disease variants not mapped in this study"]},{"year":2019,"claim":"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","pmids":["30544257","31746486","31167782","30927362","31272478"],"confidence":"High","gaps":["Several mechanistic links (KIF3B, homocysteine, alpha-synuclein, isoform) are single-lab Medium-confidence","How LoF/GoF maps to specific human seizure circuits remains incomplete"]},{"year":2020,"claim":"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","pmids":["32877683","32577763"],"confidence":"High","gaps":["Endogenous stoichiometry of S1459 phosphorylation in vivo not quantified","Long-term behavioral outcomes of antagonist rescue not established"]},{"year":2021,"claim":"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","pmids":["34186027","34354080","33420383","33897358"],"confidence":"High","gaps":["Knockdown study is single-lab Medium-confidence","How structural allostery maps onto specific gain-of-function disease variants not fully integrated"]},{"year":2022,"claim":"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","pmids":["35484243"],"confidence":"High","gaps":["Endogenous regulation of the KKK motif not characterized","Mechanism of GluN2B/AMPA suppression by excess GluN2A not fully defined"]},{"year":2023,"claim":"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","pmids":["37723282"],"confidence":"High","gaps":["Molecular pathway from GluN2A loss to delayed PV maturation not defined","Reversibility and therapeutic window not tested"]},{"year":2024,"claim":"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","pmids":["38307912","38319733","38569938"],"confidence":"Medium","gaps":["m6A and feedback-phosphorylation findings are single-lab Medium-confidence","Dominant-negative mechanism at the receptor assembly level not structurally defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,0,13,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,21,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,26,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[30]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,10,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,9,27,28,30]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[18,11,30,19]}],"complexes":["GluN1/GluN2A NMDA receptor","GluN1/GluN2A/GluN2B triheteromeric NMDA receptor","postsynaptic density"],"partners":["GRIN1","CAMK2A","DLG1","SRC","SNX27","DLG4","IQGAP1","KIF3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12879","full_name":"Glutamate receptor ionotropic, NMDA 2A","aliases":["Glutamate [NMDA] receptor subunit epsilon-1","N-methyl D-aspartate receptor subtype 2A","NMDAR2A","NR2A","hNR2A"],"length_aa":1464,"mass_kda":165.3,"function":"Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:20890276, PubMed:23933818, PubMed:23933819, PubMed:23933820, PubMed:24504326, PubMed:26875626, PubMed:26919761, PubMed:28242877, PubMed:36117210, PubMed:38538865, PubMed:8768735). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:23933818, PubMed:23933819, PubMed:23933820, PubMed:24504326, PubMed:26875626, PubMed:26919761, PubMed:27288002, PubMed:28095420, PubMed:28105280, PubMed:28126851, PubMed:28182669, PubMed:29644724, PubMed:38307912, PubMed:8768735). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium (By similarity). Each GluN2 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators (PubMed:26875626, PubMed:26919761). Participates in the synaptic plasticity regulation through activation by the L-glutamate releaseed by BEST1, into the synaptic cleft, upon F2R/PAR-1 activation in astrocyte (By similarity)","subcellular_location":"Cell projection, dendritic spine; Cell membrane; Synapse; Postsynaptic cell membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q12879/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRIN2A","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRIN2A","total_profiled":1310},"omim":[{"mim_id":"617820","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL RECESSIVE; NDHMSR","url":"https://www.omim.org/entry/617820"},{"mim_id":"615768","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 16; SCAR16","url":"https://www.omim.org/entry/615768"},{"mim_id":"614795","title":"1-@ACYLGLYCEROL-3-PHOSPHATE O-ACYLTRANSFERASE 4; AGPAT4","url":"https://www.omim.org/entry/614795"},{"mim_id":"614671","title":"CHROMOSOME 16p11.2 DUPLICATION SYNDROME","url":"https://www.omim.org/entry/614671"},{"mim_id":"614254","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT; NDHMSD","url":"https://www.omim.org/entry/614254"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Endoplasmic reticulum","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":15.1}],"url":"https://www.proteinatlas.org/search/GRIN2A"},"hgnc":{"alias_symbol":["GluN2A","NR2A"],"prev_symbol":["NMDAR2A"]},"alphafold":{"accession":"Q12879","domains":[{"cath_id":"3.40.50.2300","chopping":"34-386","consensus_level":"medium","plddt":83.9925,"start":34,"end":386},{"cath_id":"3.40.190.10","chopping":"406-543_661-797","consensus_level":"medium","plddt":87.7401,"start":406,"end":797},{"cath_id":"1.10.287,1.10.287","chopping":"544-587_598-655","consensus_level":"medium","plddt":77.9081,"start":544,"end":655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12879","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12879-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12879-F1-predicted_aligned_error_v6.png","plddt_mean":60.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRIN2A","jax_strain_url":"https://www.jax.org/strain/search?query=GRIN2A"},"sequence":{"accession":"Q12879","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12879.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12879/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12879"}},"corpus_meta":[{"pmid":"9065507","id":"PMC_9065507","title":"NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex.","date":"1997","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9065507","citation_count":499,"is_preprint":false},{"pmid":"7931566","id":"PMC_7931566","title":"The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1.","date":"1994","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7931566","citation_count":421,"is_preprint":false},{"pmid":"20890276","id":"PMC_20890276","title":"Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20890276","citation_count":404,"is_preprint":false},{"pmid":"17124177","id":"PMC_17124177","title":"NMDA receptor surface mobility depends on NR2A-2B subunits.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17124177","citation_count":295,"is_preprint":false},{"pmid":"24607230","id":"PMC_24607230","title":"Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24607230","citation_count":260,"is_preprint":false},{"pmid":"24298164","id":"PMC_24298164","title":"GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity.","date":"2013","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24298164","citation_count":224,"is_preprint":false},{"pmid":"24839611","id":"PMC_24839611","title":"GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.","date":"2014","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24839611","citation_count":207,"is_preprint":false},{"pmid":"20164351","id":"PMC_20164351","title":"Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20164351","citation_count":179,"is_preprint":false},{"pmid":"30544257","id":"PMC_30544257","title":"GRIN2A-related disorders: genotype and functional consequence predict phenotype.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30544257","citation_count":176,"is_preprint":false},{"pmid":"8987814","id":"PMC_8987814","title":"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.","date":"1996","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8987814","citation_count":164,"is_preprint":false},{"pmid":"9751209","id":"PMC_9751209","title":"Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities.","date":"1998","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9751209","citation_count":152,"is_preprint":false},{"pmid":"7836563","id":"PMC_7836563","title":"Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina.","date":"1994","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7836563","citation_count":142,"is_preprint":false},{"pmid":"15830322","id":"PMC_15830322","title":"Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15830322","citation_count":141,"is_preprint":false},{"pmid":"17113057","id":"PMC_17113057","title":"Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.","date":"2006","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17113057","citation_count":125,"is_preprint":false},{"pmid":"20810618","id":"PMC_20810618","title":"Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors.","date":"2010","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/20810618","citation_count":122,"is_preprint":false},{"pmid":"18570704","id":"PMC_18570704","title":"Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression.","date":"2008","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18570704","citation_count":116,"is_preprint":false},{"pmid":"31807283","id":"PMC_31807283","title":"Distinct roles of GRIN2A and GRIN2B variants in neurological conditions.","date":"2019","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/31807283","citation_count":115,"is_preprint":false},{"pmid":"8840166","id":"PMC_8840166","title":"Expression of NR1 and NR2A/B subunits of the NMDA receptor in cortical astrocytes.","date":"1996","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/8840166","citation_count":112,"is_preprint":false},{"pmid":"7904155","id":"PMC_7904155","title":"Optimal expression of cloned NMDAR1/NMDAR2A heteromeric glutamate receptors: a biochemical characterization.","date":"1993","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/7904155","citation_count":110,"is_preprint":false},{"pmid":"30500536","id":"PMC_30500536","title":"Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30500536","citation_count":105,"is_preprint":false},{"pmid":"12956718","id":"PMC_12956718","title":"Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation.","date":"2003","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12956718","citation_count":101,"is_preprint":false},{"pmid":"32102377","id":"PMC_32102377","title":"Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32102377","citation_count":98,"is_preprint":false},{"pmid":"30927362","id":"PMC_30927362","title":"Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/30927362","citation_count":96,"is_preprint":false},{"pmid":"12933808","id":"PMC_12933808","title":"CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12933808","citation_count":88,"is_preprint":false},{"pmid":"12724619","id":"PMC_12724619","title":"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.","date":"2003","source":"Pharmacogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12724619","citation_count":87,"is_preprint":false},{"pmid":"24227730","id":"PMC_24227730","title":"The σ-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24227730","citation_count":84,"is_preprint":false},{"pmid":"21653857","id":"PMC_21653857","title":"IQGAP1 regulates NR2A signaling, spine density, and cognitive processes.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21653857","citation_count":82,"is_preprint":false},{"pmid":"28242877","id":"PMC_28242877","title":"Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28242877","citation_count":76,"is_preprint":false},{"pmid":"19834457","id":"PMC_19834457","title":"Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19834457","citation_count":76,"is_preprint":false},{"pmid":"28126851","id":"PMC_28126851","title":"Functional Evaluation of a De Novo GRIN2A Mutation Identified in a Patient with Profound Global Developmental Delay and Refractory Epilepsy.","date":"2017","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28126851","citation_count":67,"is_preprint":false},{"pmid":"32577763","id":"PMC_32577763","title":"Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice.","date":"2020","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32577763","citation_count":66,"is_preprint":false},{"pmid":"37657442","id":"PMC_37657442","title":"Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/37657442","citation_count":58,"is_preprint":false},{"pmid":"34186027","id":"PMC_34186027","title":"Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.","date":"2021","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/34186027","citation_count":57,"is_preprint":false},{"pmid":"25596506","id":"PMC_25596506","title":"GRIN2A: an aptly named gene for speech dysfunction.","date":"2015","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25596506","citation_count":56,"is_preprint":false},{"pmid":"14699423","id":"PMC_14699423","title":"Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.","date":"2004","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/14699423","citation_count":56,"is_preprint":false},{"pmid":"24029697","id":"PMC_24029697","title":"Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring.","date":"2013","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/24029697","citation_count":55,"is_preprint":false},{"pmid":"10506512","id":"PMC_10506512","title":"Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex.","date":"1999","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10506512","citation_count":53,"is_preprint":false},{"pmid":"28182669","id":"PMC_28182669","title":"A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28182669","citation_count":52,"is_preprint":false},{"pmid":"29682799","id":"PMC_29682799","title":"The differences between GluN2A and GluN2B signaling in the brain.","date":"2018","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/29682799","citation_count":51,"is_preprint":false},{"pmid":"36914641","id":"PMC_36914641","title":"Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients.","date":"2023","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36914641","citation_count":50,"is_preprint":false},{"pmid":"31746486","id":"PMC_31746486","title":"Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.","date":"2019","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/31746486","citation_count":50,"is_preprint":false},{"pmid":"37736757","id":"PMC_37736757","title":"GRIN2A (NR2A): a gene contributing to glutamatergic involvement in schizophrenia.","date":"2023","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37736757","citation_count":49,"is_preprint":false},{"pmid":"31024297","id":"PMC_31024297","title":"Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31024297","citation_count":48,"is_preprint":false},{"pmid":"32877683","id":"PMC_32877683","title":"An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32877683","citation_count":46,"is_preprint":false},{"pmid":"23678131","id":"PMC_23678131","title":"Dendritic GluN2A synthesis mediates activity-induced NMDA receptor insertion.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23678131","citation_count":46,"is_preprint":false},{"pmid":"31167782","id":"PMC_31167782","title":"GluN2A-NMDA receptor-mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31167782","citation_count":45,"is_preprint":false},{"pmid":"29339791","id":"PMC_29339791","title":"The GluN2A Subunit Regulates Neuronal NMDA receptor-Induced Microglia-Neuron Physical Interactions.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29339791","citation_count":45,"is_preprint":false},{"pmid":"28133447","id":"PMC_28133447","title":"GluN1 and GluN2A NMDA Receptor Subunits Increase in the Hippocampus during Memory Consolidation in the Rat.","date":"2017","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28133447","citation_count":45,"is_preprint":false},{"pmid":"38319733","id":"PMC_38319733","title":"METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38319733","citation_count":41,"is_preprint":false},{"pmid":"21919190","id":"PMC_21919190","title":"Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.","date":"2011","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21919190","citation_count":39,"is_preprint":false},{"pmid":"23604599","id":"PMC_23604599","title":"GluN2A versus GluN2B: twins, but quite different.","date":"2013","source":"Neuroscience bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/23604599","citation_count":38,"is_preprint":false},{"pmid":"34354080","id":"PMC_34354080","title":"GluN2A and GluN2B NMDA receptors use distinct allosteric routes.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34354080","citation_count":37,"is_preprint":false},{"pmid":"10070151","id":"PMC_10070151","title":"Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10070151","citation_count":37,"is_preprint":false},{"pmid":"38004401","id":"PMC_38004401","title":"GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.","date":"2023","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38004401","citation_count":35,"is_preprint":false},{"pmid":"31149903","id":"PMC_31149903","title":"Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations.","date":"2019","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/31149903","citation_count":35,"is_preprint":false},{"pmid":"26797520","id":"PMC_26797520","title":"The Functional and Molecular Properties, Physiological Functions, and Pathophysiological Roles of GluN2A in the Central Nervous System.","date":"2016","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26797520","citation_count":35,"is_preprint":false},{"pmid":"34291567","id":"PMC_34291567","title":"Knockdown of astrocytic Grin2a aggravates β-amyloid-induced memory and cognitive deficits through regulating nerve growth factor.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/34291567","citation_count":34,"is_preprint":false},{"pmid":"27497478","id":"PMC_27497478","title":"Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-β1-40 in Hippocampal Cells.","date":"2016","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/27497478","citation_count":33,"is_preprint":false},{"pmid":"10379917","id":"PMC_10379917","title":"NMDA receptor NR1 and NR2A/B subunit expression in trigeminal neurons during early postnatal development.","date":"1999","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10379917","citation_count":33,"is_preprint":false},{"pmid":"37723282","id":"PMC_37723282","title":"Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37723282","citation_count":32,"is_preprint":false},{"pmid":"35484243","id":"PMC_35484243","title":"Enhancing GluN2A-type NMDA receptors impairs long-term synaptic plasticity and learning and memory.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35484243","citation_count":32,"is_preprint":false},{"pmid":"24739903","id":"PMC_24739903","title":"Somatic mutation of GRIN2A in malignant melanoma results in loss of tumor suppressor activity via aberrant NMDAR complex formation.","date":"2014","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24739903","citation_count":32,"is_preprint":false},{"pmid":"33420383","id":"PMC_33420383","title":"Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33420383","citation_count":32,"is_preprint":false},{"pmid":"30296532","id":"PMC_30296532","title":"Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression.","date":"2018","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/30296532","citation_count":31,"is_preprint":false},{"pmid":"31056842","id":"PMC_31056842","title":"Memory and plasticity impairment after binge drinking in adolescent rat hippocampus: GluN2A/GluN2B NMDA receptor subunits imbalance through HDAC2.","date":"2019","source":"Addiction biology","url":"https://pubmed.ncbi.nlm.nih.gov/31056842","citation_count":31,"is_preprint":false},{"pmid":"8298456","id":"PMC_8298456","title":"Characterization of the NR1, NR2A, and NR2C receptor proteins.","date":"1993","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/8298456","citation_count":30,"is_preprint":false},{"pmid":"26184010","id":"PMC_26184010","title":"Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation.","date":"2015","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26184010","citation_count":30,"is_preprint":false},{"pmid":"12486601","id":"PMC_12486601","title":"Postnatal development of NR2A and NR2B mRNA expression in rat auditory cortex and thalamus.","date":"2002","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/12486601","citation_count":29,"is_preprint":false},{"pmid":"26502998","id":"PMC_26502998","title":"Association between GRIN2A promoter polymorphism and recovery from concussion.","date":"2015","source":"Brain injury","url":"https://pubmed.ncbi.nlm.nih.gov/26502998","citation_count":28,"is_preprint":false},{"pmid":"29644724","id":"PMC_29644724","title":"A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder.","date":"2018","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/29644724","citation_count":28,"is_preprint":false},{"pmid":"35217385","id":"PMC_35217385","title":"De novo GRIN2A variants associated with epilepsy and autism and literature review.","date":"2022","source":"Epilepsy & behavior : E&B","url":"https://pubmed.ncbi.nlm.nih.gov/35217385","citation_count":27,"is_preprint":false},{"pmid":"35228668","id":"PMC_35228668","title":"Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35228668","citation_count":27,"is_preprint":false},{"pmid":"38836461","id":"PMC_38836461","title":"Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology.","date":"2024","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/38836461","citation_count":26,"is_preprint":false},{"pmid":"23871830","id":"PMC_23871830","title":"Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23871830","citation_count":26,"is_preprint":false},{"pmid":"24915238","id":"PMC_24915238","title":"Caffeine interaction with glutamate receptor gene GRIN2A: Parkinson's disease in Swedish population.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24915238","citation_count":25,"is_preprint":false},{"pmid":"26312887","id":"PMC_26312887","title":"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.","date":"2015","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26312887","citation_count":25,"is_preprint":false},{"pmid":"38569938","id":"PMC_38569938","title":"Homocysteine-induced sustained GluN2A NMDA receptor stimulation leads to mitochondrial ROS generation and neurotoxicity.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38569938","citation_count":24,"is_preprint":false},{"pmid":"29056244","id":"PMC_29056244","title":"GRIN2A mutations in epilepsy-aphasia spectrum disorders.","date":"2017","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/29056244","citation_count":24,"is_preprint":false},{"pmid":"24125812","id":"PMC_24125812","title":"Two patients with a GRIN2A mutation and childhood-onset epilepsy.","date":"2013","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24125812","citation_count":24,"is_preprint":false},{"pmid":"25958346","id":"PMC_25958346","title":"Correlation of functional GRIN2A gene promoter polymorphisms with schizophrenia and serum D-serine levels.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25958346","citation_count":23,"is_preprint":false},{"pmid":"24455489","id":"PMC_24455489","title":"Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival.","date":"2014","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24455489","citation_count":23,"is_preprint":false},{"pmid":"26051400","id":"PMC_26051400","title":"Different sites of alcohol action in the NMDA receptor GluN2A and GluN2B subunits.","date":"2015","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26051400","citation_count":23,"is_preprint":false},{"pmid":"28320167","id":"PMC_28320167","title":"Caffeine, creatine, GRIN2A and Parkinson's disease progression.","date":"2017","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28320167","citation_count":22,"is_preprint":false},{"pmid":"27199241","id":"PMC_27199241","title":"The GRIN2B and GRIN2A Gene Variants Are Associated With Continuous Performance Test Variables in ADHD.","date":"2016","source":"Journal of attention disorders","url":"https://pubmed.ncbi.nlm.nih.gov/27199241","citation_count":22,"is_preprint":false},{"pmid":"33897358","id":"PMC_33897358","title":"Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33897358","citation_count":22,"is_preprint":false},{"pmid":"11891879","id":"PMC_11891879","title":"Differential NR2A and NR2B expression between trigeminal neurons during early postnatal development.","date":"2002","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11891879","citation_count":21,"is_preprint":false},{"pmid":"34685369","id":"PMC_34685369","title":"Study of Early Onset Schizophrenia: Associations of GRIN2A and GRIN2B Polymorphisms.","date":"2021","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34685369","citation_count":21,"is_preprint":false},{"pmid":"22335236","id":"PMC_22335236","title":"Mass spectrometrical identification of hippocampal NMDA receptor subunits NR1, NR2A-D and five novel phosphorylation sites on NR2A and NR2B.","date":"2012","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/22335236","citation_count":20,"is_preprint":false},{"pmid":"38307912","id":"PMC_38307912","title":"Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38307912","citation_count":19,"is_preprint":false},{"pmid":"34720871","id":"PMC_34720871","title":"GRIN2A Variants Associated With Idiopathic Generalized Epilepsies.","date":"2021","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34720871","citation_count":19,"is_preprint":false},{"pmid":"35204682","id":"PMC_35204682","title":"Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35204682","citation_count":19,"is_preprint":false},{"pmid":"33420399","id":"PMC_33420399","title":"GluN2B and GluN2A-containing NMDAR are differentially involved in extinction memory destabilization and restabilization during reconsolidation.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33420399","citation_count":19,"is_preprint":false},{"pmid":"27810933","id":"PMC_27810933","title":"NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A-Ubiquitin Ligase Signaling Pathway.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27810933","citation_count":19,"is_preprint":false},{"pmid":"29318639","id":"PMC_29318639","title":"Interaction between caffeine and polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2) on Parkinson's disease risk.","date":"2018","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/29318639","citation_count":19,"is_preprint":false},{"pmid":"28102473","id":"PMC_28102473","title":"The Role of GluN2A in Cerebral Ischemia: Promoting Neuron Death and Survival in the Early Stage and Thereafter.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/28102473","citation_count":19,"is_preprint":false},{"pmid":"7909752","id":"PMC_7909752","title":"Expression of NMDAR1-1a (N598Q)/NMDAR2A receptors results in decreased cell mortality.","date":"1994","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7909752","citation_count":18,"is_preprint":false},{"pmid":"29655037","id":"PMC_29655037","title":"Genetic polymorphisms of GRIN2A and GRIN2B modify the neurobehavioral effects of low-level lead exposure in children.","date":"2018","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/29655037","citation_count":18,"is_preprint":false},{"pmid":"26220384","id":"PMC_26220384","title":"Investigation of GRIN2A in common epilepsy phenotypes.","date":"2015","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/26220384","citation_count":17,"is_preprint":false},{"pmid":"31272478","id":"PMC_31272478","title":"A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain.","date":"2019","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/31272478","citation_count":17,"is_preprint":false},{"pmid":"36516565","id":"PMC_36516565","title":"GRIN2A-related epilepsy and speech disorders: A comprehensive overview with a focus on the role of precision therapeutics.","date":"2022","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/36516565","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51374,"output_tokens":9876,"usd":0.151131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20171,"output_tokens":6615,"usd":0.133115,"stage2_stop_reason":"end_turn"},"total_usd":0.284246,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell RT-PCR combined with whole-cell patch-clamp electrophysiology in postnatal neocortical neurons in vivo\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct correlation of NR2A mRNA expression with EPSC kinetics in identified single neurons across multiple postnatal ages, replicated across many cells\",\n      \"pmids\": [\"9065507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"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.\",\n      \"method\": \"Immunocytochemistry with subunit-specific antibodies; electron microscopy of rat brain sections\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ultrastructural localization by EM with specific antibodies, replicated across brain regions\",\n      \"pmids\": [\"7931566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"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.\",\n      \"method\": \"Transient co-transfection in HEK293 cells, [3H]MK801 radioligand binding, immunological characterization with anti-NMDAR2A antibody, N-deglycosylation\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of heteromeric complex with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"7904155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mouse generation (NR2A-/-, NR2C-/-, double knockout), whole-cell recordings from cerebellar slices, motor coordination behavioral assays\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo with direct electrophysiological readout, multiple genotypes compared\",\n      \"pmids\": [\"8987814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation from PSD fractions, overlay assay with 32P-CaMKII, crosslinking with DSS, co-IP with anti-CaMKII and anti-NR2A/B antibodies\",\n      \"journal\": \"Journal of Neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus multiple orthogonal biochemical methods (overlay, crosslinking) from native brain tissue\",\n      \"pmids\": [\"9751209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro pull-down plus co-IP from native tissue plus phosphorylation site mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"12933808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Single-particle tracking and single-molecule imaging with subunit-specific antibodies against extracellular epitopes of NR2A and NR2B in cultured neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct single-molecule surface mobility measurements with subunit-specific probes, developmental time series\",\n      \"pmids\": [\"17124177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in mouse generation (Y1325F), tail suspension and forced swim tests, biochemical phosphorylation analysis, electrophysiology in striatal neurons\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo phosphorylation site knock-in with electrophysiological and behavioral readouts, multiple methods\",\n      \"pmids\": [\"19834457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown, chimeric subunit overexpression, pharmacological antagonism (Ro25-6981), whole-cell recordings in organotypic hippocampal slice cultures\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection with chimeric constructs plus pharmacology plus electrophysiology, multiple rescue experiments\",\n      \"pmids\": [\"20164351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression in Xenopus oocytes, two-electrode voltage-clamp electrophysiology\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiological reconstitution of mutant receptor, single lab but rigorous functional assay\",\n      \"pmids\": [\"20890276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, surface expression assays, NR2A-dependent pharmacological stimulation, ERK phosphorylation assays in hippocampal cultures and brain slices from IQGAP1-/- mice\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and KO neuron phenotyping with specific pharmacological dissection, single lab\",\n      \"pmids\": [\"21653857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Microfluidic chamber isolation of dendrites, activity stimulation, surface biotinylation, fluorescence visualization of local GluN2A translation and membrane insertion, CPE mutant analysis\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct visualization of local translation with functional surface insertion assay, multiple orthogonal methods including genetic CPE mutation\",\n      \"pmids\": [\"23678131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Atomic force microscopy imaging of isolated receptors, co-isolation of Sig1R with GluN1 and GluN2A, in situ proximity ligation assay in intact cells\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AFM structural imaging plus biochemical co-isolation plus in situ PLA, multiple orthogonal methods\",\n      \"pmids\": [\"24227730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Forced surface expression of recombinant triheteromers in HEK293 cells, whole-cell patch-clamp electrophysiology, pharmacological profiling with selective antagonists\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of defined triheteromeric receptor with rigorous pharmacological and kinetic characterization\",\n      \"pmids\": [\"24607230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro electrophysiology of mutant receptors expressed in heterologous cells, pharmacological screening with NMDAR blockers\",\n      \"journal\": \"Annals of Clinical and Translational Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and pharmacological characterization, single lab\",\n      \"pmids\": [\"24839611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of GluN1/GluN2A receptor under varying zinc and proton concentrations\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural determination by cryo-EM with multiple conformational states under physiologically relevant conditions\",\n      \"pmids\": [\"30500536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology of recombinant mutant receptors, cortical neuron recordings from Grin2a+/- rats, clinical phenotype-genotype correlation in 248 patients\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional electrophysiology correlated with genotype across large clinical cohort plus neuronal recordings, replicated across labs\",\n      \"pmids\": [\"30544257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology, optogenetics, immunofluorescence, intrastriatal injections of alpha-synuclein, behavioral assays, antibody treatment\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab, direct rescue with anti-alpha-synuclein antibody\",\n      \"pmids\": [\"30927362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, live imaging of NR2A vesicle transport, electrophysiology in hippocampal slices, rescue experiments in Kif3b+/- neurons\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of transport complex plus live imaging plus functional electrophysiology, single lab\",\n      \"pmids\": [\"31746486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay identifying CaMKIIα phosphorylation site, co-immunoprecipitation, surface trafficking assay, spine density measurement, synaptic transmission recording, dark rearing model\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identified kinase, phosphorylation site, downstream binding partners, trafficking outcome, and disease variant functional consequences with multiple orthogonal methods\",\n      \"pmids\": [\"32877683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of full-length human GluN1-GluN2A with distinct ligands and modulators at ~4 Å resolution\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structural determination with multiple ligand-bound states directly showing allosteric mechanisms\",\n      \"pmids\": [\"34186027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Functional electrophysiology combined with structural analysis (cryo-EM or X-ray crystallography implied by 'structural interrogation'), mutagenesis of interface residues\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — combined functional and structural interrogation with mutagenesis demonstrating distinct allosteric routes\",\n      \"pmids\": [\"34354080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Promoter-reporter assays, chromatin immunoprecipitation, siRNA knockdown of Sp4 in neurons, electrophoretic mobility shift assay\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular methods for transcriptional regulation, single lab\",\n      \"pmids\": [\"23871830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological GluN2A inhibition (NVP-AAM077), GluN2A genetic knockout neurons, Ca2+ imaging, ERK phosphorylation assays, cell viability assays in primary cortical cultures\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus genetic loss-of-function with multiple readouts, single lab\",\n      \"pmids\": [\"31167782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus biochemical pathway dissection, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"38569938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp recording, pharmacological inhibition of GluN2A (NVP-AAM077) vs GluN2B, genetic Mdm2 inhibition, GFP-GluN1 puncta imaging, protein synthesis inhibition\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological plus genetic dissection with electrophysiology and imaging, single lab\",\n      \"pmids\": [\"27810933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"High-throughput calcium flux assay, patch-clamp electrophysiology, Western blotting, confocal surface trafficking imaging in HEK293 cells, PAM rescue experiments\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple mutations characterized by orthogonal functional, expression and trafficking assays with pharmacological rescue\",\n      \"pmids\": [\"28242877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-cell and single-channel electrophysiology in heterologous cells, synaptic-like response recordings, molecular modeling of closed-channel conformation\",\n      \"journal\": \"Molecular Pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous in vitro reconstitution with single-channel analysis, pharmacological profiling, and structural modeling\",\n      \"pmids\": [\"28126851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous cell electrophysiology of mutant receptor, hippocampal slice recordings from knock-in mice, multielectrode array recordings, behavioral assays, pharmacological rescue with NMDAR antagonists\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution confirmed in native neuronal preparation (knock-in mice), multiple readouts including pharmacological rescue\",\n      \"pmids\": [\"32577763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiological recordings from PV interneurons in Grin2a+/+, +/-, and -/- mice at multiple developmental timepoints, circuit excitability analysis\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene dosage series with direct electrophysiological phenotyping across multiple developmental stages\",\n      \"pmids\": [\"37723282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression, surface biotinylation, whole-cell patch-clamp in hippocampal CA1 neurons, LTP and LTD recordings in knock-in slices, behavioral memory tasks\",\n      \"journal\": \"Molecular Psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ER retention signal identified and validated with surface expression assay, knock-in mouse with synaptic plasticity and memory phenotype\",\n      \"pmids\": [\"35484243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Grin2aN615S knock-in mice (voltage-independent Ca2+ influx mutation), EEG/LFP recordings, audiogenic seizure assay, MK-801 c-Fos mapping, behavioral tests\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific knock-in mutation removing voltage-dependence, with multiple circuit-level and behavioral readouts\",\n      \"pmids\": [\"33420383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Electrophysiology of recombinant GluN1/GluN2A receptors with co-expression of WT and mutant subunits in heterologous cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro electrophysiology, single lab\",\n      \"pmids\": [\"38307912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Dot blotting, immunofluorescence, gain/loss-of-function AAV experiments, behavioral pain assays in rodent CINP model, human DRG validation\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with multiple readouts, single lab, translational validation in human DRG\",\n      \"pmids\": [\"38319733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Functional characterization of GRIN2A mutants, NMDAR complex formation assay (co-immunoprecipitation), soft agar anchorage-independent growth, migration assay, shRNA depletion\",\n      \"journal\": \"The Journal of Investigative Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of complex formation, loss-of-function with specific cellular phenotype, single lab\",\n      \"pmids\": [\"24739903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"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).\",\n      \"method\": \"Polyclonal antibody characterization by Western blot, N-deglycosylation, brain region fractionation\",\n      \"journal\": \"Protein Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of native protein with antibodies and enzymatic deglycosylation, basic characterization\",\n      \"pmids\": [\"8298456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression confirmed in human tissue, functional reconstitution of novel isoform with GluN1, single lab\",\n      \"pmids\": [\"31272478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation of NR1-containing complexes from rat hippocampus, nano-LC-ESI-MS/MS, phosphatase treatment and reanalysis\",\n      \"journal\": \"Journal of Proteome Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification from native brain tissue with phosphatase verification, novel site identification\",\n      \"pmids\": [\"22335236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, whole-cell patch-clamp in mouse primary cortical pyramidal neurons\",\n      \"journal\": \"Lancet\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous electrophysiology in two separate experimental systems (oocytes and primary neurons) with quantitative pharmacological characterization\",\n      \"pmids\": [\"26312887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro and in vivo shRNA knockdown, Western blot, fear conditioning, seizure susceptibility assays\",\n      \"journal\": \"Frontiers in Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo specific knockdown with behavioral and seizure readouts, single lab\",\n      \"pmids\": [\"33897358\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GluN2A (GRIN2A/NR2A) is a glutamate-binding regulatory subunit that co-assembles with obligate GluN1 subunits to form functional heterotetrameric NMDA receptor ion channels with distinct biophysical properties (faster deactivation, higher Mg2+ sensitivity, and nanomolar Zn2+ inhibition through allosteric ATD mechanisms) compared to GluN2B-containing receptors; its synaptic targeting is regulated by CaMKII-dependent phosphorylation at S1459 (controlling SNX27/PSD-95 binding and trafficking), SAP97 PDZ1-domain interaction (disrupted by CaMKII phosphorylation of SAP97-S232), Src kinase phosphorylation at Tyr1325 (regulating channel potentiation and downstream DARPP-32 signaling), and local dendritic mRNA translation via CPE-mediated polyadenylation; its surface mobility is lower than GluN2B, contributing to the developmental NR2B-to-NR2A synaptic switch; disease-causing mutations cause gain- or loss-of-function depending on their domain location, with transmembrane/linker domain mutations predominantly causing gain-of-function linked to severe epileptic encephalopathy and ATD/LBD mutations causing loss-of-function linked to milder epilepsy-aphasia spectrum disorders.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#2, #1]. 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 [#0, #6]. GluN1/GluN2A diheteromers and GluN1/GluN2A/GluN2B triheteromers display distinct deactivation kinetics and antagonist/Zn2+ sensitivities [#13]. 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 [#15, #20, #21]. 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 [#4, #19]; SAP97 binds GluN2A through its PDZ1 domain, an interaction disrupted by CaMKII phosphorylation of SAP97-S232 [#5]; Src phosphorylates GluN2A at Tyr1325 to potentiate channel activity and engage DARPP-32 signaling [#7]; an ER-retention KKK motif limits surface expression [#30]; and dendritic delivery requires KIF3B-dependent vesicular transport and local CPE-mediated mRNA translation [#18, #11]. 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 [#8, #29, #31]. 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 [#16, #27, #9, #38, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-transfection in HEK293 with [3H]MK801 binding and immunological/deglycosylation characterization; parallel native protein characterization by Western blot and brain fractionation\",\n      \"pmids\": [\"7904155\", \"8298456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and subunit arrangement not resolved at this stage\", \"Channel gating properties not directly measured\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Localized NR2A protein to postsynaptic densities, establishing that the subunit operates at synapses in vivo rather than only in heterologous systems.\",\n      \"evidence\": \"Subunit-specific immunocytochemistry and electron microscopy of rat brain\",\n      \"pmids\": [\"7931566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define functional consequence of synaptic localization\", \"No subunit composition of individual PSD receptors\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked NR2A expression to faster NMDAR EPSC kinetics, providing the molecular basis for the developmental shortening of synaptic NMDAR responses.\",\n      \"evidence\": \"Single-cell RT-PCR with whole-cell patch-clamp in postnatal neocortical neurons\",\n      \"pmids\": [\"9065507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling subunit identity to deactivation rate not resolved\", \"Trafficking basis of the switch not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated in vivo functional redundancy between NR2A and NR2C in cerebellar transmission and motor coordination using genetic epistasis.\",\n      \"evidence\": \"Single and double NR2A/NR2C knockout mice with cerebellar slice recordings and behavior\",\n      \"pmids\": [\"8987814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy may be region-specific; forebrain roles not tested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified phosphorylation-controlled scaffolding interactions (CaMKII-GluN2A, SAP97-PDZ1) as regulators of synaptic targeting, addressing how receptor positioning is dynamically controlled.\",\n      \"evidence\": \"Co-IP from PSD/synaptosomes, overlay and crosslinking assays, in vitro pull-down with PDZ mutants and phospho-site analysis\",\n      \"pmids\": [\"9751209\", \"12933808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative impact on synaptic receptor number in vivo not established\", \"Interplay of multiple scaffolds not integrated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed GluN2A-containing receptors have lower surface mobility/higher stability than GluN2B, providing a trafficking mechanism for the developmental NR2B-to-NR2A switch.\",\n      \"evidence\": \"Single-particle tracking with subunit-specific extracellular probes across development in cultured neurons\",\n      \"pmids\": [\"17124177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of differential mobility not identified\", \"Relationship to scaffold binding not tested directly\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined Src phosphorylation of GluN2A-Tyr1325 as a regulator of channel potentiation and downstream DARPP-32 signaling with behavioral consequences.\",\n      \"evidence\": \"Y1325F knock-in mice with striatal electrophysiology, phosphorylation analysis, and behavioral tests\",\n      \"pmids\": [\"19834457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling Src activity at GluN2A not fully defined\", \"Generalization beyond striatum not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected the role of GluN2 cytoplasmic tails in LTP, showing the GluN2A C-tail carries inhibitory factors, clarifying subunit-specific contributions to plasticity.\",\n      \"evidence\": \"RNAi knockdown with chimeric subunit rescue, pharmacology, and recordings in hippocampal slice cultures\",\n      \"pmids\": [\"20164351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the inhibitory C-tail factors not defined\", \"In vivo relevance of chimera results not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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).\",\n      \"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\",\n      \"pmids\": [\"23871830\", \"23678131\", \"21653857\", \"24227730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved triheteromeric GluN1/GluN2A/GluN2B pharmacology and kinetics, and uncovered a tumor-suppressive role for GluN2A in melanoma with dominant-negative somatic mutants.\",\n      \"evidence\": \"Forced triheteromer expression with patch-clamp and antagonist profiling; melanoma functional assays with co-IP, soft-agar growth, migration, and shRNA depletion\",\n      \"pmids\": [\"24607230\", \"24739903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Melanoma role is single-lab Medium-confidence; downstream tumor-suppressive signaling unresolved\", \"Native abundance of triheteromers in vivo not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Characterized the pore N615K variant as gain-of-function (loss of Mg2+ block, reduced blocker sensitivity), advancing genotype-to-channel-phenotype mapping for disease.\",\n      \"evidence\": \"Two-electrode voltage clamp in oocytes and patch-clamp in primary cortical neurons\",\n      \"pmids\": [\"26312887\", \"20890276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit-level consequences not addressed in these reports\", \"Ca2+ permeability versus Mg2+ block effects partly system-dependent\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Single-channel and whole-cell electrophysiology with modeling (M817V); calcium flux, trafficking, Western blot, and PAM rescue for LoF mutants\",\n      \"pmids\": [\"28126851\", \"28242877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of rescue not performed in these studies\", \"Trafficking deficits not the cause of reduced agonist response, leaving conformational basis incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the structural mechanism of GluN2A ATD zinc/proton allostery transduced to the channel gate, explaining a hallmark biophysical property of GluN2A-NMDARs.\",\n      \"evidence\": \"Cryo-EM of GluN1/GluN2A under varying zinc and proton concentrations\",\n      \"pmids\": [\"30500536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of gating transitions not fully captured\", \"Link to specific disease variants not mapped in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"30544257\", \"31746486\", \"31167782\", \"30927362\", \"31272478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several mechanistic links (KIF3B, homocysteine, alpha-synuclein, isoform) are single-lab Medium-confidence\", \"How LoF/GoF maps to specific human seizure circuits remains incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, trafficking and spine/synaptic assays; S644G knock-in mice with slice/MEA recordings and antagonist rescue\",\n      \"pmids\": [\"32877683\", \"32577763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stoichiometry of S1459 phosphorylation in vivo not quantified\", \"Long-term behavioral outcomes of antagonist rescue not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"34186027\", \"34354080\", \"33420383\", \"33897358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Knockdown study is single-lab Medium-confidence\", \"How structural allostery maps onto specific gain-of-function disease variants not fully integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Heterologous surface biotinylation, CA1 patch-clamp, LTP/LTD recordings in knock-in mice, and memory tasks\",\n      \"pmids\": [\"35484243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulation of the KKK motif not characterized\", \"Mechanism of GluN2B/AMPA suppression by excess GluN2A not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that Grin2a loss delays parvalbumin interneuron maturation in a gene-dosage-dependent manner, linking GluN2A to inhibitory circuit development and excitability.\",\n      \"evidence\": \"Electrophysiology of PV interneurons across developmental timepoints in Grin2a+/+, +/-, and -/- mice\",\n      \"pmids\": [\"37723282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway from GluN2A loss to delayed PV maturation not defined\", \"Reversibility and therapeutic window not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"38307912\", \"38319733\", \"38569938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A and feedback-phosphorylation findings are single-lab Medium-confidence\", \"Dominant-negative mechanism at the receptor assembly level not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 0, 13, 9]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [9, 38, 27, 31]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 21, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 26, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 10, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 9, 27, 28, 30]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [18, 11, 30, 19]}\n    ],\n    \"complexes\": [\n      \"GluN1/GluN2A NMDA receptor\",\n      \"GluN1/GluN2A/GluN2B triheteromeric NMDA receptor\",\n      \"postsynaptic density\"\n    ],\n    \"partners\": [\n      \"GRIN1\",\n      \"CAMK2A\",\n      \"DLG1\",\n      \"SRC\",\n      \"SNX27\",\n      \"DLG4\",\n      \"IQGAP1\",\n      \"KIF3B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n\nNote: GO:0005216 is not in the allowed molecular_activity list; replacing with the allowed term.\n\n```json\n{\"correction\": {\"molecular_activity\": [{\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 0, 13, 9]}, {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 13]}, {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 21, 20]}, {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [9, 38, 27, 31]}]}}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}