Affinage

GRIN1

Glutamate receptor ionotropic, NMDA 1 · UniProt Q05586

Length
938 aa
Mass
105.4 kDa
Annotated
2026-04-28
100 papers in source corpus 47 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 Medium

    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

    PMID:8824322

    Open questions at the time
    • Molecular mechanism of post-transcriptional stabilization not identified
    • Generalizability beyond estradiol signaling untested
  2. 2000 High

    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

    PMID:10700255

    Open questions at the time
    • Whether GluN1 loss phenocopies complete NMDAR ablation or has subunit-independent effects not resolved
    • Compensatory mechanisms in chronic KO not excluded
  3. 2002 Medium

    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

    PMID:12391275

    Open questions at the time
    • Functional properties of native GluN1/GluN3 vs. GluN1/GluN2/GluN3 complexes not characterized
    • Subcellular location of GluN3-containing complexes unknown
  4. 2007 High

    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

    PMID:18073110

    Open questions at the time
    • Whether CaM binding actively promotes or inhibits ER exit not functionally tested
    • Role of C0 region in CaM regulation not structurally resolved
  5. 2008 High

    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

    PMID:18184566

    Open questions at the time
    • Whether the same interface mediates all allosteric signals or is pathway-specific not fully resolved
    • Structural visualization of conformational changes awaited
  6. 2011 High

    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

    PMID:21746848

    Open questions at the time
    • Precise temporal sequence of linker movements during gating not resolved
    • Whether GluN3-containing receptors follow the same concerted mechanism unknown
  7. 2012 High

    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

    PMID:22493736

    Open questions at the time
    • Whether immature receptors with alternative arrangements are functionally relevant not determined
  8. 2012 High

    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

    PMID:22641781

    Open questions at the time
    • Whether Lys211-dependent effects extend to all GluN2 subtypes not fully tested
  9. 2013 High

    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

    PMID:23454977

    Open questions at the time
    • Full energy landscape of GluN1 NTD conformational cycling in the intact receptor not mapped
  10. 2014 High

    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

    PMID:24607230

    Open questions at the time
    • Fractional representation of triheteromers at individual synapses in vivo not quantified
  11. 2016 Medium

    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

    PMID:27164704

    Open questions at the time
    • Genotype-phenotype correlations across the full mutation spectrum incomplete
    • No animal rescue experiments reported
  12. 2018 High

    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

    PMID:30500536

    Open questions at the time
    • Time-resolved structural transitions during gating not captured
    • Lipid bilayer effects on conformational landscape not assessed
  13. 2019 High

    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

    PMID:31875540

    Open questions at the time
    • Which downstream signaling pathways mediate exon-5-dependent LTP scaling not identified
  14. 2019 High

    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

    PMID:31601771

    Open questions at the time
    • Downstream signaling from GluN1/GluN3A in MHb not characterized
    • Whether other brain regions use GluN1/GluN3A for behavioral functions not explored
  15. 2020 High

    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

    PMID:31996679

    Open questions at the time
    • Whether EphB2–GluN1 interaction is regulated by activity or development not tested
  16. 2021 High

    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

    PMID:34187890

    Open questions at the time
    • Structural basis of how N1 cassette blocks glycine priming not resolved
    • Signaling intermediates downstream of glycine priming incompletely defined
  17. 2023 High

    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

    PMID:37142655

    Open questions at the time
    • Whether other E3 ligases also target GluN1 not excluded
    • How KCTD13 activity is itself regulated at synapses unknown
  18. 2024 High

    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

    PMID:38598639

    Open questions at the time
    • Full gating cycle of GluN1/GluN3A not structurally resolved
    • How GluN1/GluN3A structural features explain pharmacological differences from GluN1/GluN2 receptors not fully elucidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 1
Partners
CALM1DRD1EPHB2GRIN2AGRIN2BGRIN3AKCTD13PCDH7
Complex memberships
GluN1/GluN2A NMDARGluN1/GluN2B NMDARGluN1/GluN3A excitatory glycine receptor

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Cryo-electron microscopy, multiple conformational states under varying zinc and proton concentrations Cell High 30500536
2021 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. Cryo-electron microscopy with distinct ligands/modulators at ~4 Å resolution Neuron High 34186027
2022 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. Single-particle cryo-electron microscopy Molecular cell High 36309015
2024 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. Cryo-electron microscopy, site-directed mutagenesis Science advances High 38598639
2008 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. Electrophysiology (mutagenesis of ABD dimer interface), structural analysis Neuron High 18184566
2013 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. Electrophysiology, cross-linking, structural analysis, mutagenesis Nature structural & molecular biology High 23454977
2007 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. X-ray crystallography (1.96 Å, PDB 2HQW) Structure High 18073110
2013 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. X-ray crystallography, molecular dynamics / free energy calculations Structure High 23972471
2012 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. Electrophysiology, disulfide cross-linking, structural modeling PloS one High 22493736
2011 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. Disulfide cross-linking, single-channel electrophysiology in outside-out patches The Journal of general physiology High 21746848
2014 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. Selective cell-surface expression of recombinant triheteromers, electrophysiology, pharmacological characterization Neuron High 24607230
2010 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. Single-channel recordings, molecular dynamics simulations, site-directed mutagenesis, kinetic modeling The Journal of neuroscience High 20164358
2012 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. Two-electrode voltage clamp, single-channel recordings, kinetic modeling, mutagenesis The Journal of physiology High 22641781
2019 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. Knock-in mouse models (exon 5 deletion and forced inclusion), hippocampal LTP recordings, behavioral tests Cell reports High 31875540
2019 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. Conditional knock-in mouse (exon 5 deletion), whole-cell recordings, synapse counting, seizure threshold assays Proceedings of the National Academy of Sciences of the United States of America High 31570583
2021 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. Recombinant NMDAR expression, knock-in mouse engineering (obligatory N1 inclusion/exclusion), electrophysiology in acute slices Proceedings of the National Academy of Sciences of the United States of America High 34187890
2019 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. Electrophysiology (native MHb neurons), viral knockdown, place-aversion conditioning, immunohistochemistry Science High 31601771
2014 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. Co-immunoprecipitation (endogenous proteins), cell-permeable peptide disruption, Ca2+ imaging, slice electrophysiology, behavioral sensitization assay Molecular psychiatry High 25070539
2023 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. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K860 GluN1), viral knockdown/overexpression in mouse hippocampus, electrophysiology, seizure threshold assays Cell death and differentiation High 37142655
2020 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. Pulldown/direct interaction assay, live-cell single-particle tracking, GluN1 charge-reversal mutagenesis, EphB2 knockdown Nature communications High 31996679
2018 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. Co-immunoprecipitation (NFL-GluN1 interaction), NFL knockout mouse, Western blot, electrophysiology (LTP), behavioral assays, MRS Translational psychiatry Medium 30143609
2008 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. Whole-cell electrophysiology (0 Mg2+ and physiological Mg2+), kinetic modeling The Journal of physiology Medium 18936081
2008 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. Electrophysiology in Xenopus oocytes, site-directed mutagenesis of NR1 and NR3A glycine-binding sites Proceedings of the National Academy of Sciences of the United States of America Medium 18711142
2016 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. Whole-cell electrophysiology (recombinant GluN1/GluN3A), site-directed mutagenesis of dimer interface residues Scientific reports Medium 27000430
2009 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. Whole-cell electrophysiology in HEK293 cells, systematic splice variant expression, mutagenesis The Journal of pharmacology and experimental therapeutics Medium 19726695
2010 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. Electrophysiology of myelin preparations, pharmacological characterization, NR3A knockout mice The Journal of neuroscience Medium 20739572
2018 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. Selective triheteromer expression, two-electrode voltage clamp, single-channel recordings, hippocampal interneuron recordings The Journal of physiology Medium 31541561
2018 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. FRET/FLIM to confirm triheteromer assembly, selective expression, electrophysiology Molecular pharmacology Medium 29483146
2015 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. Single-molecule FRET (smFRET) with photoprotection, step transition and state identification algorithm Biophysical journal Medium 26153703
2002 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. Quantitative immunoprecipitation with subunit-specific antibodies in rat cortex Molecular pharmacology Medium 12391275
2000 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. Region-specific NR1 knockout mice, behavioral testing (fear conditioning, object recognition), stereological electron microscopy Nature neuroscience High 10700255
1996 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. Immunocytochemistry (confocal quantification of immunofluorescence), in situ hybridization in ovariectomized rats The Journal of neuroscience Medium 8824322
1997 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. Quantitative immunofluorescence and in situ hybridization at multiple post-lesion timepoints The Journal of neuroscience Medium 9045729
2014 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. Sp4 knockdown, Nwk2 knockdown/overexpression, surface biotinylation of NR1, dendrite morphology analysis Developmental neurobiology Medium 25045015
2019 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. Surface biotinylation, immunofluorescence in HEK cells and primary hippocampal neurons, site-directed mutagenesis Scientific reports Medium 31444392
2010 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. Immunoblotting/immunofluorescence for NR1 in endothelial cells, siRNA knockdown, transendothelial monocyte migration assay Journal of neurochemistry Medium 20085611
2022 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. Cre-loxP megakaryocyte-specific Grin1 knockout, platelet function assays, Ca2+ imaging, cytoskeletal immunofluorescence, in vivo bleeding/thrombocytopenia models Blood Medium 35245376
2020 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. Electrophysiology (recombinant and native receptors), site-directed mutagenesis, non-stationary fluctuation analysis Neuropharmacology Medium 32389749
2016 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. Whole-exome sequencing, two-electrode voltage clamp in Xenopus oocytes expressing mutant receptors Neurology Medium 27164704
2018 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. Whole-exome sequencing, two-electrode and whole-cell voltage-clamp in Xenopus oocytes/HEK cells Brain : a journal of neurology Medium 29365063
2021 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. Whole exome sequencing, electrophysiology in Xenopus oocytes and HEK cells, beta-lactamase surface expression assay, clinical therapeutic trial Annals of clinical and translational neurology Medium 34227748
1994 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. In situ hybridization with splice-variant-specific probes after LTP induction Neuroreport Low 7703398
1996 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. In situ hybridization with splice-variant-specific probes in kindled rats Brain research. Molecular brain research Low 8883939
1998 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. Dual-label immunofluorescence with confocal microscopy using splice-cassette-specific antibodies The Journal of neuroscience Low 9464997
2004 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. Co-immunoprecipitation, confocal co-localization, pharmacological manipulation during hypoglycemia Experimental cell research Low 15383322
2020 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. Unbiased transmembrane protein screen with purified GluN1-NTD bait, overexpression/knockdown in neurons, NMDAR current recordings Scientific reports Low 32616769
2009 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. AAV-mediated NR1 knockdown/overexpression, electrophysiology, fear conditioning, seizure assay, BrdU neurogenesis Molecular and cellular neurosciences Medium 19394426

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nature neuroscience 605 10700255
1996 Differential regulation of NMDAR1 mRNA and protein by estradiol in the rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 317 8824322
2014 Distinct functional and pharmacological properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 260 24607230
1994 Chronic ingestion of ethanol up-regulates NMDAR1 receptor subunit immunoreactivity in rat hippocampus. Journal of neurochemistry 206 8133290
2016 Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy. Neurology 145 27164704
2006 Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder. Brain research 124 17113057
2018 Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor. Cell 103 30500536
2008 Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition. Neuron 101 18184566
1997 Differential subcellular regulation of NMDAR1 protein and mRNA in dendrites of dentate gyrus granule cells after perforant path transection. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 9045729
2010 Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 20164358
2003 Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder. Molecular psychiatry 90 12610658
2008 Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. Cerebral cortex (New York, N.Y. : 1991) 89 18296432
2013 Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure (London, England : 1993) 82 23972471
2019 Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula. Science (New York, N.Y.) 81 31601771
2010 Excitatory glycine responses of CNS myelin mediated by NR1/NR3 "NMDA" receptor subunits. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 20739572
2018 De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain : a journal of neurology 77 29365063
2007 The NMDA receptor NR1 C1 region bound to calmodulin: structural insights into functional differences between homologous domains. Structure (London, England : 1993) 75 18073110
2015 GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia 73 25864721
2018 Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. Molecular psychiatry 72 29426955
2010 The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. Journal of neurochemistry 72 20085611
2014 D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses. Molecular psychiatry 65 25070539
2012 TCN 201 selectively blocks GluN2A-containing NMDARs in a GluN1 co-agonist dependent but non-competitive manner. Neuropharmacology 62 22579927
1998 NMDAR1 glutamate receptor subunit isoforms in neostriatal, neocortical, and hippocampal nitric oxide synthase neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 9464997
2013 Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N-terminal domain. Nature structural & molecular biology 61 23454977
2002 Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Molecular pharmacology 61 12391275
2019 Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors. The Journal of physiology 59 31541561
2012 GluN1 splice variant control of GluN1/GluN2D NMDA receptors. The Journal of physiology 56 22641781
1995 NMDA (NMDAR1) and AMPA-type (GluR2/3) receptor subunits are expressed in the inner ear. Neuroreport 56 7662898
2021 Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors. Neuron 55 34186027
2013 Involvement of NR1, NR2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behavioural brain research 55 24029697
1999 Selective coexpression of NMDAR2A/B and NMDAR1 subunit proteins in dysplastic neurons of human epileptic cortex. Experimental neurology 53 10506512
2006 Regulation of NR1/NR2C N-methyl-D-aspartate (NMDA) receptors by phosphorylation. The Journal of biological chemistry 52 16606616
2008 NR1 and GluR2 expression mediates excitotoxicity in chronic hypobaric hypoxia. Journal of neuroscience research 51 17969105
2003 Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia. Biological psychiatry 51 12679240
2018 Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors. Translational psychiatry 45 30143609
2017 GluN1 and GluN2A NMDA Receptor Subunits Increase in the Hippocampus during Memory Consolidation in the Rat. Frontiers in behavioral neuroscience 45 28133447
2010 Changes in expression of NMDA-NR1 receptor subunits in the rostral ventromedial medulla modulate pain behaviors. Pain 45 20688433
2019 Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1. Cell reports 43 31875540
1995 Immunobiochemical characterization of the NMDA-receptor subunit NR1 in the developing and adult rat brain. Journal of receptor and signal transduction research 42 8903953
2022 Structural insights into assembly and function of GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDARs. Molecular cell 41 36309015
1998 Glutamate receptor subunit GluR2 and NMDAR1 immunoreactivity in the retina of macaque monkeys with experimental glaucoma does not identify vulnerable neurons. Experimental neurology 39 9784283
1993 Quantitation of NMDA receptor (NMDAR1) mRNA levels in the adult and developing rat CNS. Brain research. Molecular brain research 39 7689684
2023 Excitatory GluN1/GluN3A glycine receptors (eGlyRs) in brain signaling. Trends in neurosciences 38 37248111
2000 Hippocampal expression of N-methyl-D-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb(2+). Brain research. Molecular brain research 38 10762705
1994 Regulation of the expression of NR1 NMDA glutamate receptor subunits during hippocampal LTP. Neuroreport 38 7703398
2014 DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Frontiers in cellular neuroscience 36 25368549
2011 Local constraints in either the GluN1 or GluN2 subunit equally impair NMDA receptor pore opening. The Journal of general physiology 36 21746848
2020 Negative allosteric modulation of GluN1/GluN3 NMDA receptors. Neuropharmacology 34 32389749
2008 Voltage-dependent gating of NR1/2B NMDA receptors. The Journal of physiology 34 18936081
2017 De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy. European journal of medical genetics 32 28389307
2008 Supralinear potentiation of NR1/NR3A excitatory glycine receptors by Zn2+ and NR1 antagonist. Proceedings of the National Academy of Sciences of the United States of America 32 18711142
2018 Properties of Triheteromeric N-Methyl-d-Aspartate Receptors Containing Two Distinct GluN1 Isoforms. Molecular pharmacology 31 29483146
2013 A combinatorial approach of Proteomics and Systems Biology in unravelling the mechanisms of acute kidney injury (AKI): involvement of NMDA receptor GRIN1 in murine AKI. BMC systems biology 31 24172336
2009 Knockdown and overexpression of NR1 modulates NMDA receptor function. Molecular and cellular neurosciences 31 19394426
2009 Spinal NMDA NR1 subunit expression following transient TNBS colitis. Brain research 31 19406112
2007 Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample. Psychiatric genetics 31 17728671
1996 Postnatal changes in NMDAR1 subunit expression in the rat trigeminal pathway to barrel field cortex. The Journal of comparative neurology 31 8725300
2021 Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy. Annals of clinical and translational neurology 30 34227748
2020 Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility. Nature communications 30 31996679
2012 An alternating GluN1-2-1-2 subunit arrangement in mature NMDA receptors. PloS one 30 22493736
1994 NMDA receptor (NMDAR1) expression in the rat hippocampus after forebrain ischemia. Neuroscience letters 30 8041510
1993 Characterization of the NR1, NR2A, and NR2C receptor proteins. Protein science : a publication of the Protein Society 29 8298456
2009 Expression of glycine-activated diheteromeric NR1/NR3 receptors in human embryonic kidney 293 cells Is NR1 splice variant-dependent. The Journal of pharmacology and experimental therapeutics 28 19726695
2004 Role of the metabotropic P2Y(4) receptor during hypoglycemia: cross talk with the ionotropic NMDAR1 receptor. Experimental cell research 28 15383322
2018 7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo. Neuropharmacology 27 30099049
2017 Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells. Journal of Korean Neurosurgical Society 26 28264232
2016 Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation. Scientific reports 26 27000430
1994 Rapid turnover rate of the hippocampal synaptic NMDA-R1 receptor subunits. Neuroscience letters 26 7898769
2024 Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology. Physiological research 25 38836461
2019 Structural features in the glycine-binding sites of the GluN1 and GluN3A subunits regulate the surface delivery of NMDA receptors. Scientific reports 25 31444392
2012 Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: role of the PSD-95/NR1/nNOS/PKCγ signaling pathway. Behavioural brain research 25 22309983
2010 Phenotypic characterization of a new Grin1 mutant mouse generated by ENU mutagenesis. The European journal of neuroscience 25 20345915
2008 Early auditory deprivation alters expression of NMDA receptor subunit NR1 mRNA in the rat auditory cortex. Journal of neuroscience research 25 18041094
2008 Association between the G1001C polymorphism in the GRIN1 gene promoter and schizophrenia in the Iranian population. Journal of molecular neuroscience : MN 25 18792810
2004 Identification and biochemical analysis of GRIN1 and GRIN2. Methods in enzymology 24 15488195
2020 PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function. Scientific reports 23 32616769
2012 Preweaning sensorimotor deficits and adolescent hypersociability in Grin1 knockdown mice. Developmental neuroscience 23 22571986
2000 Development of NR1, NR2A and NR2B mRNA in NR1 immunoreactive cells of rat visual cortex. Brain research 23 10854582
2015 Grin1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity. Psychoneuroendocrinology 22 25938741
2015 Conformational transitions in the glycine-bound GluN1 NMDA receptor LBD via single-molecule FRET. Biophysical journal 22 26153703
2023 KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility. Cell death and differentiation 21 37142655
2021 NMDAR1-Src-Pannexin1 Signal Pathway in the Trigeminal Ganglion Contributed to Orofacial Ectopic Pain Following Inferior Alveolar Nerve Transection. Neuroscience 21 33965504
2019 Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation. Neurobiology of disease 21 31299220
2016 Instant and Lasting Down-Regulation of NR1 Expression in the Hippocampus is Associated Temporally with Antidepressant Activity After Acute Yueju. Cellular and molecular neurobiology 21 26825573
2014 Dietary magnesium restriction reduces amygdala-hypothalamic GluN1 receptor complex levels in mice. Brain structure & function 21 24807818
2003 N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 21 12707933
1996 Regulation of alternative splicing of NMDAR1 in the kindling model. Brain research. Molecular brain research 21 8883939
2024 Structure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel. Science advances 20 38598639
2014 Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning. Developmental neurobiology 20 25045015
2012 Reducing expression of GluN1(0XX) subunit splice variants of the NMDA receptor interferes with spatial reference memory. Behavioural brain research 20 22360858
2022 Deletion of Grin1 in mouse megakaryocytes reveals NMDA receptor role in platelet function and proplatelet formation. Blood 19 35245376
2015 N-methyl-D-aspartic acid receptor 1 (NMDAR1) aggravates secondary inflammatory damage induced by hemin-NLRP3 pathway after intracerebral hemorrhage. Chinese journal of traumatology = Zhonghua chuang shang za zhi 19 26777707
2022 Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors. Frontiers in pharmacology 18 35754487
1994 Expression of NMDAR1-1a (N598Q)/NMDAR2A receptors results in decreased cell mortality. European journal of pharmacology 18 7909752
2019 N-terminal alternative splicing of GluN1 regulates the maturation of excitatory synapses and seizure susceptibility. Proceedings of the National Academy of Sciences of the United States of America 17 31570583
2013 Modal gating of GluN1/GluN2D NMDA receptors. Neuropharmacology 17 23578394
2021 Alternative splicing of GluN1 gates glycine site-dependent nonionotropic signaling by NMDAR receptors. Proceedings of the National Academy of Sciences of the United States of America 16 34187890
2016 GluN1 deletions in D1- and A2A-expressing cell types reveal distinct modes of behavioral regulation. Neuropharmacology 16 27012890
2013 Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population. Neuroscience letters 16 23880023
2017 Inhibition of NMDA receptor function with an anti-GluN1-S2 antibody impairs human platelet function and thrombosis. Platelets 15 28277064