{"gene":"GRIN1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2018,"finding":"Cryo-EM structures of GluN1/GluN2A NMDA receptor reveal that zinc binding to the GluN2A amino-terminal domain elicits conformational changes transduced through the ligand-binding domain, resulting in constriction of the ion channel gate; proton inhibition acts via a similar allosteric pathway.","method":"Cryo-electron microscopy, multiple conformational states under varying zinc and proton concentrations","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural determination with multiple conformational states and direct mechanistic interpretation","pmids":["30500536"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of human GluN1-GluN2A NMDA receptor show that positive allosteric modulator binding shortens the distance between ligand-binding domains and the transmembrane domain to stretch the channel gate open; a 'foot-in-the-door' blocker (9-aminoacridine) binds within the LBD-TMD linker region rather than the conventional vestibule site.","method":"Cryo-electron microscopy with distinct ligands/modulators at ~4 Å resolution","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with multiple ligand states providing direct mechanistic insight into gating and block","pmids":["34186027"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of GluN1-GluN2C, GluN1-GluN2A-GluN2C triheteromeric, and GluN1-GluN2D NMDARs reveal unique inter-subunit and domain arrangements of GluN2C NMDARs that contribute to functional regulation and formation of a positive allosteric modulator (PYD-106) binding pocket distinct from GluN2D.","method":"Single-particle cryo-electron microscopy","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of multiple NMDAR subtypes with functional correlates","pmids":["36309015"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of GluN1-GluN3A NMDARs reveal a 1-3-1-3 subunit heterotetrameric arrangement; comparison of glycine-bound vs. CNQX-bound structures shows an unprecedented GluN3A subunit orientation shift, and disruption of the unique subunit interface in the glycine-bound structure mitigated desensitization.","method":"Cryo-electron microscopy, site-directed mutagenesis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures combined with mutagenesis validating structural-functional link","pmids":["38598639"],"is_preprint":false},{"year":2008,"finding":"The agonist-binding domain (ABD) dimer interface of NR1/NR2A NMDA receptors is a major structural determinant coupling the NR2A N-terminal domain (NTD) zinc-binding site to the channel gate; rearrangements at the ABD dimer interface mediate both Zn2+ allosteric inhibition and proton inhibition.","method":"Electrophysiology (mutagenesis of ABD dimer interface), structural analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis + electrophysiology with clear mechanistic framework, replicated across inhibition types","pmids":["18184566"],"is_preprint":false},{"year":2013,"finding":"GluN1 N-terminal domain (NTD) is dynamic rather than static: perturbing its conformation affects receptor gating and pharmacological properties; GluN1 NTD undergoes hinge bending, twisting, and untwisting motions and acts in trans with GluN2 NTD to influence glutamate (but not glycine) binding.","method":"Electrophysiology, cross-linking, structural analysis, mutagenesis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (electrophysiology, cross-linking, mutagenesis) in one study","pmids":["23454977"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of calcium-saturated calmodulin bound to the NR1 C1 region (NR1C1 peptide, residues 875–898) shows that NR1 S890 (whose phosphorylation regulates membrane localization) is solvent-protected in the CaM complex, while the ER retention motif is solvent-exposed; NR1 F880 fills the CaM C-domain hydrophobic pocket.","method":"X-ray crystallography (1.96 Å, PDB 2HQW)","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional interpretation of phosphorylation-site accessibility","pmids":["18073110"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of GluN1 and GluN3A ligand-binding domains in apo states reveal open- and closed-cleft conformations, respectively; computed free-energy landscapes indicate GluN1 (and GluN2A, GluN3A) apo-state LBDs sample closed-cleft conformations, suggesting agonist binding via conformational selection rather than induced-fit.","method":"X-ray crystallography, molecular dynamics / free energy calculations","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — crystal structures plus computational free-energy landscapes supporting binding mechanism","pmids":["23972471"],"is_preprint":false},{"year":2012,"finding":"Using electrophysiology and cross-linking experiments, functional GluN1/GluN2A receptors adopt an alternating 1/2/1/2 subunit arrangement in which GluN1 subunits occupy a 'proximal' position closer to the channel pore axis than GluN2 subunits; immature intracellular receptors can adopt different arrangements.","method":"Electrophysiology, disulfide cross-linking, structural modeling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — orthogonal electrophysiology and cross-linking methods in mature vs. immature receptor pools","pmids":["22493736"],"is_preprint":false},{"year":2011,"finding":"Intrasubunit disulfide bonds constraining the M3-S2 and S2-M4 linkers in either GluN1 or GluN2A equally impair NMDA receptor pore opening without altering single-channel conductance, demonstrating that concerted conformational dynamics at LBD-TMD linkers in all four subunits are required for pore opening.","method":"Disulfide cross-linking, single-channel electrophysiology in outside-out patches","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1/2 — engineered disulfide bonds with single-channel recordings providing direct mechanistic evidence","pmids":["21746848"],"is_preprint":false},{"year":2014,"finding":"Triheteromeric GluN1/GluN2A/GluN2B NMDARs have glutamate deactivation kinetics distinct from either diheteromeric receptor; subunit-selective antagonists (ifenprodil, CP-101,606, TCN-201, Zn2+) modulate triheteromers with properties intermediate to and distinct from diheteromers, with variation in the ifenprodil binding site geometry.","method":"Selective cell-surface expression of recombinant triheteromers, electrophysiology, pharmacological characterization","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — novel method for selective triheteromer expression combined with kinetic and pharmacological analysis","pmids":["24607230"],"is_preprint":false},{"year":2010,"finding":"D-cycloserine (DCS) acts as a partial agonist at the GluN1 glycine-binding site with efficacy dependent on which GluN2 subunit is present; at NR1/NR2C receptors DCS has higher relative efficacy than glycine by accelerating a fast pregating step and reducing the closing rate; residues at the ABD dimer interface regulate DCS efficacy.","method":"Single-channel recordings, molecular dynamics simulations, site-directed mutagenesis, kinetic modeling","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 — single-channel analysis, mutagenesis, MD simulations and kinetic modeling in one study","pmids":["20164358"],"is_preprint":false},{"year":2012,"finding":"GluN1 exon 5-encoded residues (N1 cassette in the NTD) are key determinants of GluN1/GluN2D receptor function: exon 5-containing GluN1-1b/GluN2D receptors deactivate ~3-fold faster and have ~2-fold higher open probability than exon 5-lacking GluN1-1a/GluN2D; residue Lys211 in GluN1-1b is identified as a key determinant; exon 5 influences multiple rate-limiting gating steps.","method":"Two-electrode voltage clamp, single-channel recordings, kinetic modeling, mutagenesis","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1/2 — single-channel analysis, mutagenesis, and kinetic modeling identifying specific residue","pmids":["22641781"],"is_preprint":false},{"year":2019,"finding":"GluN1 exon 5 (N1 cassette) controls LTP magnitude and spatial memory: mice lacking the N1 cassette (GluN1a) show enhanced hippocampal LTP and faster spatial learning vs. mice obligatorily expressing N1 (GluN1b), demonstrating alternative splicing of GluN1 as a mechanism controlling synaptic plasticity and learning.","method":"Knock-in mouse models (exon 5 deletion and forced inclusion), hippocampal LTP recordings, behavioral tests","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — two reciprocal knock-in lines with electrophysiology and behavioral readouts","pmids":["31875540"],"is_preprint":false},{"year":2019,"finding":"N-terminal alternative splicing of GluN1 (exon 5) regulates the developmental shortening of NMDAR-mediated EPSCs in thalamic neurons and synaptic maturation; deletion of exon 5 causes overproduction of excitatory synapses in cortical layer 5 pyramidal neurons and increases seizure susceptibility.","method":"Conditional knock-in mouse (exon 5 deletion), whole-cell recordings, synapse counting, seizure threshold assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse model with electrophysiology and anatomical readouts","pmids":["31570583"],"is_preprint":false},{"year":2021,"finding":"Nonionotropic signaling by glycine binding to GluN1 (glycine priming of NMDAR internalization) is gated by GluN1 alternative splicing: splice variants lacking the N1 cassette support glycine priming; those containing N1 block it. C-terminal cassettes (C1, C2, C2') each permit glycine priming. In vivo, CA1 pyramidal neuron synaptic NMDARs undergo glycine priming, while CA1 interneuron NMDARs do not, correlating with their endogenous GluN1 isoform content.","method":"Recombinant NMDAR expression, knock-in mouse engineering (obligatory N1 inclusion/exclusion), electrophysiology in acute slices","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse models and electrophysiology with multiple orthogonal readouts","pmids":["34187890"],"is_preprint":false},{"year":2019,"finding":"GluN1/GluN3A receptors (excitatory glycine receptors, eGlyRs) are functionally expressed in adult medial habenula neurons; glial-derived glycine activates these receptors to tune neuronal activity; reducing GluN1/GluN3A levels in the MHb prevents conditioned place aversion.","method":"Electrophysiology (native MHb neurons), viral knockdown, place-aversion conditioning, immunohistochemistry","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — native electrophysiology plus in vivo knockdown with behavioral readout, replicated across methods","pmids":["31601771"],"is_preprint":false},{"year":2014,"finding":"D1 dopamine receptor (D1R) and GluN1 subunit of NMDAR form direct physical complexes in striatal medium spiny neurons upon co-stimulation; disrupting D1R/GluN1 association with a cell-permeable peptide (TAT-GluN1C1) prevents D1R-mediated facilitation of NMDAR calcium influx and ERK activation without affecting individual D1R or NMDAR signaling; D1R/GluN1 complexes are required for D1R-dependent LTP and behavioral sensitization to cocaine.","method":"Co-immunoprecipitation (endogenous proteins), cell-permeable peptide disruption, Ca2+ imaging, slice electrophysiology, behavioral sensitization assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP of endogenous proteins, functional peptide disruption, electrophysiology, and behavior","pmids":["25070539"],"is_preprint":false},{"year":2023,"finding":"KCTD13 (a cullin3-based E3 ubiquitin ligase adapter) directly ubiquitinates GluN1 at lysine 860 with K48-linked polyubiquitin chains, targeting GluN1 for proteasomal degradation; KCTD13 knockdown increases GluN1 membrane expression and NMDAR-mediated synaptic transmission, enhancing seizure susceptibility.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K860 GluN1), viral knockdown/overexpression in mouse hippocampus, electrophysiology, seizure threshold assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — in vitro ubiquitination assay with specific site mutagenesis, in vivo mouse model, and electrophysiology","pmids":["37142655"],"is_preprint":false},{"year":2020,"finding":"The positive surface charge of the hinge region of the GluN1 N-terminal domain directly mediates interaction with a negatively charged phospho-tyrosine on EphB2; this extracellular interaction constrains NMDAR mobility at dendritic spine synapses; loss of EphB-NMDAR interaction (by GluN1 mutation or EphB2 knockdown) increases NMDAR lateral mobility.","method":"Pulldown/direct interaction assay, live-cell single-particle tracking, GluN1 charge-reversal mutagenesis, EphB2 knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct interaction mapped to specific charged residues, validated by live-cell mobility assays","pmids":["31996679"],"is_preprint":false},{"year":2018,"finding":"NFL (neurofilament light) directly interacts with GluN1 subunit; NFL deficiency reduces dendritic spine density and GluN1 protein levels, elevates ubiquitin-dependent GluN1 turnover, and depresses hippocampal LTP, producing an NMDAR hypofunction phenotype.","method":"Co-immunoprecipitation (NFL-GluN1 interaction), NFL knockout mouse, Western blot, electrophysiology (LTP), behavioral assays, MRS","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus KO mouse with multiple functional readouts, single lab","pmids":["30143609"],"is_preprint":false},{"year":2008,"finding":"NR1/NR2B NMDA receptor activity is enhanced by depolarization independent of Mg2+ block (voltage-dependent gating); a kinetic model identifies voltage-dependent conformational changes in the NR2B subunit as the mechanism; these changes underlie the slow component of Mg2+ unblock during dendritic spikes.","method":"Whole-cell electrophysiology (0 Mg2+ and physiological Mg2+), kinetic modeling","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative kinetic modeling plus electrophysiology, single lab","pmids":["18936081"],"is_preprint":false},{"year":2008,"finding":"Micromolar Zn2+ produces ~10-fold potentiation of NR1/NR3A excitatory glycine receptor responses; point mutations in the NR1 glycine-binding site abolish both the potentiating and agonistic effects of Zn2+, showing Zn2+ acts at the NR1 ligand-binding domain of NR1/NR3A receptors as a positive modulator and agonist.","method":"Electrophysiology in Xenopus oocytes, site-directed mutagenesis of NR1 and NR3A glycine-binding sites","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1/2 — mutagenesis identifying binding site, electrophysiology, single lab","pmids":["18711142"],"is_preprint":false},{"year":2016,"finding":"Extracellular acidification potentiates GluN1/GluN3A glycine-gated currents (half-maximal effect in physiological pH range) by slowing desensitization and accelerating recovery from desensitization; this effect is mediated by residues at the GluN1-GluN3A ligand-binding domain heterodimer interface.","method":"Whole-cell electrophysiology (recombinant GluN1/GluN3A), site-directed mutagenesis of dimer interface residues","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis identifying mechanistic residues combined with quantitative electrophysiology, single lab","pmids":["27000430"],"is_preprint":false},{"year":2009,"finding":"Expression of functional diheteromeric NR1/NR3 glycine-gated receptors in mammalian HEK293 cells is NR1 splice variant-dependent: variants lacking the C1 cassette (NR1-2a, NR1-3a, NR1-4a) support robust glycine currents, whereas NR1-1a does not; a phenylalanine in NR1-1a that restricts glycine access, when mutated to alanine, rescues NR1-1a/NR3A currents.","method":"Whole-cell electrophysiology in HEK293 cells, systematic splice variant expression, mutagenesis","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — systematic splice variant screen and mutagenesis identifying key residue, single lab","pmids":["19726695"],"is_preprint":false},{"year":2010,"finding":"NR1/NR3 receptors are expressed in CNS myelin and mediate excitatory glycine responses; these responses are activated by glycine or d-serine and blocked by the glycine-site antagonist CNQX but not by the glutamate-site antagonist d-APV; responses are absent in NR3A-deficient mice.","method":"Electrophysiology of myelin preparations, pharmacological characterization, NR3A knockout mice","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — knockout validation plus pharmacological characterization in native tissue","pmids":["20739572"],"is_preprint":false},{"year":2018,"finding":"Triheteromeric GluN1/GluN2B/GluN2D NMDARs have functional properties (agonist potency, open probability, deactivation) intermediate to GluN1/GluN2B and GluN1/GluN2D diheteromers; GluN1/GluN2B/2D receptors are more sensitive to ketamine/memantine block than GluN1/GluN2B; GluN2B-selective positive allosteric modulator spermine enhances GluN1/2B/2D but not GluN1/2A/2B.","method":"Selective triheteromer expression, two-electrode voltage clamp, single-channel recordings, hippocampal interneuron recordings","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — recombinant triheteromer pharmacology confirmed in native interneuron recordings, single lab","pmids":["31541561"],"is_preprint":false},{"year":2018,"finding":"Triheteromeric GluN1-1a/GluN1-1b/GluN2A and GluN1-1a/GluN1-1b/GluN2B receptors form in neurons; they exhibit intermediate deactivation kinetics and pharmacological properties relative to the respective diheteromeric GluN1-1a/2 and GluN1-1b/2 receptors; GluN1 (vs GluN2) pore residues contribute asymmetrically to Mg2+ block and Ca2+ permeability.","method":"FRET/FLIM to confirm triheteromer assembly, selective expression, electrophysiology","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — FRET confirmation of assembly plus functional characterization, single lab","pmids":["29483146"],"is_preprint":false},{"year":2015,"finding":"Single-molecule FRET of the glycine-bound GluN1 LBD reveals multiple equilibrium conformational states with reversible transitions (cleft-opening/closing) occurring on long timescales; the LBD proceeds primarily between adjacent FRET states consistent with a stepwise cleft-opening/closing mechanism.","method":"Single-molecule FRET (smFRET) with photoprotection, step transition and state identification algorithm","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 — single-molecule structural dynamics, but conformational data not yet linked to channel opening kinetics","pmids":["26153703"],"is_preprint":false},{"year":2002,"finding":"NR3A co-assembles with both NR1 and NR2 subunits in vivo; ~80% of NR3A is associated with NR1 in postnatal day 10 rat cortex (declining to 38% in adult); ~9.7% of NR1, 8.7% of NR2A, and 5% of NR2B are associated with NR3A at P10, with all associations declining by half in adult cortex.","method":"Quantitative immunoprecipitation with subunit-specific antibodies in rat cortex","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 — quantitative co-IP across development, single lab; strong evidence for subunit assembly","pmids":["12391275"],"is_preprint":false},{"year":2000,"finding":"CA1-specific knockout of NMDA receptor NR1 subunit impairs object recognition, olfactory discrimination, and contextual fear memory, demonstrating that NMDA receptor activity in CA1 is critical for hippocampus-dependent nonspatial memory formation; enriched experience rescued these deficits and increased CA1 synapse density in both knockouts and controls.","method":"Region-specific NR1 knockout mice, behavioral testing (fear conditioning, object recognition), stereological electron microscopy","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — region-specific KO with multiple behavioral readouts and structural measurement, highly cited foundational study","pmids":["10700255"],"is_preprint":false},{"year":1996,"finding":"Estradiol post-transcriptionally upregulates NMDAR1 subunit protein levels in CA1 pyramidal cell somata and dendrites without changing NMDAR1 mRNA levels, suggesting estradiol modulates NMDA receptor function via post-transcriptional regulation of the GluN1 subunit protein.","method":"Immunocytochemistry (confocal quantification of immunofluorescence), in situ hybridization in ovariectomized rats","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — orthogonal protein vs. mRNA measurement, mechanistic inference of post-transcriptional regulation","pmids":["8824322"],"is_preprint":false},{"year":1997,"finding":"Following perforant path deafferentation, NMDAR1 mRNA increases throughout the full dendritic extent of dentate gyrus granule cells (including non-denervated segments), but NMDAR1 protein accumulates selectively in the denervated outer molecular layer, demonstrating that local protein synthesis is restricted to zones of disrupted afferent activity while mRNA transport is more widespread.","method":"Quantitative immunofluorescence and in situ hybridization at multiple post-lesion timepoints","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — orthogonal protein/mRNA measurements with dissociation revealing dendritic trafficking mechanism","pmids":["9045729"],"is_preprint":false},{"year":2014,"finding":"Transcription factor Sp4 activates transcription of Nwk2 (Fchsd1), which in turn regulates cell-surface expression of GluN1 (NR1) and dendrite patterning in cerebellar granule neurons; Sp4 depletion reduces surface (but not total) NR1, and Nwk2 re-expression rescues surface NR1 levels.","method":"Sp4 knockdown, Nwk2 knockdown/overexpression, surface biotinylation of NR1, dendrite morphology analysis","journal":"Developmental neurobiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — pathway placement via genetic epistasis (Sp4→Nwk2→NR1 surface), surface biotinylation, single lab","pmids":["25045015"],"is_preprint":false},{"year":2019,"finding":"Structural features (glycine-binding cleft) of GluN1 and GluN3A subunits regulate forward trafficking (surface delivery) of NMDARs; mutations in the GluN1 or GluN3A glycine-binding sites reduce surface expression in mammalian cells and primary neurons; a clinically relevant GluN3A mutation significantly reduces surface delivery.","method":"Surface biotinylation, immunofluorescence in HEK cells and primary hippocampal neurons, site-directed mutagenesis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2/3 — mutagenesis linked to surface expression, multiple cell types, single lab","pmids":["31444392"],"is_preprint":false},{"year":2010,"finding":"NR1 subunit is expressed in human brain endothelial cells; NR1 in these cells regulates tissue-type plasminogen activator (tPA)-induced signal transduction and controls monocyte transmigration through the blood-brain barrier.","method":"Immunoblotting/immunofluorescence for NR1 in endothelial cells, siRNA knockdown, transendothelial monocyte migration assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — NR1 knockdown with defined cellular functional readout, single lab","pmids":["20085611"],"is_preprint":false},{"year":2022,"finding":"Platelet lineage-specific knockout of GluN1 (Pf4-Grin1-/- mice) causes defects in megakaryopoiesis, thrombopoiesis, and platelet function including reduced proplatelet formation; the mechanism involves impaired Ca2+ signaling and disrupted reorganization of F-actin and α-tubulin cytoskeleton, and reduced MK-ECM interaction.","method":"Cre-loxP megakaryocyte-specific Grin1 knockout, platelet function assays, Ca2+ imaging, cytoskeletal immunofluorescence, in vivo bleeding/thrombocytopenia models","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined mechanistic (cytoskeletal/Ca2+) and in vivo readouts, single lab","pmids":["35245376"],"is_preprint":false},{"year":2020,"finding":"GluN1/GluN3 NMDA receptors are inhibited by the negative allosteric modulator EU1180-438 in a voltage-independent, non-competitive manner; site-directed mutagenesis identifies structural determinants near a pre-M1 helix below the agonist-binding domain; EU1180-438 inhibits native GluN1/GluN3A currents in CA1 pyramidal neurons without affecting conductance.","method":"Electrophysiology (recombinant and native receptors), site-directed mutagenesis, non-stationary fluctuation analysis","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis identifying binding determinants, confirmed in native neurons","pmids":["32389749"],"is_preprint":false},{"year":2016,"finding":"De novo GRIN1 mutations in patients with NMDA receptor encephalopathy cluster within transmembrane segments and produce loss of channel function of varying severity with dominant-negative effects; two homozygous GRIN1 mutations also cause severe neurodevelopmental phenotypes; functional analysis in Xenopus oocytes confirmed loss-of-function mechanism.","method":"Whole-exome sequencing, two-electrode voltage clamp in Xenopus oocytes expressing mutant receptors","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization in Xenopus with multiple mutations, clear genotype-phenotype mechanism","pmids":["27164704"],"is_preprint":false},{"year":2018,"finding":"De novo missense GRIN1 mutations associated with polymicrogyria cluster in the S2 region of the GluN1 ligand-binding domain or adjacent M3 helix; voltage-clamp analysis showed three mutations increase agonist potency while one reduces proton inhibition—gain-of-function effects distinct from prior loss-of-function GRIN1 mutations.","method":"Whole-exome sequencing, two-electrode and whole-cell voltage-clamp in Xenopus oocytes/HEK cells","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — functional electrophysiology of multiple mutations defining mechanism, single study","pmids":["29365063"],"is_preprint":false},{"year":2021,"finding":"A recurrent GRIN1 variant (p.Met641Ile in the channel-lining M2 region) enhances NMDAR agonist potency and reduces Mg2+ block; GluN1-M641I-containing NMDARs are more sensitive to memantine, ketamine, and dextromethorphan; addition of memantine to treatment significantly reduced seizure burden in the patient.","method":"Whole exome sequencing, electrophysiology in Xenopus oocytes and HEK cells, beta-lactamase surface expression assay, clinical therapeutic trial","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro gain-of-function mechanism confirmed, drug sensitivity characterized, clinical validation","pmids":["34227748"],"is_preprint":false},{"year":1994,"finding":"LTP induction in dentate gyrus granule cells selectively increases mRNA for NR1 splice variants containing the PKC phosphorylation consensus site (C1 cassette, exon 21) by ~50% at 48 h, while NR1 variants lacking this site are unchanged, suggesting splice-variant-specific regulation during LTP maintenance.","method":"In situ hybridization with splice-variant-specific probes after LTP induction","journal":"Neuroreport","confidence":"Low","confidence_rationale":"Tier 3 — single method (ISH) showing mRNA-level correlate of LTP, no protein-level or functional validation","pmids":["7703398"],"is_preprint":false},{"year":1996,"finding":"Kindling transiently reduces expression of NMDAR1 splice isoforms containing exon 21 (C1 cassette) in hippocampus; no changes in other NMDAR1 isoforms are detected, suggesting kindling-induced seizures specifically regulate C-terminal alternative splicing of GluN1.","method":"In situ hybridization with splice-variant-specific probes in kindled rats","journal":"Brain research. Molecular brain research","confidence":"Low","confidence_rationale":"Tier 3 — single ISH method with no functional validation of splice-variant change","pmids":["8883939"],"is_preprint":false},{"year":1998,"finding":"NOS-positive neurons in neostriatum, neocortex, and hippocampus express NMDAR1 but selectively lack the C1 splice cassette and instead preferentially express the C2' terminus (produced when C2 exon is absent), demonstrating cell-type-specific alternative splicing of GluN1 in nNOS neurons.","method":"Dual-label immunofluorescence with confocal microscopy using splice-cassette-specific antibodies","journal":"The Journal of neuroscience","confidence":"Low","confidence_rationale":"Tier 3 — immunofluorescence identifying splice-cassette expression pattern, no functional consequence tested","pmids":["9464997"],"is_preprint":false},{"year":2004,"finding":"P2Y4 purinergic receptor co-localizes and co-immunoprecipitates with NMDAR1 at the plasma membrane in cerebellar granule neurons and HEK-293 cells; during hypoglycemia, P2Y4 is upregulated while NMDAR1 is downregulated, and both P2 and NMDA antagonists can restore basal NMDAR1 expression, suggesting a functional cross-talk between the two receptors.","method":"Co-immunoprecipitation, confocal co-localization, pharmacological manipulation during hypoglycemia","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP plus co-localization, no reconstitution or mechanistic dissection of interaction","pmids":["15383322"],"is_preprint":false},{"year":2020,"finding":"Protocadherin 7 (PCDH7) interacts with the GluN1 N-terminal domain; PCDH7 overexpression reduces synaptic NMDAR currents, while knockdown and overexpression produce opposing changes in dendritic spine morphology, placing PCDH7 as a GluN1 NTD-interacting regulator of NMDAR function and spine structure.","method":"Unbiased transmembrane protein screen with purified GluN1-NTD bait, overexpression/knockdown in neurons, NMDAR current recordings","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — screen-identified interaction confirmed by electrophysiology and morphology, but interaction biochemistry not deeply validated","pmids":["32616769"],"is_preprint":false},{"year":2009,"finding":"Adeno-associated virus-mediated knockdown of NR1 in rat hippocampus reduces NMDAR-mediated synaptic currents and impairs fear memory acquisition, while NR1 overexpression enhances fear memory and neurogenesis but paradoxically delays severe seizure onset, establishing bidirectional control of plasticity and seizure threshold by NR1 levels.","method":"AAV-mediated NR1 knockdown/overexpression, electrophysiology, fear conditioning, seizure assay, BrdU neurogenesis","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional in vivo manipulation with electrophysiological and behavioral readouts, single lab","pmids":["19394426"],"is_preprint":false}],"current_model":"GluN1 (GRIN1) encodes the obligatory subunit of all NMDA receptors, forming tetrameric ion channels (typically GluN1₂/GluN2₂ heterotetramers in an alternating 1-2-1-2 arrangement) that require co-binding of glycine (at GluN1) and glutamate (at GluN2) for activation; its N-terminal domain undergoes dynamic conformational rearrangements that allosterically modulate gating and pharmacology, its ligand-binding domain cleft closures signal through LBD–TMD linkers to open the channel pore in a concerted four-subunit mechanism, its eight alternatively spliced isoforms (particularly the N1/exon-5 cassette) tune deactivation kinetics, LTP magnitude, synaptic maturation, and nonionotropic glycine-priming signaling, calmodulin binds the C0/C1 cytoplasmic regions to regulate surface localization, KCTD13-mediated K48-polyubiquitination at K860 targets GluN1 for proteasomal degradation, EphB2 constrains NMDAR lateral mobility via a direct extracellular charge-mediated interaction with the GluN1 NTD hinge, and when co-assembled with GluN3 subunits (without GluN2), GluN1 forms excitatory glycine-gated receptors that regulate specific behaviors including aversion."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that GluN1 protein levels can be regulated post-transcriptionally answered the question of how receptor abundance is controlled independent of mRNA, revealing a layer of regulation beyond transcription.","evidence":"Immunocytochemistry and in situ hybridization in ovariectomized rats showed estradiol upregulated GluN1 protein without changing mRNA","pmids":["8824322"],"confidence":"Medium","gaps":["Molecular mechanism of post-transcriptional stabilization not identified","Generalizability beyond estradiol signaling untested"]},{"year":2000,"claim":"Region-specific GluN1 knockout demonstrated that NMDAR activity in hippocampal CA1 is essential for nonspatial memory, establishing the in vivo requirement for the obligatory subunit in defined cognitive functions.","evidence":"CA1-restricted NR1 knockout mice with behavioral testing (object recognition, contextual fear) and electron microscopy","pmids":["10700255"],"confidence":"High","gaps":["Whether GluN1 loss phenocopies complete NMDAR ablation or has subunit-independent effects not resolved","Compensatory mechanisms in chronic KO not excluded"]},{"year":2002,"claim":"Quantitative demonstration that GluN3A co-assembles with GluN1 and GluN2 in vivo with a developmentally declining stoichiometry established the native existence of GluN3-containing receptors and their temporal regulation.","evidence":"Quantitative immunoprecipitation with subunit-specific antibodies in rat cortex across postnatal development","pmids":["12391275"],"confidence":"Medium","gaps":["Functional properties of native GluN1/GluN3 vs. GluN1/GluN2/GluN3 complexes not characterized","Subcellular location of GluN3-containing complexes unknown"]},{"year":2007,"claim":"The crystal structure of calmodulin bound to the GluN1 C1 region revealed how CaM engagement shields the S890 phosphorylation site while leaving the ER retention motif exposed, providing a structural basis for CaM-dependent trafficking regulation.","evidence":"X-ray crystallography at 1.96 Å resolution of Ca2+-CaM/NR1-C1 complex","pmids":["18073110"],"confidence":"High","gaps":["Whether CaM binding actively promotes or inhibits ER exit not functionally tested","Role of C0 region in CaM regulation not structurally resolved"]},{"year":2008,"claim":"Identification of the agonist-binding domain dimer interface as the structural relay coupling GluN2A NTD zinc binding to the channel gate resolved how allosteric inhibition is transduced across receptor domains.","evidence":"Mutagenesis of ABD dimer interface residues combined with electrophysiology measuring zinc and proton inhibition","pmids":["18184566"],"confidence":"High","gaps":["Whether the same interface mediates all allosteric signals or is pathway-specific not fully resolved","Structural visualization of conformational changes awaited"]},{"year":2011,"claim":"Demonstration that constraining LBD–TMD linkers in any single subunit equally impairs gating established that pore opening requires concerted conformational changes across all four subunits, not sequential or asymmetric motions.","evidence":"Engineered disulfide bonds in M3-S2 and S2-M4 linkers of GluN1 or GluN2A with single-channel recordings","pmids":["21746848"],"confidence":"High","gaps":["Precise temporal sequence of linker movements during gating not resolved","Whether GluN3-containing receptors follow the same concerted mechanism unknown"]},{"year":2012,"claim":"Functional cross-linking confirmed that mature GluN1/GluN2A receptors adopt an alternating 1-2-1-2 arrangement with GluN1 proximal to the pore axis, resolving the subunit stoichiometry and geometry debate.","evidence":"Disulfide cross-linking and electrophysiology distinguishing mature surface from immature intracellular receptors","pmids":["22493736"],"confidence":"High","gaps":["Whether immature receptors with alternative arrangements are functionally relevant not determined"]},{"year":2012,"claim":"Identification of GluN1 exon-5 (N1 cassette) and specifically Lys211 as key determinants of GluN2D-containing receptor deactivation and open probability revealed how N-terminal alternative splicing tunes channel kinetics.","evidence":"Single-channel recordings, kinetic modeling, and Lys211 mutagenesis in GluN1-1a vs. GluN1-1b/GluN2D","pmids":["22641781"],"confidence":"High","gaps":["Whether Lys211-dependent effects extend to all GluN2 subtypes not fully tested"]},{"year":2013,"claim":"Demonstration that the GluN1 NTD is conformationally dynamic and allosterically influences glutamate binding in trans with GluN2 NTD overturned the view that GluN1 NTD is a passive scaffold, establishing it as an active modulator of receptor pharmacology.","evidence":"Electrophysiology, cross-linking, and mutagenesis showing GluN1 NTD hinge motions affect gating","pmids":["23454977"],"confidence":"High","gaps":["Full energy landscape of GluN1 NTD conformational cycling in the intact receptor not mapped"]},{"year":2014,"claim":"Characterization of triheteromeric GluN1/GluN2A/GluN2B receptors revealed distinct deactivation kinetics and pharmacological profiles that could not be predicted from diheteromer properties, establishing triheteromers as functionally unique receptor populations.","evidence":"Selective cell-surface expression of recombinant triheteromers with electrophysiology and pharmacology","pmids":["24607230"],"confidence":"High","gaps":["Fractional representation of triheteromers at individual synapses in vivo not quantified"]},{"year":2016,"claim":"Discovery that de novo GRIN1 mutations cause NMDA receptor encephalopathy via dominant-negative loss of channel function established GluN1 as a disease gene and linked transmembrane-domain mutations to neurodevelopmental pathology.","evidence":"Whole-exome sequencing of patients with functional electrophysiology of mutant receptors in Xenopus oocytes","pmids":["27164704"],"confidence":"Medium","gaps":["Genotype-phenotype correlations across the full mutation spectrum incomplete","No animal rescue experiments reported"]},{"year":2018,"claim":"Cryo-EM structures of GluN1/GluN2A captured multiple conformational states under zinc and proton modulation, directly visualizing the allosteric pathway from GluN2A NTD through the LBD to channel gate constriction that had been inferred from mutagenesis.","evidence":"Cryo-EM at multiple zinc/proton concentrations resolving distinct conformational states","pmids":["30500536"],"confidence":"High","gaps":["Time-resolved structural transitions during gating not captured","Lipid bilayer effects on conformational landscape not assessed"]},{"year":2019,"claim":"Reciprocal knock-in mouse models showed that the GluN1 exon-5 cassette bidirectionally controls hippocampal LTP magnitude and spatial learning, directly demonstrating that a single alternative splicing event in the obligatory subunit scales synaptic plasticity in vivo.","evidence":"GluN1a-only and GluN1b-only knock-in mice with hippocampal LTP recordings and spatial memory tests","pmids":["31875540"],"confidence":"High","gaps":["Which downstream signaling pathways mediate exon-5-dependent LTP scaling not identified"]},{"year":2019,"claim":"GluN1/GluN3A excitatory glycine receptors were shown to be functional in adult medial habenula neurons and to regulate aversion behavior, establishing a physiological role for GluN2-free NMDAR assemblies in a defined neural circuit.","evidence":"Native electrophysiology in MHb neurons, viral GluN3A knockdown, and conditioned place aversion behavioral assay","pmids":["31601771"],"confidence":"High","gaps":["Downstream signaling from GluN1/GluN3A in MHb not characterized","Whether other brain regions use GluN1/GluN3A for behavioral functions not explored"]},{"year":2020,"claim":"Mapping the EphB2–GluN1 extracellular interaction to a charge-complementary interface at the GluN1 NTD hinge revealed how an extracellular binding partner constrains NMDAR lateral mobility at synapses, linking receptor retention to a specific structural epitope.","evidence":"Direct pulldown with charge-reversal GluN1 mutants and single-particle tracking of NMDAR mobility","pmids":["31996679"],"confidence":"High","gaps":["Whether EphB2–GluN1 interaction is regulated by activity or development not tested"]},{"year":2021,"claim":"Discovery that GluN1 alternative splicing gates nonionotropic glycine-priming signaling—with N1-lacking isoforms permitting and N1-containing isoforms blocking internalization—revealed a splice-variant-specific mechanism for metabotropic NMDAR signaling.","evidence":"Obligatory-splice knock-in mice, recombinant receptor expression, and electrophysiology in acute hippocampal slices","pmids":["34187890"],"confidence":"High","gaps":["Structural basis of how N1 cassette blocks glycine priming not resolved","Signaling intermediates downstream of glycine priming incompletely defined"]},{"year":2023,"claim":"Identification of KCTD13 as the E3 ligase adapter that K48-polyubiquitinates GluN1 at K860 for proteasomal degradation provided the first specific ubiquitin-dependent mechanism controlling GluN1 protein turnover and linked it to seizure susceptibility.","evidence":"In vitro ubiquitination assay, K860R mutagenesis, KCTD13 knockdown/overexpression in mouse hippocampus, electrophysiology, seizure assays","pmids":["37142655"],"confidence":"High","gaps":["Whether other E3 ligases also target GluN1 not excluded","How KCTD13 activity is itself regulated at synapses unknown"]},{"year":2024,"claim":"Cryo-EM structures of GluN1/GluN3A receptors revealed a 1-3-1-3 subunit arrangement with an unprecedented GluN3A orientation shift upon ligand binding, providing the first structural framework for understanding excitatory glycine receptor gating and desensitization.","evidence":"Cryo-EM of glycine-bound and CNQX-bound GluN1/GluN3A with mutagenesis validation","pmids":["38598639"],"confidence":"High","gaps":["Full gating cycle of GluN1/GluN3A not structurally resolved","How GluN1/GluN3A structural features explain pharmacological differences from GluN1/GluN2 receptors not fully elucidated"]},{"year":null,"claim":"Key unresolved questions include the time-resolved structural dynamics of the full gating cycle across NMDAR subtypes, the complete repertoire of E3 ligases and post-translational modifications controlling GluN1 turnover, the structural basis by which the N1 cassette gates nonionotropic signaling, and the physiological functions of GluN1/GluN3 receptors outside the medial habenula.","evidence":"","pmids":[],"confidence":"High","gaps":["Time-resolved gating transitions not captured structurally","Complete post-translational modification map of GluN1 lacking","Structural mechanism of N1 cassette-dependent nonionotropic signaling unknown","Circuit-level functions of GluN1/GluN3 receptors largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,9,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,12,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,19,33,34]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,9,13,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[18]}],"complexes":["GluN1/GluN2A NMDAR","GluN1/GluN2B NMDAR","GluN1/GluN3A excitatory glycine receptor"],"partners":["GRIN2A","GRIN2B","GRIN3A","CALM1","EPHB2","KCTD13","DRD1","PCDH7"],"other_free_text":[]},"mechanistic_narrative":"GRIN1 encodes GluN1, the obligatory subunit of all NMDA-type ionotropic glutamate receptors, which assemble as heterotetramers with GluN2 or GluN3 subunits in an alternating arrangement and require co-agonist binding (glycine at GluN1, glutamate at GluN2) for channel activation [PMID:8824322, PMID:22493736, PMID:30500536]. The GluN1 N-terminal domain undergoes dynamic hinge-bending motions that allosterically transduce zinc- and proton-mediated inhibition through the ligand-binding domain dimer interface to the channel gate, while concerted conformational changes at LBD–TMD linkers in all four subunits are required for pore opening [PMID:23454977, PMID:18184566, PMID:21746848, PMID:34186027]. Alternative splicing of eight GluN1 isoforms—particularly the N-terminal exon-5 (N1) cassette—tunes receptor deactivation kinetics, LTP magnitude, synaptic maturation, seizure susceptibility, and nonionotropic glycine-priming signaling, while C-terminal domains regulate surface trafficking through calmodulin binding and KCTD13-mediated K48-polyubiquitination at K860 targeting GluN1 for proteasomal degradation [PMID:22641781, PMID:31875540, PMID:31570583, PMID:34187890, PMID:18073110, PMID:37142655]. De novo GRIN1 mutations cause neurodevelopmental disorders including NMDA receptor encephalopathy (loss-of-function) and polymicrogyria (gain-of-function), and when co-assembled with GluN3 subunits in the absence of GluN2, GluN1 forms excitatory glycine receptors that regulate aversion behavior in the medial habenula [PMID:27164704, PMID:29365063, PMID:31601771]."},"prefetch_data":{"uniprot":{"accession":"Q05586","full_name":"Glutamate receptor ionotropic, NMDA 1","aliases":["Glutamate [NMDA] receptor subunit zeta-1","N-methyl-D-aspartate receptor subunit NR1","NMD-R1","hNR1"],"length_aa":938,"mass_kda":105.4,"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:21376300, PubMed:26875626, PubMed:26919761, PubMed:28126851, PubMed:28228639, PubMed:36959261, PubMed:7679115, PubMed:7681588, PubMed:7685113). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) (PubMed:26875626). 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:21376300, PubMed:26875626, PubMed:26919761, PubMed:27164704, PubMed:28095420, PubMed:28105280, PubMed:28126851, PubMed:28228639, PubMed:36959261, PubMed:38538865, PubMed:7679115, PubMed:7681588, PubMed:7685113). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium (By similarity). Each GluN2 or GluN3 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, PubMed:36309015, PubMed:38598639)","subcellular_location":"Cell membrane; Postsynaptic cell membrane; Postsynaptic density membrane; Synaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q05586/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRIN1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRIN1","total_profiled":1310},"omim":[{"mim_id":"619814","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 101; DEE101","url":"https://www.omim.org/entry/619814"},{"mim_id":"618306","title":"PROLINE-RICH PROTEIN 7; PRR7","url":"https://www.omim.org/entry/618306"},{"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":"616690","title":"CENTROSOMAL PROTEIN, 104-KD; CEP104","url":"https://www.omim.org/entry/616690"},{"mim_id":"614795","title":"1-@ACYLGLYCEROL-3-PHOSPHATE O-ACYLTRANSFERASE 4; AGPAT4","url":"https://www.omim.org/entry/614795"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":215.2}],"url":"https://www.proteinatlas.org/search/GRIN1"},"hgnc":{"alias_symbol":["GluN1","NR1"],"prev_symbol":["NMDAR1"]},"alphafold":{"accession":"Q05586","domains":[{"cath_id":"3.40.50.2300","chopping":"21-114_277-334","consensus_level":"high","plddt":87.3249,"start":21,"end":334},{"cath_id":"3.40.50.2300","chopping":"143-273_349-373","consensus_level":"high","plddt":90.69,"start":143,"end":373},{"cath_id":"3.40.190.10","chopping":"398-532","consensus_level":"high","plddt":89.4225,"start":398,"end":532},{"cath_id":"3.40.190.10","chopping":"534-547_660-758","consensus_level":"medium","plddt":91.0427,"start":534,"end":758},{"cath_id":"1.10.287.70","chopping":"559-585_600-656","consensus_level":"high","plddt":86.7213,"start":559,"end":656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05586","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q05586-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q05586-F1-predicted_aligned_error_v6.png","plddt_mean":82.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRIN1","jax_strain_url":"https://www.jax.org/strain/search?query=GRIN1"},"sequence":{"accession":"Q05586","fasta_url":"https://rest.uniprot.org/uniprotkb/Q05586.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q05586/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05586"}},"corpus_meta":[{"pmid":"10700255","id":"PMC_10700255","title":"Enrichment 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proton inhibition acts via a similar allosteric pathway.\",\n      \"method\": \"Cryo-electron microscopy, multiple conformational states under varying zinc and proton concentrations\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural determination with multiple conformational states and direct mechanistic interpretation\",\n      \"pmids\": [\"30500536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of human GluN1-GluN2A NMDA receptor show that positive allosteric modulator binding shortens the distance between ligand-binding domains and the transmembrane domain to stretch the channel gate open; a 'foot-in-the-door' blocker (9-aminoacridine) binds within the LBD-TMD linker region rather than the conventional vestibule site.\",\n      \"method\": \"Cryo-electron microscopy with distinct ligands/modulators at ~4 Å resolution\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with multiple ligand states providing direct mechanistic insight into gating and block\",\n      \"pmids\": [\"34186027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of GluN1-GluN2C, GluN1-GluN2A-GluN2C triheteromeric, and GluN1-GluN2D NMDARs reveal unique inter-subunit and domain arrangements of GluN2C NMDARs that contribute to functional regulation and formation of a positive allosteric modulator (PYD-106) binding pocket distinct from GluN2D.\",\n      \"method\": \"Single-particle cryo-electron microscopy\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of multiple NMDAR subtypes with functional correlates\",\n      \"pmids\": [\"36309015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of GluN1-GluN3A NMDARs reveal a 1-3-1-3 subunit heterotetrameric arrangement; comparison of glycine-bound vs. CNQX-bound structures shows an unprecedented GluN3A subunit orientation shift, and disruption of the unique subunit interface in the glycine-bound structure mitigated desensitization.\",\n      \"method\": \"Cryo-electron microscopy, site-directed mutagenesis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures combined with mutagenesis validating structural-functional link\",\n      \"pmids\": [\"38598639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The agonist-binding domain (ABD) dimer interface of NR1/NR2A NMDA receptors is a major structural determinant coupling the NR2A N-terminal domain (NTD) zinc-binding site to the channel gate; rearrangements at the ABD dimer interface mediate both Zn2+ allosteric inhibition and proton inhibition.\",\n      \"method\": \"Electrophysiology (mutagenesis of ABD dimer interface), structural analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis + electrophysiology with clear mechanistic framework, replicated across inhibition types\",\n      \"pmids\": [\"18184566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GluN1 N-terminal domain (NTD) is dynamic rather than static: perturbing its conformation affects receptor gating and pharmacological properties; GluN1 NTD undergoes hinge bending, twisting, and untwisting motions and acts in trans with GluN2 NTD to influence glutamate (but not glycine) binding.\",\n      \"method\": \"Electrophysiology, cross-linking, structural analysis, mutagenesis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (electrophysiology, cross-linking, mutagenesis) in one study\",\n      \"pmids\": [\"23454977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of calcium-saturated calmodulin bound to the NR1 C1 region (NR1C1 peptide, residues 875–898) shows that NR1 S890 (whose phosphorylation regulates membrane localization) is solvent-protected in the CaM complex, while the ER retention motif is solvent-exposed; NR1 F880 fills the CaM C-domain hydrophobic pocket.\",\n      \"method\": \"X-ray crystallography (1.96 Å, PDB 2HQW)\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional interpretation of phosphorylation-site accessibility\",\n      \"pmids\": [\"18073110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of GluN1 and GluN3A ligand-binding domains in apo states reveal open- and closed-cleft conformations, respectively; computed free-energy landscapes indicate GluN1 (and GluN2A, GluN3A) apo-state LBDs sample closed-cleft conformations, suggesting agonist binding via conformational selection rather than induced-fit.\",\n      \"method\": \"X-ray crystallography, molecular dynamics / free energy calculations\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures plus computational free-energy landscapes supporting binding mechanism\",\n      \"pmids\": [\"23972471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Using electrophysiology and cross-linking experiments, functional GluN1/GluN2A receptors adopt an alternating 1/2/1/2 subunit arrangement in which GluN1 subunits occupy a 'proximal' position closer to the channel pore axis than GluN2 subunits; immature intracellular receptors can adopt different arrangements.\",\n      \"method\": \"Electrophysiology, disulfide cross-linking, structural modeling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal electrophysiology and cross-linking methods in mature vs. immature receptor pools\",\n      \"pmids\": [\"22493736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Intrasubunit disulfide bonds constraining the M3-S2 and S2-M4 linkers in either GluN1 or GluN2A equally impair NMDA receptor pore opening without altering single-channel conductance, demonstrating that concerted conformational dynamics at LBD-TMD linkers in all four subunits are required for pore opening.\",\n      \"method\": \"Disulfide cross-linking, single-channel electrophysiology in outside-out patches\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — engineered disulfide bonds with single-channel recordings providing direct mechanistic evidence\",\n      \"pmids\": [\"21746848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Triheteromeric GluN1/GluN2A/GluN2B NMDARs have glutamate deactivation kinetics distinct from either diheteromeric receptor; subunit-selective antagonists (ifenprodil, CP-101,606, TCN-201, Zn2+) modulate triheteromers with properties intermediate to and distinct from diheteromers, with variation in the ifenprodil binding site geometry.\",\n      \"method\": \"Selective cell-surface expression of recombinant triheteromers, electrophysiology, pharmacological characterization\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel method for selective triheteromer expression combined with kinetic and pharmacological analysis\",\n      \"pmids\": [\"24607230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"D-cycloserine (DCS) acts as a partial agonist at the GluN1 glycine-binding site with efficacy dependent on which GluN2 subunit is present; at NR1/NR2C receptors DCS has higher relative efficacy than glycine by accelerating a fast pregating step and reducing the closing rate; residues at the ABD dimer interface regulate DCS efficacy.\",\n      \"method\": \"Single-channel recordings, molecular dynamics simulations, site-directed mutagenesis, kinetic modeling\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — single-channel analysis, mutagenesis, MD simulations and kinetic modeling in one study\",\n      \"pmids\": [\"20164358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GluN1 exon 5-encoded residues (N1 cassette in the NTD) are key determinants of GluN1/GluN2D receptor function: exon 5-containing GluN1-1b/GluN2D receptors deactivate ~3-fold faster and have ~2-fold higher open probability than exon 5-lacking GluN1-1a/GluN2D; residue Lys211 in GluN1-1b is identified as a key determinant; exon 5 influences multiple rate-limiting gating steps.\",\n      \"method\": \"Two-electrode voltage clamp, single-channel recordings, kinetic modeling, mutagenesis\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — single-channel analysis, mutagenesis, and kinetic modeling identifying specific residue\",\n      \"pmids\": [\"22641781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GluN1 exon 5 (N1 cassette) controls LTP magnitude and spatial memory: mice lacking the N1 cassette (GluN1a) show enhanced hippocampal LTP and faster spatial learning vs. mice obligatorily expressing N1 (GluN1b), demonstrating alternative splicing of GluN1 as a mechanism controlling synaptic plasticity and learning.\",\n      \"method\": \"Knock-in mouse models (exon 5 deletion and forced inclusion), hippocampal LTP recordings, behavioral tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two reciprocal knock-in lines with electrophysiology and behavioral readouts\",\n      \"pmids\": [\"31875540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"N-terminal alternative splicing of GluN1 (exon 5) regulates the developmental shortening of NMDAR-mediated EPSCs in thalamic neurons and synaptic maturation; deletion of exon 5 causes overproduction of excitatory synapses in cortical layer 5 pyramidal neurons and increases seizure susceptibility.\",\n      \"method\": \"Conditional knock-in mouse (exon 5 deletion), whole-cell recordings, synapse counting, seizure threshold assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model with electrophysiology and anatomical readouts\",\n      \"pmids\": [\"31570583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nonionotropic signaling by glycine binding to GluN1 (glycine priming of NMDAR internalization) is gated by GluN1 alternative splicing: splice variants lacking the N1 cassette support glycine priming; those containing N1 block it. C-terminal cassettes (C1, C2, C2') each permit glycine priming. In vivo, CA1 pyramidal neuron synaptic NMDARs undergo glycine priming, while CA1 interneuron NMDARs do not, correlating with their endogenous GluN1 isoform content.\",\n      \"method\": \"Recombinant NMDAR expression, knock-in mouse engineering (obligatory N1 inclusion/exclusion), electrophysiology in acute slices\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse models and electrophysiology with multiple orthogonal readouts\",\n      \"pmids\": [\"34187890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GluN1/GluN3A receptors (excitatory glycine receptors, eGlyRs) are functionally expressed in adult medial habenula neurons; glial-derived glycine activates these receptors to tune neuronal activity; reducing GluN1/GluN3A levels in the MHb prevents conditioned place aversion.\",\n      \"method\": \"Electrophysiology (native MHb neurons), viral knockdown, place-aversion conditioning, immunohistochemistry\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — native electrophysiology plus in vivo knockdown with behavioral readout, replicated across methods\",\n      \"pmids\": [\"31601771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"D1 dopamine receptor (D1R) and GluN1 subunit of NMDAR form direct physical complexes in striatal medium spiny neurons upon co-stimulation; disrupting D1R/GluN1 association with a cell-permeable peptide (TAT-GluN1C1) prevents D1R-mediated facilitation of NMDAR calcium influx and ERK activation without affecting individual D1R or NMDAR signaling; D1R/GluN1 complexes are required for D1R-dependent LTP and behavioral sensitization to cocaine.\",\n      \"method\": \"Co-immunoprecipitation (endogenous proteins), cell-permeable peptide disruption, Ca2+ imaging, slice electrophysiology, behavioral sensitization assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP of endogenous proteins, functional peptide disruption, electrophysiology, and behavior\",\n      \"pmids\": [\"25070539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KCTD13 (a cullin3-based E3 ubiquitin ligase adapter) directly ubiquitinates GluN1 at lysine 860 with K48-linked polyubiquitin chains, targeting GluN1 for proteasomal degradation; KCTD13 knockdown increases GluN1 membrane expression and NMDAR-mediated synaptic transmission, enhancing seizure susceptibility.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K860 GluN1), viral knockdown/overexpression in mouse hippocampus, electrophysiology, seizure threshold assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro ubiquitination assay with specific site mutagenesis, in vivo mouse model, and electrophysiology\",\n      \"pmids\": [\"37142655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The positive surface charge of the hinge region of the GluN1 N-terminal domain directly mediates interaction with a negatively charged phospho-tyrosine on EphB2; this extracellular interaction constrains NMDAR mobility at dendritic spine synapses; loss of EphB-NMDAR interaction (by GluN1 mutation or EphB2 knockdown) increases NMDAR lateral mobility.\",\n      \"method\": \"Pulldown/direct interaction assay, live-cell single-particle tracking, GluN1 charge-reversal mutagenesis, EphB2 knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped to specific charged residues, validated by live-cell mobility assays\",\n      \"pmids\": [\"31996679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NFL (neurofilament light) directly interacts with GluN1 subunit; NFL deficiency reduces dendritic spine density and GluN1 protein levels, elevates ubiquitin-dependent GluN1 turnover, and depresses hippocampal LTP, producing an NMDAR hypofunction phenotype.\",\n      \"method\": \"Co-immunoprecipitation (NFL-GluN1 interaction), NFL knockout mouse, Western blot, electrophysiology (LTP), behavioral assays, MRS\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus KO mouse with multiple functional readouts, single lab\",\n      \"pmids\": [\"30143609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NR1/NR2B NMDA receptor activity is enhanced by depolarization independent of Mg2+ block (voltage-dependent gating); a kinetic model identifies voltage-dependent conformational changes in the NR2B subunit as the mechanism; these changes underlie the slow component of Mg2+ unblock during dendritic spikes.\",\n      \"method\": \"Whole-cell electrophysiology (0 Mg2+ and physiological Mg2+), kinetic modeling\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative kinetic modeling plus electrophysiology, single lab\",\n      \"pmids\": [\"18936081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Micromolar Zn2+ produces ~10-fold potentiation of NR1/NR3A excitatory glycine receptor responses; point mutations in the NR1 glycine-binding site abolish both the potentiating and agonistic effects of Zn2+, showing Zn2+ acts at the NR1 ligand-binding domain of NR1/NR3A receptors as a positive modulator and agonist.\",\n      \"method\": \"Electrophysiology in Xenopus oocytes, site-directed mutagenesis of NR1 and NR3A glycine-binding sites\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis identifying binding site, electrophysiology, single lab\",\n      \"pmids\": [\"18711142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Extracellular acidification potentiates GluN1/GluN3A glycine-gated currents (half-maximal effect in physiological pH range) by slowing desensitization and accelerating recovery from desensitization; this effect is mediated by residues at the GluN1-GluN3A ligand-binding domain heterodimer interface.\",\n      \"method\": \"Whole-cell electrophysiology (recombinant GluN1/GluN3A), site-directed mutagenesis of dimer interface residues\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis identifying mechanistic residues combined with quantitative electrophysiology, single lab\",\n      \"pmids\": [\"27000430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Expression of functional diheteromeric NR1/NR3 glycine-gated receptors in mammalian HEK293 cells is NR1 splice variant-dependent: variants lacking the C1 cassette (NR1-2a, NR1-3a, NR1-4a) support robust glycine currents, whereas NR1-1a does not; a phenylalanine in NR1-1a that restricts glycine access, when mutated to alanine, rescues NR1-1a/NR3A currents.\",\n      \"method\": \"Whole-cell electrophysiology in HEK293 cells, systematic splice variant expression, mutagenesis\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic splice variant screen and mutagenesis identifying key residue, single lab\",\n      \"pmids\": [\"19726695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NR1/NR3 receptors are expressed in CNS myelin and mediate excitatory glycine responses; these responses are activated by glycine or d-serine and blocked by the glycine-site antagonist CNQX but not by the glutamate-site antagonist d-APV; responses are absent in NR3A-deficient mice.\",\n      \"method\": \"Electrophysiology of myelin preparations, pharmacological characterization, NR3A knockout mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — knockout validation plus pharmacological characterization in native tissue\",\n      \"pmids\": [\"20739572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Triheteromeric GluN1/GluN2B/GluN2D NMDARs have functional properties (agonist potency, open probability, deactivation) intermediate to GluN1/GluN2B and GluN1/GluN2D diheteromers; GluN1/GluN2B/2D receptors are more sensitive to ketamine/memantine block than GluN1/GluN2B; GluN2B-selective positive allosteric modulator spermine enhances GluN1/2B/2D but not GluN1/2A/2B.\",\n      \"method\": \"Selective triheteromer expression, two-electrode voltage clamp, single-channel recordings, hippocampal interneuron recordings\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — recombinant triheteromer pharmacology confirmed in native interneuron recordings, single lab\",\n      \"pmids\": [\"31541561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Triheteromeric GluN1-1a/GluN1-1b/GluN2A and GluN1-1a/GluN1-1b/GluN2B receptors form in neurons; they exhibit intermediate deactivation kinetics and pharmacological properties relative to the respective diheteromeric GluN1-1a/2 and GluN1-1b/2 receptors; GluN1 (vs GluN2) pore residues contribute asymmetrically to Mg2+ block and Ca2+ permeability.\",\n      \"method\": \"FRET/FLIM to confirm triheteromer assembly, selective expression, electrophysiology\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — FRET confirmation of assembly plus functional characterization, single lab\",\n      \"pmids\": [\"29483146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Single-molecule FRET of the glycine-bound GluN1 LBD reveals multiple equilibrium conformational states with reversible transitions (cleft-opening/closing) occurring on long timescales; the LBD proceeds primarily between adjacent FRET states consistent with a stepwise cleft-opening/closing mechanism.\",\n      \"method\": \"Single-molecule FRET (smFRET) with photoprotection, step transition and state identification algorithm\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — single-molecule structural dynamics, but conformational data not yet linked to channel opening kinetics\",\n      \"pmids\": [\"26153703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NR3A co-assembles with both NR1 and NR2 subunits in vivo; ~80% of NR3A is associated with NR1 in postnatal day 10 rat cortex (declining to 38% in adult); ~9.7% of NR1, 8.7% of NR2A, and 5% of NR2B are associated with NR3A at P10, with all associations declining by half in adult cortex.\",\n      \"method\": \"Quantitative immunoprecipitation with subunit-specific antibodies in rat cortex\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — quantitative co-IP across development, single lab; strong evidence for subunit assembly\",\n      \"pmids\": [\"12391275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CA1-specific knockout of NMDA receptor NR1 subunit impairs object recognition, olfactory discrimination, and contextual fear memory, demonstrating that NMDA receptor activity in CA1 is critical for hippocampus-dependent nonspatial memory formation; enriched experience rescued these deficits and increased CA1 synapse density in both knockouts and controls.\",\n      \"method\": \"Region-specific NR1 knockout mice, behavioral testing (fear conditioning, object recognition), stereological electron microscopy\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — region-specific KO with multiple behavioral readouts and structural measurement, highly cited foundational study\",\n      \"pmids\": [\"10700255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Estradiol post-transcriptionally upregulates NMDAR1 subunit protein levels in CA1 pyramidal cell somata and dendrites without changing NMDAR1 mRNA levels, suggesting estradiol modulates NMDA receptor function via post-transcriptional regulation of the GluN1 subunit protein.\",\n      \"method\": \"Immunocytochemistry (confocal quantification of immunofluorescence), in situ hybridization in ovariectomized rats\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — orthogonal protein vs. mRNA measurement, mechanistic inference of post-transcriptional regulation\",\n      \"pmids\": [\"8824322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Following perforant path deafferentation, NMDAR1 mRNA increases throughout the full dendritic extent of dentate gyrus granule cells (including non-denervated segments), but NMDAR1 protein accumulates selectively in the denervated outer molecular layer, demonstrating that local protein synthesis is restricted to zones of disrupted afferent activity while mRNA transport is more widespread.\",\n      \"method\": \"Quantitative immunofluorescence and in situ hybridization at multiple post-lesion timepoints\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — orthogonal protein/mRNA measurements with dissociation revealing dendritic trafficking mechanism\",\n      \"pmids\": [\"9045729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Transcription factor Sp4 activates transcription of Nwk2 (Fchsd1), which in turn regulates cell-surface expression of GluN1 (NR1) and dendrite patterning in cerebellar granule neurons; Sp4 depletion reduces surface (but not total) NR1, and Nwk2 re-expression rescues surface NR1 levels.\",\n      \"method\": \"Sp4 knockdown, Nwk2 knockdown/overexpression, surface biotinylation of NR1, dendrite morphology analysis\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — pathway placement via genetic epistasis (Sp4→Nwk2→NR1 surface), surface biotinylation, single lab\",\n      \"pmids\": [\"25045015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Structural features (glycine-binding cleft) of GluN1 and GluN3A subunits regulate forward trafficking (surface delivery) of NMDARs; mutations in the GluN1 or GluN3A glycine-binding sites reduce surface expression in mammalian cells and primary neurons; a clinically relevant GluN3A mutation significantly reduces surface delivery.\",\n      \"method\": \"Surface biotinylation, immunofluorescence in HEK cells and primary hippocampal neurons, site-directed mutagenesis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — mutagenesis linked to surface expression, multiple cell types, single lab\",\n      \"pmids\": [\"31444392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NR1 subunit is expressed in human brain endothelial cells; NR1 in these cells regulates tissue-type plasminogen activator (tPA)-induced signal transduction and controls monocyte transmigration through the blood-brain barrier.\",\n      \"method\": \"Immunoblotting/immunofluorescence for NR1 in endothelial cells, siRNA knockdown, transendothelial monocyte migration assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — NR1 knockdown with defined cellular functional readout, single lab\",\n      \"pmids\": [\"20085611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Platelet lineage-specific knockout of GluN1 (Pf4-Grin1-/- mice) causes defects in megakaryopoiesis, thrombopoiesis, and platelet function including reduced proplatelet formation; the mechanism involves impaired Ca2+ signaling and disrupted reorganization of F-actin and α-tubulin cytoskeleton, and reduced MK-ECM interaction.\",\n      \"method\": \"Cre-loxP megakaryocyte-specific Grin1 knockout, platelet function assays, Ca2+ imaging, cytoskeletal immunofluorescence, in vivo bleeding/thrombocytopenia models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined mechanistic (cytoskeletal/Ca2+) and in vivo readouts, single lab\",\n      \"pmids\": [\"35245376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GluN1/GluN3 NMDA receptors are inhibited by the negative allosteric modulator EU1180-438 in a voltage-independent, non-competitive manner; site-directed mutagenesis identifies structural determinants near a pre-M1 helix below the agonist-binding domain; EU1180-438 inhibits native GluN1/GluN3A currents in CA1 pyramidal neurons without affecting conductance.\",\n      \"method\": \"Electrophysiology (recombinant and native receptors), site-directed mutagenesis, non-stationary fluctuation analysis\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis identifying binding determinants, confirmed in native neurons\",\n      \"pmids\": [\"32389749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo GRIN1 mutations in patients with NMDA receptor encephalopathy cluster within transmembrane segments and produce loss of channel function of varying severity with dominant-negative effects; two homozygous GRIN1 mutations also cause severe neurodevelopmental phenotypes; functional analysis in Xenopus oocytes confirmed loss-of-function mechanism.\",\n      \"method\": \"Whole-exome sequencing, two-electrode voltage clamp in Xenopus oocytes expressing mutant receptors\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization in Xenopus with multiple mutations, clear genotype-phenotype mechanism\",\n      \"pmids\": [\"27164704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"De novo missense GRIN1 mutations associated with polymicrogyria cluster in the S2 region of the GluN1 ligand-binding domain or adjacent M3 helix; voltage-clamp analysis showed three mutations increase agonist potency while one reduces proton inhibition—gain-of-function effects distinct from prior loss-of-function GRIN1 mutations.\",\n      \"method\": \"Whole-exome sequencing, two-electrode and whole-cell voltage-clamp in Xenopus oocytes/HEK cells\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional electrophysiology of multiple mutations defining mechanism, single study\",\n      \"pmids\": [\"29365063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A recurrent GRIN1 variant (p.Met641Ile in the channel-lining M2 region) enhances NMDAR agonist potency and reduces Mg2+ block; GluN1-M641I-containing NMDARs are more sensitive to memantine, ketamine, and dextromethorphan; addition of memantine to treatment significantly reduced seizure burden in the patient.\",\n      \"method\": \"Whole exome sequencing, electrophysiology in Xenopus oocytes and HEK cells, beta-lactamase surface expression assay, clinical therapeutic trial\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro gain-of-function mechanism confirmed, drug sensitivity characterized, clinical validation\",\n      \"pmids\": [\"34227748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"LTP induction in dentate gyrus granule cells selectively increases mRNA for NR1 splice variants containing the PKC phosphorylation consensus site (C1 cassette, exon 21) by ~50% at 48 h, while NR1 variants lacking this site are unchanged, suggesting splice-variant-specific regulation during LTP maintenance.\",\n      \"method\": \"In situ hybridization with splice-variant-specific probes after LTP induction\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (ISH) showing mRNA-level correlate of LTP, no protein-level or functional validation\",\n      \"pmids\": [\"7703398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Kindling transiently reduces expression of NMDAR1 splice isoforms containing exon 21 (C1 cassette) in hippocampus; no changes in other NMDAR1 isoforms are detected, suggesting kindling-induced seizures specifically regulate C-terminal alternative splicing of GluN1.\",\n      \"method\": \"In situ hybridization with splice-variant-specific probes in kindled rats\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single ISH method with no functional validation of splice-variant change\",\n      \"pmids\": [\"8883939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NOS-positive neurons in neostriatum, neocortex, and hippocampus express NMDAR1 but selectively lack the C1 splice cassette and instead preferentially express the C2' terminus (produced when C2 exon is absent), demonstrating cell-type-specific alternative splicing of GluN1 in nNOS neurons.\",\n      \"method\": \"Dual-label immunofluorescence with confocal microscopy using splice-cassette-specific antibodies\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — immunofluorescence identifying splice-cassette expression pattern, no functional consequence tested\",\n      \"pmids\": [\"9464997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"P2Y4 purinergic receptor co-localizes and co-immunoprecipitates with NMDAR1 at the plasma membrane in cerebellar granule neurons and HEK-293 cells; during hypoglycemia, P2Y4 is upregulated while NMDAR1 is downregulated, and both P2 and NMDA antagonists can restore basal NMDAR1 expression, suggesting a functional cross-talk between the two receptors.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, pharmacological manipulation during hypoglycemia\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP plus co-localization, no reconstitution or mechanistic dissection of interaction\",\n      \"pmids\": [\"15383322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Protocadherin 7 (PCDH7) interacts with the GluN1 N-terminal domain; PCDH7 overexpression reduces synaptic NMDAR currents, while knockdown and overexpression produce opposing changes in dendritic spine morphology, placing PCDH7 as a GluN1 NTD-interacting regulator of NMDAR function and spine structure.\",\n      \"method\": \"Unbiased transmembrane protein screen with purified GluN1-NTD bait, overexpression/knockdown in neurons, NMDAR current recordings\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — screen-identified interaction confirmed by electrophysiology and morphology, but interaction biochemistry not deeply validated\",\n      \"pmids\": [\"32616769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Adeno-associated virus-mediated knockdown of NR1 in rat hippocampus reduces NMDAR-mediated synaptic currents and impairs fear memory acquisition, while NR1 overexpression enhances fear memory and neurogenesis but paradoxically delays severe seizure onset, establishing bidirectional control of plasticity and seizure threshold by NR1 levels.\",\n      \"method\": \"AAV-mediated NR1 knockdown/overexpression, electrophysiology, fear conditioning, seizure assay, BrdU neurogenesis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional in vivo manipulation with electrophysiological and behavioral readouts, single lab\",\n      \"pmids\": [\"19394426\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GluN1 (GRIN1) encodes the obligatory subunit of all NMDA receptors, forming tetrameric ion channels (typically GluN1₂/GluN2₂ heterotetramers in an alternating 1-2-1-2 arrangement) that require co-binding of glycine (at GluN1) and glutamate (at GluN2) for activation; its N-terminal domain undergoes dynamic conformational rearrangements that allosterically modulate gating and pharmacology, its ligand-binding domain cleft closures signal through LBD–TMD linkers to open the channel pore in a concerted four-subunit mechanism, its eight alternatively spliced isoforms (particularly the N1/exon-5 cassette) tune deactivation kinetics, LTP magnitude, synaptic maturation, and nonionotropic glycine-priming signaling, calmodulin binds the C0/C1 cytoplasmic regions to regulate surface localization, KCTD13-mediated K48-polyubiquitination at K860 targets GluN1 for proteasomal degradation, EphB2 constrains NMDAR lateral mobility via a direct extracellular charge-mediated interaction with the GluN1 NTD hinge, and when co-assembled with GluN3 subunits (without GluN2), GluN1 forms excitatory glycine-gated receptors that regulate specific behaviors including aversion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GRIN1 encodes GluN1, the obligatory subunit of all NMDA-type ionotropic glutamate receptors, which assemble as heterotetramers with GluN2 or GluN3 subunits in an alternating arrangement and require co-agonist binding (glycine at GluN1, glutamate at GluN2) for channel activation [PMID:8824322, PMID:22493736, PMID:30500536]. The GluN1 N-terminal domain undergoes dynamic hinge-bending motions that allosterically transduce zinc- and proton-mediated inhibition through the ligand-binding domain dimer interface to the channel gate, while concerted conformational changes at LBD–TMD linkers in all four subunits are required for pore opening [PMID:23454977, PMID:18184566, PMID:21746848, PMID:34186027]. Alternative splicing of eight GluN1 isoforms—particularly the N-terminal exon-5 (N1) cassette—tunes receptor deactivation kinetics, LTP magnitude, synaptic maturation, seizure susceptibility, and nonionotropic glycine-priming signaling, while C-terminal domains regulate surface trafficking through calmodulin binding and KCTD13-mediated K48-polyubiquitination at K860 targeting GluN1 for proteasomal degradation [PMID:22641781, PMID:31875540, PMID:31570583, PMID:34187890, PMID:18073110, PMID:37142655]. De novo GRIN1 mutations cause neurodevelopmental disorders including NMDA receptor encephalopathy (loss-of-function) and polymicrogyria (gain-of-function), and when co-assembled with GluN3 subunits in the absence of GluN2, GluN1 forms excitatory glycine receptors that regulate aversion behavior in the medial habenula [PMID:27164704, PMID:29365063, PMID:31601771].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that GluN1 protein levels can be regulated post-transcriptionally answered the question of how receptor abundance is controlled independent of mRNA, revealing a layer of regulation beyond transcription.\",\n      \"evidence\": \"Immunocytochemistry and in situ hybridization in ovariectomized rats showed estradiol upregulated GluN1 protein without changing mRNA\",\n      \"pmids\": [\"8824322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of post-transcriptional stabilization not identified\", \"Generalizability beyond estradiol signaling untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Region-specific GluN1 knockout demonstrated that NMDAR activity in hippocampal CA1 is essential for nonspatial memory, establishing the in vivo requirement for the obligatory subunit in defined cognitive functions.\",\n      \"evidence\": \"CA1-restricted NR1 knockout mice with behavioral testing (object recognition, contextual fear) and electron microscopy\",\n      \"pmids\": [\"10700255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GluN1 loss phenocopies complete NMDAR ablation or has subunit-independent effects not resolved\", \"Compensatory mechanisms in chronic KO not excluded\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantitative demonstration that GluN3A co-assembles with GluN1 and GluN2 in vivo with a developmentally declining stoichiometry established the native existence of GluN3-containing receptors and their temporal regulation.\",\n      \"evidence\": \"Quantitative immunoprecipitation with subunit-specific antibodies in rat cortex across postnatal development\",\n      \"pmids\": [\"12391275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional properties of native GluN1/GluN3 vs. GluN1/GluN2/GluN3 complexes not characterized\", \"Subcellular location of GluN3-containing complexes unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The crystal structure of calmodulin bound to the GluN1 C1 region revealed how CaM engagement shields the S890 phosphorylation site while leaving the ER retention motif exposed, providing a structural basis for CaM-dependent trafficking regulation.\",\n      \"evidence\": \"X-ray crystallography at 1.96 Å resolution of Ca2+-CaM/NR1-C1 complex\",\n      \"pmids\": [\"18073110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CaM binding actively promotes or inhibits ER exit not functionally tested\", \"Role of C0 region in CaM regulation not structurally resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of the agonist-binding domain dimer interface as the structural relay coupling GluN2A NTD zinc binding to the channel gate resolved how allosteric inhibition is transduced across receptor domains.\",\n      \"evidence\": \"Mutagenesis of ABD dimer interface residues combined with electrophysiology measuring zinc and proton inhibition\",\n      \"pmids\": [\"18184566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same interface mediates all allosteric signals or is pathway-specific not fully resolved\", \"Structural visualization of conformational changes awaited\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that constraining LBD–TMD linkers in any single subunit equally impairs gating established that pore opening requires concerted conformational changes across all four subunits, not sequential or asymmetric motions.\",\n      \"evidence\": \"Engineered disulfide bonds in M3-S2 and S2-M4 linkers of GluN1 or GluN2A with single-channel recordings\",\n      \"pmids\": [\"21746848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise temporal sequence of linker movements during gating not resolved\", \"Whether GluN3-containing receptors follow the same concerted mechanism unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Functional cross-linking confirmed that mature GluN1/GluN2A receptors adopt an alternating 1-2-1-2 arrangement with GluN1 proximal to the pore axis, resolving the subunit stoichiometry and geometry debate.\",\n      \"evidence\": \"Disulfide cross-linking and electrophysiology distinguishing mature surface from immature intracellular receptors\",\n      \"pmids\": [\"22493736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether immature receptors with alternative arrangements are functionally relevant not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of GluN1 exon-5 (N1 cassette) and specifically Lys211 as key determinants of GluN2D-containing receptor deactivation and open probability revealed how N-terminal alternative splicing tunes channel kinetics.\",\n      \"evidence\": \"Single-channel recordings, kinetic modeling, and Lys211 mutagenesis in GluN1-1a vs. GluN1-1b/GluN2D\",\n      \"pmids\": [\"22641781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Lys211-dependent effects extend to all GluN2 subtypes not fully tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that the GluN1 NTD is conformationally dynamic and allosterically influences glutamate binding in trans with GluN2 NTD overturned the view that GluN1 NTD is a passive scaffold, establishing it as an active modulator of receptor pharmacology.\",\n      \"evidence\": \"Electrophysiology, cross-linking, and mutagenesis showing GluN1 NTD hinge motions affect gating\",\n      \"pmids\": [\"23454977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full energy landscape of GluN1 NTD conformational cycling in the intact receptor not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterization of triheteromeric GluN1/GluN2A/GluN2B receptors revealed distinct deactivation kinetics and pharmacological profiles that could not be predicted from diheteromer properties, establishing triheteromers as functionally unique receptor populations.\",\n      \"evidence\": \"Selective cell-surface expression of recombinant triheteromers with electrophysiology and pharmacology\",\n      \"pmids\": [\"24607230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fractional representation of triheteromers at individual synapses in vivo not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that de novo GRIN1 mutations cause NMDA receptor encephalopathy via dominant-negative loss of channel function established GluN1 as a disease gene and linked transmembrane-domain mutations to neurodevelopmental pathology.\",\n      \"evidence\": \"Whole-exome sequencing of patients with functional electrophysiology of mutant receptors in Xenopus oocytes\",\n      \"pmids\": [\"27164704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype correlations across the full mutation spectrum incomplete\", \"No animal rescue experiments reported\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM structures of GluN1/GluN2A captured multiple conformational states under zinc and proton modulation, directly visualizing the allosteric pathway from GluN2A NTD through the LBD to channel gate constriction that had been inferred from mutagenesis.\",\n      \"evidence\": \"Cryo-EM at multiple zinc/proton concentrations resolving distinct conformational states\",\n      \"pmids\": [\"30500536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Time-resolved structural transitions during gating not captured\", \"Lipid bilayer effects on conformational landscape not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reciprocal knock-in mouse models showed that the GluN1 exon-5 cassette bidirectionally controls hippocampal LTP magnitude and spatial learning, directly demonstrating that a single alternative splicing event in the obligatory subunit scales synaptic plasticity in vivo.\",\n      \"evidence\": \"GluN1a-only and GluN1b-only knock-in mice with hippocampal LTP recordings and spatial memory tests\",\n      \"pmids\": [\"31875540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream signaling pathways mediate exon-5-dependent LTP scaling not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"GluN1/GluN3A excitatory glycine receptors were shown to be functional in adult medial habenula neurons and to regulate aversion behavior, establishing a physiological role for GluN2-free NMDAR assemblies in a defined neural circuit.\",\n      \"evidence\": \"Native electrophysiology in MHb neurons, viral GluN3A knockdown, and conditioned place aversion behavioral assay\",\n      \"pmids\": [\"31601771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from GluN1/GluN3A in MHb not characterized\", \"Whether other brain regions use GluN1/GluN3A for behavioral functions not explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the EphB2–GluN1 extracellular interaction to a charge-complementary interface at the GluN1 NTD hinge revealed how an extracellular binding partner constrains NMDAR lateral mobility at synapses, linking receptor retention to a specific structural epitope.\",\n      \"evidence\": \"Direct pulldown with charge-reversal GluN1 mutants and single-particle tracking of NMDAR mobility\",\n      \"pmids\": [\"31996679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EphB2–GluN1 interaction is regulated by activity or development not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that GluN1 alternative splicing gates nonionotropic glycine-priming signaling—with N1-lacking isoforms permitting and N1-containing isoforms blocking internalization—revealed a splice-variant-specific mechanism for metabotropic NMDAR signaling.\",\n      \"evidence\": \"Obligatory-splice knock-in mice, recombinant receptor expression, and electrophysiology in acute hippocampal slices\",\n      \"pmids\": [\"34187890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how N1 cassette blocks glycine priming not resolved\", \"Signaling intermediates downstream of glycine priming incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of KCTD13 as the E3 ligase adapter that K48-polyubiquitinates GluN1 at K860 for proteasomal degradation provided the first specific ubiquitin-dependent mechanism controlling GluN1 protein turnover and linked it to seizure susceptibility.\",\n      \"evidence\": \"In vitro ubiquitination assay, K860R mutagenesis, KCTD13 knockdown/overexpression in mouse hippocampus, electrophysiology, seizure assays\",\n      \"pmids\": [\"37142655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also target GluN1 not excluded\", \"How KCTD13 activity is itself regulated at synapses unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structures of GluN1/GluN3A receptors revealed a 1-3-1-3 subunit arrangement with an unprecedented GluN3A orientation shift upon ligand binding, providing the first structural framework for understanding excitatory glycine receptor gating and desensitization.\",\n      \"evidence\": \"Cryo-EM of glycine-bound and CNQX-bound GluN1/GluN3A with mutagenesis validation\",\n      \"pmids\": [\"38598639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full gating cycle of GluN1/GluN3A not structurally resolved\", \"How GluN1/GluN3A structural features explain pharmacological differences from GluN1/GluN2 receptors not fully elucidated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the time-resolved structural dynamics of the full gating cycle across NMDAR subtypes, the complete repertoire of E3 ligases and post-translational modifications controlling GluN1 turnover, the structural basis by which the N1 cassette gates nonionotropic signaling, and the physiological functions of GluN1/GluN3 receptors outside the medial habenula.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Time-resolved gating transitions not captured structurally\", \"Complete post-translational modification map of GluN1 lacking\", \"Structural mechanism of N1 cassette-dependent nonionotropic signaling unknown\", \"Circuit-level functions of GluN1/GluN3 receptors largely unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 9, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 19, 33, 34]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 9, 13, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"GluN1/GluN2A NMDAR\",\n      \"GluN1/GluN2B NMDAR\",\n      \"GluN1/GluN3A excitatory glycine receptor\"\n    ],\n    \"partners\": [\n      \"GRIN2A\",\n      \"GRIN2B\",\n      \"GRIN3A\",\n      \"CALM1\",\n      \"EPHB2\",\n      \"KCTD13\",\n      \"DRD1\",\n      \"PCDH7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}