Affinage

GRIN3A

Glutamate receptor ionotropic, NMDA 3A · UniProt Q8TCU5

Length
1115 aa
Mass
125.5 kDa
Annotated
2026-06-10
66 papers in source corpus 26 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRIN3A encodes GluN3A, an atypical NMDA receptor subunit that operates through two distinct receptor modes: assembled with GluN1 it forms excitatory glycine receptors (eGlyRs) gated by glycine alone and insensitive to glutamate, while incorporation into conventional GluN1/GluN2 receptors yields triheteromers with altered ion-conduction properties (PMID:30425244, PMID:22814002). As eGlyRs, GluN1/GluN3A receptors are auto-inhibited by GluN1 (relieved by CGP-78608), redox-modulated via an endogenous GluN3A disulfide, and gated by conformational changes in the extracellular domain whose efficacy is set by the GluN3A N-terminal domain and modulated by protons (PMID:30425244, PMID:26777280, PMID:25017909, PMID:27000430). These mostly extrasynaptic eGlyRs are driven by ambient glycine to tonically control excitability of defined adult circuits — medial habenula neurons governing aversion, basolateral amygdala principal cells controlling fear-memory stability, and neocortical and hippocampal somatostatin interneurons shaping cortical state and network oscillations (PMID:31601771, PMID:35700736, PMID:39256046, PMID:41472680). When incorporated into GluN1/GluN2 triheteromers, GluN3A reduces Mg2+ and open-channel-blocker sensitivity and lowers Ca2+ influx, acting as an inhibitory subunit that restrains plasticity (PMID:22814002, PMID:22564863, PMID:39256046). GluN3A limits synaptic plasticity through several intracellular routes: it suppresses CaMKII-dependent LTP (PMID:23006484), binds the scaffold GIT1 to inhibit the βPIX/Rac1/PAK actin axis that drives spine growth and to block GIT1/mTOR-dependent translation of activity-regulated mRNAs such as Bdnf and Arc (PMID:24297929, PMID:25009255, PMID:34787081), and restrains MEF2C-driven inducible transcription via nuclear p38 MAPK (PMID:32393578). Surface expression of GluN3A-NMDARs is controlled by clathrin-mediated endocytosis through a C-terminal YWL/AP2 motif phosphorylated by Src kinases, by the GluN3A-specific endocytic adaptor PACSIN1, and by N-glycosylation and glycine-binding-site features required for forward trafficking (PMID:23447623, PMID:23852340, PMID:29915530, PMID:31444392). Developmentally, GluN3A times the maturation of synaptic NMDAR composition by selectively tuning GluN2A surface diffusion and maintaining GluN2B enrichment, and directs region-specific callosal axon targeting via dendritic patterning (PMID:37149869, PMID:39256046, PMID:42150879). Disruption of PACSIN1-dependent GluN3A endocytosis by mutant huntingtin elevates surface GluN3A and drives synapse degeneration in Huntington's disease models, where GluN3A deletion is neuroprotective (PMID:23852340).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 Medium

    Establishing how GluN3A modifies conventional NMDARs answered whether it acts as a regulatory, plasticity-limiting subunit: deletion enhances CaMKII-dependent LTP, and incorporation into triheteromers reshapes channel pharmacology and Ca2+ handling.

    Evidence GluN3A KO hippocampal LTP recordings with CaMKII inhibition; ex vivo and oocyte electrophysiology of triheteromeric GluN1/GluN2/GluN3A with channel-blocker mutagenesis; transgenic overexpression in striatal excitotoxicity

    PMID:22564863 PMID:22801082 PMID:22814002 PMID:23006484

    Open questions at the time
    • Triheteromeric stoichiometry and native abundance not resolved at this stage
    • Link between altered Ca2+ permeability and downstream plasticity signaling not directly established
  2. 2013 High

    Identifying GluN3A's intracellular partners and trafficking machinery explained how it limits spine growth and how its surface level is set: GluN3A binds GIT1 to suppress the βPIX/Rac1/PAK actin axis, and is internalized via a Src-phosphorylated YWL/AP2 motif and the PACSIN1 adaptor.

    Evidence Reciprocal Co-IP, Rac1 activation assays and shRNA/KO in primary neurons; mutagenesis of the YWL endocytic motif with Src activation and surface assays; HTT-PACSIN1 Co-IP with YAC128 genetic crosses

    PMID:23447623 PMID:23852340 PMID:24297929

    Open questions at the time
    • Structural basis of the GluN3A-GIT1 interaction unresolved
    • How synaptic activity switches GIT1 binding not mechanistically defined
  3. 2014 Medium

    Live imaging and biophysics connected GluN3A surface residence to spine dynamics and provided direct evidence of eGlyR gating, showing surface dwell-time governs spine pruning and that agonist binding drives an extracellular conformational change.

    Evidence Time-lapse imaging of spines with endocytosis-deficient and GIT1-binding mutants; atomic force microscopy of reconstituted GluN1/GluN3A receptors

    PMID:25009255 PMID:25017909

    Open questions at the time
    • AFM conformational change not linked to a defined gating state
    • Spine-dynamics effects measured in slice cultures, not in vivo
  4. 2016 High

    Domain-level dissection defined the structural determinants of eGlyR efficacy and modulation, showing the GluN3A NTD constrains channel efficacy and that protons and GluN1 splice cassettes tune steady-state activity.

    Evidence Oocyte and HEK electrophysiology with NTD deletion, intersubunit crosslinking, LBD-interface and GluN1 C-terminal cassette mutagenesis

    PMID:26777280 PMID:27000430 PMID:28365212

    Open questions at the time
    • No high-resolution structure of the diheteromeric eGlyR at this stage
    • Physiological relevance of proton/zinc modulation in vivo untested
  5. 2018 High

    Demonstrating functional eGlyRs in native neurons and resolving their glycosylation requirements established GluN1/GluN3A as a bona fide glycine-gated receptor whose surface delivery depends on specific N-glycans.

    Evidence Patch-clamp in juvenile hippocampal slices with CGP-78608 and redox reagents; mutagenesis of GluN3A N-glycosylation sites with lectin and single-particle surface mobility assays

    PMID:29915530 PMID:30425244

    Open questions at the time
    • Endogenous trigger relieving GluN1 auto-inhibition in vivo not identified
    • Glycan-dependent partners controlling surface mobility unknown
  6. 2019 High

    Mapping eGlyRs onto specific circuits and trafficking checkpoints linked GluN1/GluN3A signaling to behavior and refined how trafficking is controlled, showing glia-tuned eGlyRs in medial habenula drive aversion and that glycine-binding-site structure governs forward trafficking.

    Evidence Ex vivo electrophysiology, viral GluN3A knockdown and place-aversion behavior in MHb; glycine-binding-site mutagenesis with surface biotinylation; synaptosomal release assay with anti-GluN3A blockade

    PMID:30734226 PMID:31444392 PMID:31601771

    Open questions at the time
    • Mechanism of glial control of eGlyR activity not defined
    • Identity of the presynaptic GluN3A-containing autoreceptor (non-diheteromeric) not resolved
  7. 2021 High

    Discovery of a GluN3A-GIT1-mTOR-Raptor complex and a p38/MEF2C transcriptional route unified GluN3A's role as a brake on protein synthesis and gene expression underlying memory, showing GluN3A removal potentiates mTOR-dependent translation and MEF2C-driven transcription.

    Evidence Reciprocal Co-IP of GIT1-mTOR-Raptor, mTOR activity assays, RNA-seq and conditional-KO memory tests; shRNA knockdown with reporter assays, kinase imaging and uncaging in neurons

    PMID:32393578 PMID:34787081

    Open questions at the time
    • How GluN3A competes with mTOR for GIT1 structurally undefined
    • Coupling between eGlyR/triheteromeric channel activity and these signaling complexes not directly demonstrated
  8. 2022 High

    Extending eGlyR physiology to amygdala and neocortex established GluN1/GluN3A as a tonic, neuromodulated regulator of fear memory and cortical state in defined principal cells and interneurons.

    Evidence Patch-clamp, conditional GluN3A KO, in vivo recordings and fear-conditioning in basolateral amygdala and neocortical SST interneurons

    PMID:35700736

    Open questions at the time
    • Source and dynamics of the ambient glycine driving tonic eGlyR current not defined
    • Mechanism of dopaminergic modulation of eGlyRs unresolved
  9. 2023 High

    Single-molecule tracking revealed a developmental function in setting NMDAR composition, showing GluN3A selectively controls GluN2A (but not GluN2B) surface diffusion and synaptic anchoring within an early postnatal window.

    Evidence Single-molecule tracking with surface biotinylation and electrophysiology in rodent neurons under GluN3A knockdown and overexpression

    PMID:37149869

    Open questions at the time
    • Cell-surface receptor mediating altered GluN2A diffusion not identified
    • Molecular basis of GluN2A vs GluN2B selectivity unknown
  10. 2024 High

    Regional analysis showed GluN3A maintains a GluN2B-enriched, low-Ca2+ synaptic state in adult ventral hippocampus, refining its role in constraining NMDAR-dependent Ca2+ influx and LTP in specific circuits.

    Evidence Patch-clamp, LTP, calcium imaging, IHC and fractionation comparing ventral vs dorsal hippocampus in GluN3A KO mice

    PMID:39256046

    Open questions at the time
    • Whether the ventral-hippocampal effect reflects eGlyR or triheteromeric GluN3A is not disentangled
    • Behavioral consequence of ventral-specific GluN3A loss not tested here
  11. 2025 Medium

    Structural and pharmacological tools matured the GluN3A field, providing the triheteromeric GluN1/GluN2A/GluN3A architecture and selective allosteric modulators that enable targeted manipulation of eGlyRs in native circuits.

    Evidence Cryo-EM, proteoliposome single-channel recording and AzF photo-crosslinking of triheteromers (preprint); whole-cell and single-channel electrophysiology of selective PAM UCM-A86 (preprint) and selective NAMs EU1180-560/590; hippocampal interneuron eGlyR characterization across development and species (preprint)

    PMID:41713186

    Open questions at the time
    • Cryo-EM triheteromer structure and several modulator studies remain preprints
    • In vivo efficacy and circuit-level effects of the new modulators not yet established
  12. 2026 High

    A developmental wiring role was defined, showing GluN3A loss disrupts layer-specific callosal axon targeting through non-cell-autonomous control of postsynaptic dendritic patterning.

    Evidence In utero electroporation, longitudinal confocal imaging of axonal and dendritic arbors, and constitutive plus conditional GluN3A KO in somatosensory cortex

    PMID:42150879

    Open questions at the time
    • Whether eGlyR or conventional NMDAR signaling mediates the dendritic phenotype is unresolved
    • Downstream effectors linking GluN3A to dendritic bifurcation not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how GluN3A's channel modes (glycine-gated eGlyR versus glutamate-gated triheteromer) are coupled to its intracellular GIT1/mTOR and trafficking functions, and what physiological signals set the balance between these modes in specific neurons.
  • No direct demonstration linking eGlyR/triheteromer activity to GIT1/mTOR signaling
  • Endogenous determinants of mode selection in vivo unidentified
  • No human disease mutation functionally characterized beyond a trafficking defect

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 1
Partners
ARHGEF7GIT1GRIN1GRIN2AGRIN2BMTORPACSIN1RPTOR
Complex memberships
GIT1/mTOR/Raptor complexGluN1/GluN2/GluN3A triheteromeric NMDARGluN1/GluN3A excitatory glycine receptor (eGlyR)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 GluN1/GluN3A receptors form excitatory glycine receptors (eGlyRs) activated by glycine alone (not glutamate). The compound CGP-78608 (a GluN1 antagonist) greatly enhances GluN1/GluN3A responses by relieving GluN1-mediated auto-inhibition. An endogenous disulfide bond in GluN3A confers redox modulation: under reducing conditions, ambient glycine is sufficient for tonic activation. These functional eGlyRs were demonstrated in native juvenile mouse hippocampal neurons (P8–P12). Electrophysiology (whole-cell patch-clamp) in recombinant systems and native hippocampal slices; pharmacological dissection with CGP-78608 and redox reagents Nature communications High 30425244
2019 GluN1/GluN3A excitatory glycine receptors are operationally expressed in adult medial habenula (MHb) neurons. Glial cells (not glycinergic neurons) tune MHb neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in MHb prevented conditioned place-aversion, establishing a role in aversive emotional associations. Ex vivo electrophysiology, viral knockdown of GluN3A in MHb, behavioral place-aversion conditioning in mice Science (New York, N.Y.) High 31601771
2013 GluN3A binds directly to the postsynaptic scaffold GIT1, limiting synaptic localization of GIT1 and its ability to complex βPIX, thereby decreasing Rac1 and PAK activation in dendritic spines. This inhibition of the GIT1/βPIX/Rac1/PAK actin signaling axis reduces spine density and size. Knockout of GluN3A favors GIT1/βPIX complex formation and increases Rac1 activity. GluN3A binding to GIT1 is regulated by synaptic activity. Co-immunoprecipitation, biochemical fractionation, immunocytochemistry, Rac1 activation assays, shRNA knockdown and overexpression in primary cultured neurons Proceedings of the National Academy of Sciences of the United States of America High 24297929
2013 GluN3A-containing NMDARs are endocytosed via a YWL motif in the GluN3A C-terminal tail that binds the clathrin adaptor AP2. Alanine mutation of the YWL motif blocked clathrin-dependent internalization and increased surface expression. Tyrosine phosphorylation of this motif by Src family kinases promotes internalization and reduces surface expression of GluN3A-NMDARs. Mutagenesis (alanine substitutions, phosphomimetic mutations), immunocytochemistry, electrophysiology, Src kinase activation assays in recombinant systems and primary rat neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 23447623
2013 Mutant huntingtin (HTT) sequesters PACSIN1, the endocytic adaptor specific for GluN3A, disrupting its subcellular localization and thereby increasing surface expression of GluN3A-containing NMDARs on striatal neurons. This aberrant GluN3A surface expression promotes synapse pruning and mediates enhanced NMDAR currents linked to neuronal death. Genetic deletion of GluN3A prevented synapse degeneration, improved motor/cognitive decline, and reduced striatal atrophy in YAC128 HD mice. Co-immunoprecipitation (HTT–PACSIN1 interaction), surface biotinylation, electrophysiology, mouse genetics (GluN3A KO × YAC128), behavioral assays, histology Nature medicine High 23852340
2013 Cocaine exposure drives insertion of GluN3A/GluN2B-containing NMDARs that are quasi-Ca2+-impermeable into VTA dopamine neurons, reducing NMDAR-EPSC amplitude. These GluN3A-containing NMDARs are necessary for the expression of cocaine-evoked plasticity of AMPARs. An mGluR1-dependent mechanism involving Homer/Shank interactions and protein synthesis removes these noncanonical NMDARs. Ex vivo patch-clamp in mouse VTA slices, mouse genetics (GluN3A KO), subcellular Ca2+ imaging, pharmacological dissection Neuron High 24183704
2014 GluN3A overexpression reduces dendritic spine density and increases spine elimination, while GluN3A silencing reduces spine elimination and favors stability. The activity-dependent effect on spine destabilization requires GluN3A binding to GIT1. An endocytosis-deficient GluN3A mutant enhanced spine pruning, indicating that GluN3A surface residence time governs its effect on spine dynamics. Confocal time-lapse imaging in rat hippocampal organotypic slices, overexpression and shRNA knockdown, endocytosis-deficient GluN3A mutant, PACSIN1 silencing The Journal of neuroscience : the official journal of the Society for Neuroscience High 25009255
2021 GluN3A forms a signaling complex with GIT1, mTOR, and Raptor. GluN3A expression negatively regulates GIT1 binding to mTOR, thereby inhibiting synaptic mTOR activation and mTOR-dependent translation of activity-regulated mRNAs (e.g., Bdnf, Arc). GluN3A removal enables GIT1/mTOR complex formation, potentiates mTOR-dependent protein synthesis, and facilitates consolidation of associative and spatial memories. Co-immunoprecipitation (GIT1–mTOR–Raptor complex), GluN3A overexpression/silencing, mTOR activity assays, RNA-seq, behavioral memory tests in mice with conditional GluN3A deletion eLife High 34787081
2016 Extracellular acidification (pH decrease into the physiological range) potentiates glycine-gated GluN1/GluN3A currents primarily by slowing desensitisation and accelerating recovery from desensitisation. This effect is mediated by residues facing the heterodimer interface of the ligand-binding domain. Whole-cell electrophysiology on recombinant GluN1/GluN3A in HEK cells; site-directed mutagenesis of LBD interface residues Scientific reports High 27000430
2016 The N-terminal domain (NTD) of GluN3A is a crucial regulatory determinant of GluN1/GluN3A receptor efficacy. Deletion of the GluN3A NTD substantially increases glycine-induced maximum current (Imax) and impairs GluN1 antagonist-mediated potentiation. Oxidative crosslinking of the homophilic GluN3A NTD intersubunit interface decreases Imax, while mutations in the region linking the NTD to the LBD have opposite effects. Xenopus oocyte expression with NTD deletion and crosslinking mutants, two-electrode voltage-clamp electrophysiology, metabolic/surface labeling to confirm stoichiometry Neuropharmacology High 26777280
2017 Residues in the GluN1 C-terminal alternatively spliced cassettes control steady-state activity level and modulation of GluN1/GluN3A receptors by zinc and protons. Phosphorylation status of cassette-specific sites further modulates channel activity, indicating C-terminal splicing confers cell-specific and activity-dependent regulation of GluN1/GluN3A current. Whole-cell electrophysiology on recombinant GluN1/GluN3A variants in HEK293 cells; phosphomimetic mutations Neuropharmacology Medium 28365212
2018 N-glycosylation at specific asparagine residues in GluN3A (N145, N264, N275) is required for surface delivery of GluN3A-containing NMDARs. GluN3A subunits carry extensively modified hybrid/complex N-glycan structures. Surface mobility of GluN3A-NMDARs in hippocampal neurons is increased by inhibiting complex N-glycan formation (DMM) and decreased by specific lectins. Microscopy, biochemistry (deglycosylation, lectin assays), electrophysiology, mutagenesis of N-glycosylation sites in mammalian cell lines and primary rat hippocampal neurons Frontiers in molecular neuroscience High 29915530
2019 Structural features of the glycine-binding site in GluN3A (as well as GluN1) regulate forward trafficking of GluN3A-containing NMDARs to the cell surface. A clinically relevant mutation in the human GluN3A glycine-binding site significantly reduces surface delivery. Site-directed mutagenesis of glycine-binding site residues, surface biotinylation, electrophysiology in mammalian cell lines and primary rat hippocampal neurons Scientific reports Medium 31444392
2020 GluN3A knockdown in rat hippocampal neurons promotes inducible transcription of a subset of NMDAR-sensitive genes (Bdnf, Arc). This enhancement is mediated by accumulation of phosphorylated p38 MAPK in the nucleus, which activates the transcription factor MEF2C. shRNA knockdown in primary rat hippocampal neurons, reporter gene assays, qRT-PCR, RNA-Seq, immunostaining, two-photon glutamate uncaging with calcium imaging The Journal of biological chemistry High 32393578
2012 GluN3A deletion in adult mice increases CaMKII expression in forebrain and elevates phosphorylated CaMKII upon LTP induction, leading to enhanced hippocampal LTP. CaMKII inhibition abrogated the enhanced LTP in GluN3A KO slices, placing GluN3A upstream of CaMKII in synaptic plasticity. GluN3A KO mice, hippocampal slice LTP recording, Western blot for CaMKII phosphorylation, CaMKII inhibitor experiments The Journal of physiology Medium 23006484
2012 GluN3A overexpression protects striatal neurons from 3-nitropropionic acid (3-NP) excitotoxicity in a dose-dependent manner, associated with a potent reduction of calpain activation (measured as decreased fodrin and STEP cleavage). Transgenic GluN3A incorporates into extrasynaptic compartments in mouse striatum. Transgenic GluN3A overexpressing mice, 3-NP excitotoxicity model, calpain substrate cleavage assay (Western blot), subcellular fractionation Neurobiology of disease Medium 22801082
2014 Activation of GluN1/GluN3A excitatory glycine receptors (by glycine or d-serine but not glutamate) induces an ~1 nm reduction in height of the extracellular domain, as detected by atomic force microscopy imaging in lipid bilayers, representing direct evidence of agonist-induced conformational change. Atomic force microscopy (AFM) imaging of isolated GluN1/GluN3A receptors reconstituted in lipid bilayers; glycine antagonist control Biochemical and biophysical research communications Medium 25017909
2022 GluN1/GluN3A excitatory glycine receptors (eGlyRs) are expressed as mostly extrasynaptic receptors in principal cells of the basolateral amygdala (BLA) and SST-positive interneurons of neocortex. Tonic eGlyR currents in BLA are sensitive to fear-conditioning protocols and subject to dopaminergic neuromodulation; they control stability of fear memories. In neocortex, eGlyRs control in vivo spiking of SST-INs and behavior-dependent modulation of cortical activity. Patch-clamp electrophysiology, GluN3A conditional KO mice, in vivo recordings, fear-conditioning behavioral assays, immunohistochemistry Neuron High 35700736
2023 Surface GluN3A-NMDARs form a highly diffusive receptor pool loosely anchored to synapses. Changes in GluN3A expression selectively alter the surface diffusion and synaptic anchoring of GluN2A- but not GluN2B-NMDARs, possibly through altered interactions with cell surface receptors. This effect is restricted to an early postnatal developmental window. Single-molecule tracking, confocal imaging, biochemistry (surface biotinylation), electrophysiology in rodent neurons; GluN3A knockdown and overexpression Cell reports High 37149869
2012 Triheteromeric GluN1/GluN2/GluN3A receptors exist at layer 1/motor-cortex inputs onto layer 5 pyramidal neurons in somatosensory cortex with distinct biophysical properties (threshold-like activation, strong outward rectification) not observed in GluN1/GluN2-only or GluN1/GluN3-only receptors. Unlike GluN1/GluN3 diheteromers, these triheteromers are activated by glutamate, blocked by d-AP5, and are Ca2+-permeable. Ex vivo patch-clamp electrophysiology with pharmacological dissection in mouse somatosensory cortex slices Neuroscience Medium 22814002
2012 GluN3A incorporation into triheteromeric GluN1/GluN2A/GluN3A receptors reduces Mg2+ and open-channel blocker (memantine, MK-801, philanthotoxin-343) sensitivity compared to GluN1/GluN2A. N- and N+1-site mutations in GluN3A partially restore block, implicating both sites or additional residues in determining blocker access. Two-electrode voltage-clamp in Xenopus oocytes expressing different NMDAR subunit combinations; site-directed mutagenesis of pore-lining residues European journal of pharmacology Medium 22564863
2019 Presynaptic GluN3A-containing NMDA autoreceptors are present on mouse hippocampal glutamatergic nerve endings (synaptosomes), as confirmed by confocal microscopy for GluN1, GluN2A, GluN2B, and GluN3A subunits. Anti-GluN3A antibody prevented NMDA/glycine-evoked glutamate release. The NMDA-evoked release component was not mediated by GluN1/GluN3A diheteromers (glycine-only activated). Confocal microscopy of synaptosomes, [3H]D-aspartate release assay with antibody-mediated blockade, surface biotinylation Molecular neurobiology Medium 30734226
2024 GluN3A is enriched in the adult ventral hippocampus (VH), where it localizes to synaptic and extrasynaptic sites on CA1 pyramidal cells and assembles as functional eGlyRs. GluN3A deletion accelerated NMDAR decay kinetics and reduced ifenprodil sensitivity in VH, indicating GluN3A expression maintains GluN2B enrichment at VH synapses. GluN3A KO also enhanced NMDAR-dependent Ca2+ influx and LTP in VH. Electrophysiology (patch-clamp, LTP recording), calcium imaging, immunohistochemistry, fractionation, GluN3A KO mice; ventral vs dorsal hippocampus comparison The Journal of neuroscience : the official journal of the Society for Neuroscience High 39256046
2025 Cryo-EM structure of purified triheteromeric GluN1/GluN2A/GluN3A NMDARs determined. Single-channel recordings in proteoliposomes showed these receptors are activated by co-binding of glycine and glutamate and display two distinct conductance levels. Photo-crosslinking with p-azido-phenylalanine in the GluN2A and GluN2B NTDs enabled crosslinking with GluN3A both in vitro and in vivo, defining subunit arrangement. Cryo-EM structure determination, two-step affinity chromatography purification, proteoliposome single-channel recording, structural click-chemistry photo-crosslinking (AzF) bioRxivpreprint Medium
2025 UCM-A86 is a selective positive allosteric modulator of GluN1/GluN3A and GluN1/GluN3B receptors with no activity at GluN1/GluN2A-D. It potentiates GluN1/GluN3A by ~436% and primarily acts by increasing channel open probability without affecting mean conductance. Modulation requires agonist binding or channel gating. UCM-A86 selectively potentiates native eGlyRs in cortical somatostatin interneurons. Whole-cell and single-channel electrophysiology in recombinant systems (HEK cells) and native cortical SST interneurons; selectivity panel against GluN1/GluN2 and other receptors bioRxivpreprint Medium
2025 Novel selective negative allosteric modulators EU1180-560 and EU1180-590 inhibit GluN1/GluN3A (IC50 ~2.6 and ~3.7 µM respectively) with no detectable effect on GluN1/GluN3B, producing non-competitive, voltage-independent inhibition consistent with allosteric mechanism. EU1180-590 shows promising brain penetration. Whole-cell electrophysiology on recombinant GluN1/GluN3A and GluN1/GluN3B in HEK cells; selectivity against NMDA, AMPA, GABA, glycine, P2X, kainate receptors Molecular pharmacology Medium 41713186
2025 Hippocampal somatostatin interneurons (Sst-INs) and neurogliaform cells (NGFCs) express functional eGlyRs (GluN1/GluN3A) from early postnatal through adult ages. In the developing hippocampus, eGlyR-mediated excitation of NGFCs by ambient glycine increases GABAergic tone and influences generation of giant depolarizing potentials (GDPs). In mature hippocampus, eGlyR-mediated excitation of Sst-INs regulates sharp wave ripples (SWRs). This function is evolutionarily conserved in non-human primates. Patch-clamp electrophysiology in developing and adult hippocampal slices from mice and non-human primates; GluN3A KO; pharmacological dissection with CGP-78608 Research squarepreprint Medium 41472680
2026 Loss-of-function of GluN3A disrupts region- and layer-specific contralateral targeting by callosal axons in L2/3 neurons of mouse somatosensory cortex, without affecting early axonal navigation. GluN3A deletion drives premature and proximal bifurcation of apical dendrites of L2/3 neurons, and inward expansion of recipient dendritic trees matches displaced callosal axon profiles. Conditional KO experiments support that dendritic patterning of postsynaptic neurons directs callosal axon position. In utero electroporation with fluorescent reporters, confocal imaging of axonal/dendritic arbors throughout postnatal development, GluN3A constitutive and conditional KO mice The Journal of neuroscience : the official journal of the Society for Neuroscience High 42150879

Source papers

Stage 0 corpus · 66 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 106 24183704
2013 Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nature medicine 103 23852340
2019 Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula. Science (New York, N.Y.) 83 31601771
2018 Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nature communications 83 30425244
2014 Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PloS one 57 24663672
2013 GluN3A: an NMDA receptor subunit with exquisite properties and functions. Neural plasticity 55 24386575
2012 Regulatory roles of the NMDA receptor GluN3A subunit in locomotion, pain perception and cognitive functions in adult mice. The Journal of physiology 47 23006484
2022 GluN3A excitatory glycine receptors control adult cortical and amygdalar circuits. Neuron 45 35700736
2021 Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A. Alzheimer's & dementia : the journal of the Alzheimer's Association 45 34151525
2012 A population-specific uncommon variant in GRIN3A associated with schizophrenia. Biological psychiatry 44 23237318
2014 GluN3A promotes dendritic spine pruning and destabilization during postnatal development. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 25009255
2023 Excitatory GluN1/GluN3A glycine receptors (eGlyRs) in brain signaling. Trends in neurosciences 39 37248111
2013 GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 signaling. Proceedings of the National Academy of Sciences of the United States of America 36 24297929
2013 Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors. European journal of pharmacology 35 23872415
2021 GluN3A NMDA receptor subunits: more enigmatic than ever? The Journal of physiology 33 33942912
2013 Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 23447623
2021 Temporal Dynamics and Neuronal Specificity of Grin3a Expression in the Mouse Forebrain. Cerebral cortex (New York, N.Y. : 1991) 32 33290502
2016 Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation. Scientific reports 27 27000430
2012 The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation. Neurobiology of disease 27 22801082
2019 Structural features in the glycine-binding sites of the GluN1 and GluN3A subunits regulate the surface delivery of NMDA receptors. Scientific reports 26 31444392
2015 Expression of the NMDA receptor subunit GluN3A (NR3A) in the olfactory system and its regulatory role on olfaction in the adult mouse. Brain structure & function 26 26334321
2018 Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit. Experimental neurology 25 29554474
2015 A neuroprotective role of the NMDA receptor subunit GluN3A (NR3A) in ischemic stroke of the adult mouse. American journal of physiology. Cell physiology 25 25652449
2016 GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models. Neurobiology of disease 24 27072890
2018 N-Glycosylation Regulates the Trafficking and Surface Mobility of GluN3A-Containing NMDA Receptors. Frontiers in molecular neuroscience 20 29915530
2013 Association between GRIN3A gene polymorphism in Kawasaki disease and coronary artery aneurysms in Taiwanese children. PloS one 20 24278430
2020 The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription. The Journal of biological chemistry 19 32393578
2018 RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin. Molecular therapy : the journal of the American Society of Gene Therapy 19 29914757
2013 The GluN3A subunit exerts a neuroprotective effect in brain ischemia and the hypoxia process. ASN neuro 19 23883441
2012 Triheteromeric N-methyl-D-aspartate receptors differentiate synaptic inputs onto pyramidal neurons in somatosensory cortex: involvement of the GluN3A subunit. Neuroscience 17 22814002
2012 Open-channel blockade is less effective on GluN3B than GluN3A subunit-containing NMDA receptors. European journal of pharmacology 16 22564863
2010 Significant association of glutamate receptor, ionotropic N-methyl-D-aspartate 3A (GRIN3A), with nicotine dependence in European- and African-American smokers. Human genetics 16 20084518
2023 GluN3A subunit tunes NMDA receptor synaptic trafficking and content during postnatal brain development. Cell reports 15 37149869
2015 Modulation of GluN3A expression in Huntington disease: a new n-methyl-D-aspartate receptor-based therapeutic approach? JAMA neurology 15 25686081
2009 Exomic sequencing of the ionotropic glutamate receptor N-methyl-D-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia. Schizophrenia research 15 19665356
2021 Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife 13 34787081
2019 Immuno-Pharmacological Characterization of Presynaptic GluN3A-Containing NMDA Autoreceptors: Relevance to Anti-NMDA Receptor Autoimmune Diseases. Molecular neurobiology 13 30734226
2017 Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N-methyl-d-aspartate receptors. Neuropharmacology 12 28365212
2016 The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors. Neuropharmacology 12 26777280
2014 The assessment of the T102C polymorphism of the 5HT2a receptor gene, 3723G/A polymorphism of the NMDA receptor 3A subunit gene (GRIN3A) and 421C/A polymorphism of the NMDA receptor 2B subunit gene (GRIN2B) among cardiac surgery patients with and without delirium. General hospital psychiatry 10 25041634
2024 GluN3A and Excitatory Glycine Receptors in the Adult Hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 39256046
2019 Demonstration of critical role of GRIN3A in nicotine dependence through both genetic association and molecular functional studies. Addiction biology 9 30741440
2018 Impacts of GRIN3A, GRM6 and TPH2 genetic polymorphisms on quality of life in methadone maintenance therapy population. PloS one 8 30059533
2023 Strain hypothesis and additional evidence of the GluN3A deficiency-mediated pathogenesis of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 6 37485581
2016 GRIN3A and MAPT stimulate nerve overgrowth in macrodactyly. Molecular medicine reports 5 27840953
2014 Activation-induced structural change in the GluN1/GluN3A excitatory glycine receptor. Biochemical and biophysical research communications 5 25017909
2025 Discovery of novel GluN1/GluN3A NMDA receptor inhibitors using a deep learning-based method. Acta pharmacologica Sinica 4 40355656
2024 Hippocampal tau-induced GRIN3A deficiency in Alzheimer's disease. FEBS open bio 4 39396906
2023 Correlations between GRIN2B and GRIN3A gene polymorphisms and postpartum depressive symptoms in Chinese parturients undergoing cesarean section: A prospective cohort study. Journal of psychosomatic research 4 36898314
2023 Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits. Journal of affective disorders 4 36997126
2021 A new insight into mechanisms of interferon alpha neurotoxicity: Expression of GRIN3A subunit of NMDA receptors and NMDA-evoked exocytosis. Progress in neuro-psychopharmacology & biological psychiatry 4 33785426
2021 A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia. Personalized medicine 4 34406079
2025 Discovery of selective GluN1/GluN3A NMDA receptor inhibitors using integrated AI and physics-based approaches. Acta pharmacologica Sinica 3 40659855
2025 AI-enhanced virtual screening approach to hit identification for GluN1/GluN3A NMDA receptor. Acta pharmacologica Sinica 3 40858884
2023 No evidence for cognitive decline or neurodegeneration in strain-matched Grin3a knockout mice. Alzheimer's & dementia : the journal of the Alzheimer's Association 3 37483152
2025 An efficient deep learning-based strategy to screen inhibitors for GluN1/GluN3A receptor. Acta pharmacologica Sinica 2 40069493
2025 Contrastive learning-based drug screening model for GluN1/GluN3A inhibitors. Acta pharmacologica Sinica 2 40481214
2025 Identification of small-molecule inhibitors for GluN1/GluN3A NMDA receptors via a multiscale CNN-based prediction model. Acta pharmacologica Sinica 2 40797112
2025 Gastric bypass surgery improves lipid metabolism and mitochondrial function through the glutamate receptor Grin3a-mediated CaMKKβ/AMPK pathway in a rat model of type 2 diabetes. Diabetic medicine : a journal of the British Diabetic Association 2 41255364
2026 A subunit-selective negative allosteric modulator of GluN1/GluN3A glycine-activated receptor. Molecular pharmacology 1 41713186
2025 Isoliquiritigenin as a Neuronal Radiation Mitigant: Mitigating Radiation-Induced Anhedonia Tendency Targeting Grik3/Grm8/Grin3a via Integrated Proteomics and AI-Driven Discovery. Pharmaceuticals (Basel, Switzerland) 1 41011178
2025 Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution. Research square 1 41472680
2023 Roux-en-Y Gastric Bypass Improves Insulin Sensitivity in Obese Rats with Type 2 Diabetes Mellitus by Regulating the Grin3a/AMPK Signal Axis in Hypothalamic Arcuate Nucleus. Diabetes, metabolic syndrome and obesity : targets and therapy 1 38028990
2026 GRIN3A defines an immunosuppressive niche in advanced prostate cancer. Medical oncology (Northwood, London, England) 0 41642561
2026 GluN3A is required for coordinated postnatal development of axonal and dendritic branching patterns in mouse L2/3 callosal projection neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 0 42150879
2025 Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution. bioRxiv : the preprint server for biology 0 41473287

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