Affinage

GRIN3A

Glutamate receptor ionotropic, NMDA 3A · UniProt Q8TCU5

Length
1115 aa
Mass
125.5 kDa
Annotated
2026-04-28
65 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRIN3A encodes GluN3A, an atypical NMDA receptor subunit that functions both as a glycine-binding subunit in diheteromeric GluN1/GluN3A excitatory glycine receptors (eGlyRs) activated by glycine alone and as a modulatory subunit in triheteromeric GluN1/GluN2/GluN3A complexes activated by glutamate and glycine, where it reduces Ca²⁺ permeability and Mg²⁺ sensitivity by altering channel pore properties (PMID:22564863, PMID:30425244, PMID:35700736). GluN3A acts as a molecular brake on synapse maturation by binding the scaffold protein GIT1 to suppress Rac1/PAK-dependent actin remodeling and to restrict mTOR/Raptor-dependent translation of activity-regulated transcripts such as Bdnf and Arc, thereby constraining LTP, spine stability, and memory consolidation (PMID:24297929, PMID:34787081, PMID:23006484). Surface expression of GluN3A is tightly regulated through a Src-phosphorylatable YWL/AP2 endocytic motif, PACSIN1-dependent internalization, N-glycosylation of specific asparagine residues, and conformational gating by the GluN3A N-terminal domain; disruption of this trafficking by mutant huntingtin-mediated sequestration of PACSIN1 causes pathological GluN3A surface accumulation and synapse loss in Huntington disease models (PMID:23447623, PMID:23852340, PMID:29915530, PMID:26777280). In the adult brain, tonically active eGlyRs in basolateral amygdala principal neurons, somatostatin interneurons, medial habenula neurons, and hippocampal interneurons control circuit excitability, fear memory, place-aversion conditioning, and sharp wave ripples (PMID:31601771, PMID:35700736, PMID:39256046).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2012 High

    Establishing that GluN3A incorporation fundamentally alters the NMDAR channel pore — reducing Mg²⁺ block and memantine sensitivity — answered how this subunit changes the biophysical identity of NMDARs and provided a mechanistic basis for its dominant-negative effects on Ca²⁺ signaling.

    Evidence Two-electrode voltage clamp in Xenopus oocytes with site-directed pore mutagenesis of GluN3A N and N+1 sites

    PMID:22564863

    Open questions at the time
    • Pore structure of triheteromeric GluN1/GluN2/GluN3A channels not resolved at atomic level
    • Relative stoichiometry of subunits in native triheteromeric assemblies unknown
  2. 2012 High

    Demonstrating that GluN3A deletion enhances hippocampal LTP through increased CaMKII activation established GluN3A as a physiological constraint on synaptic plasticity in the adult brain.

    Evidence GluN3A KO mice, hippocampal slice LTP recordings, Western blot for CaMKII, pharmacological rescue with CaMKII inhibitor

    PMID:23006484

    Open questions at the time
    • Whether LTP enhancement reflects loss of GluN3A from triheteromeric or diheteromeric receptors was unresolved
    • Behavioral consequences of enhanced LTP not tested in this study
  3. 2013 High

    Identification of the YWL endocytic motif and its regulation by Src-mediated phosphorylation and AP2 binding resolved the molecular mechanism controlling GluN3A surface removal, explaining how developmental downregulation is executed.

    Evidence Mutagenesis of C-terminal motif, biotinylation surface assays, electrophysiology in recombinant systems and primary neurons

    PMID:23447623

    Open questions at the time
    • In vivo phosphorylation dynamics at the YWL motif not characterized
    • Relationship between Src activity and developmental GluN3A removal not demonstrated in intact brain
  4. 2013 High

    Discovery that GluN3A binds GIT1 to suppress Rac1/PAK actin signaling and reduce spine density revealed a non-ionotropic signaling mechanism through which GluN3A limits synapse maturation independently of its channel function.

    Evidence Reciprocal co-immunoprecipitation, GluN3A KO mouse biochemistry, spine morphology analysis in cultured neurons

    PMID:24297929

    Open questions at the time
    • Whether GluN3A-GIT1 interaction is direct or scaffolded was not resolved
    • Activity-dependent regulation of this interaction was shown but upstream signals not identified
  5. 2013 High

    Showing that mutant huntingtin sequesters PACSIN1 to redirect GluN3A to the neuronal surface, and that GluN3A deletion rescues synapse degeneration in HD models, established a causal disease mechanism linking GluN3A trafficking to Huntington disease pathology.

    Evidence YAC128 HD model crossed with GluN3A KO, immunofluorescence, electrophysiology, behavioral assays

    PMID:23852340

    Open questions at the time
    • Whether pharmacological GluN3A inhibition can substitute for genetic deletion in HD rescue
    • Mechanism by which surface GluN3A drives synapse elimination in HD not fully delineated
  6. 2013 High

    Demonstrating that cocaine drives insertion of GluN3A-containing quasi-Ca²⁺-impermeable NMDARs into VTA dopamine neurons, and that these are required for subsequent AMPAR plasticity, revealed GluN3A as a metaplasticity switch in the addiction circuit.

    Evidence Ex vivo patch-clamp, subcellular Ca²⁺ imaging, GluN3A KO mice, mGluR1/Homer/Shank pathway analysis

    PMID:24183704

    Open questions at the time
    • Whether GluN3A insertion is a general response to psychostimulants or cocaine-specific
    • Molecular trigger for GluN3A insertion upon cocaine exposure not identified
  7. 2014 High

    Live imaging showed that GluN3A overexpression destabilizes spines through combined surface retention (blocked by PACSIN1-dependent endocytosis) and GIT1 binding, unifying the trafficking and signaling mechanisms into a single model of GluN3A-mediated spine elimination.

    Evidence Confocal time-lapse imaging in organotypic slices, endocytosis-deficient mutants, shRNA knockdown of PACSIN1

    PMID:25009255

    Open questions at the time
    • In vivo spine dynamics in GluN3A mutants not examined
    • Contribution of ionotropic versus non-ionotropic signaling to spine loss not disentangled
  8. 2016 High

    Identifying the GluN3A N-terminal domain as a conformational gate that constrains GluN1/GluN3A receptor efficacy — with NTD deletion dramatically increasing glycine currents — revealed a structural mechanism for the low intrinsic activity of these receptors.

    Evidence Xenopus oocyte expression, NTD deletion and cysteine-crosslinking mutagenesis, two-electrode voltage clamp

    PMID:26777280

    Open questions at the time
    • Atomic-resolution structure of the NTD intersubunit interface not available at this time
    • Endogenous modulators acting through the NTD not identified
  9. 2016 High

    Showing that extracellular acidification potentiates GluN1/GluN3A by slowing desensitization at the LBD heterodimer interface established that pH — unlike its inhibitory effect on conventional NMDARs — is a positive modulator of GluN1/GluN3A, implying enhanced activity under pathological acidosis.

    Evidence Recombinant electrophysiology in HEK cells with site-directed mutagenesis of LBD interface residues

    PMID:27430000

    Open questions at the time
    • Whether pH potentiation contributes to GluN3A-mediated neuroprotection or excitotoxicity in vivo untested
  10. 2018 High

    The discovery that CGP-78608 (a GluN1 glycine-site antagonist) converts small desensitizing GluN1/GluN3A currents into large stable responses, combined with detection of native glycine-gated currents in juvenile hippocampal neurons, provided the first definitive pharmacological tool and native validation of functional diheteromeric eGlyRs.

    Evidence Recombinant electrophysiology in HEK cells, redox chemistry, mutagenesis, hippocampal slice recordings

    PMID:30425244

    Open questions at the time
    • Whether CGP-78608 acts identically on triheteromeric receptors not addressed
    • Endogenous redox state of the GluN3A disulfide in vivo not determined
  11. 2018 High

    Mapping specific N-glycosylation sites on GluN1 and GluN3A required for surface delivery, and showing that glycan remodeling alters GluN3A surface mobility, revealed a quality-control checkpoint for GluN3A-containing receptor trafficking.

    Evidence Site-directed mutagenesis of asparagine residues, deglycosylation, lectin analysis, electrophysiology in HEK cells, hippocampal neurons, and CDG patient fibroblasts

    PMID:29915530

    Open questions at the time
    • How glycosylation interacts with the PACSIN1 endocytic pathway not addressed
    • Whether glycosylation changes during development regulate the GluN3A expression window
  12. 2019 High

    Demonstration that GluN1/GluN3A eGlyRs are functional in adult medial habenula neurons and that glial glycine tunes neuronal activity via these receptors, with behavioral impact on place-aversion, established eGlyRs as a physiologically relevant receptor class in the adult brain — not merely a developmental oddity.

    Evidence Patch-clamp in adult brain slices, pharmacology, viral knockdown in medial habenula, behavioral conditioning in mice

    PMID:31601771

    Open questions at the time
    • Source and dynamics of glycine release controlling eGlyRs in MHb not fully characterized
    • Whether eGlyR signaling in MHb generalizes to aversion beyond place conditioning
  13. 2020 High

    Showing that GluN3A knockdown enables synaptic activity-driven nuclear accumulation of phospho-p38 MAPK and MEF2C-dependent transcription of Bdnf and Arc identified a specific signaling cascade through which GluN3A constrains activity-dependent gene expression.

    Evidence shRNA in primary hippocampal neurons, RNA-seq, qRT-PCR, reporter assays, two-photon glutamate uncaging with Ca²⁺ imaging

    PMID:32393578

    Open questions at the time
    • Whether p38/MEF2C pathway operates independently of or downstream of the GIT1/mTOR axis
    • In vivo relevance of p38/MEF2C axis in GluN3A-dependent plasticity not tested
  14. 2021 High

    Discovery that GluN3A forms a complex with GIT1, mTOR, and Raptor, and that GluN3A negatively regulates mTOR-dependent translation of plasticity-related mRNAs to constrain memory consolidation, unified the GIT1-binding and plasticity-braking functions into a single signaling pathway.

    Evidence Reciprocal co-immunoprecipitation, GluN3A KO and overexpression, two-photon Ca²⁺ imaging, behavioral memory assays in mice

    PMID:34787081

    Open questions at the time
    • Whether mTOR regulation is through direct protein-protein interaction or mediated by GIT1 scaffold
    • Stimulus-dependent dynamics of GluN3A-mTOR complex assembly unknown
  15. 2022 High

    Comprehensive characterization of tonic eGlyR currents in BLA principal cells and neocortical SST interneurons, modulated by dopamine and fear conditioning, established eGlyRs as circuit-level regulators of fear memory and cortical state.

    Evidence Patch-clamp, pharmacology, mouse genetics, in vivo recordings, behavioral assays across multiple brain regions

    PMID:35700736

    Open questions at the time
    • Molecular mechanism of dopaminergic modulation of eGlyRs not resolved
    • Whether eGlyR expression in SST interneurons is uniform or subtype-specific
  16. 2023 High

    Single-molecule tracking revealed that surface GluN3A-NMDARs are highly mobile and loosely synapse-anchored, and that GluN3A expression selectively controls synaptic anchoring of GluN2A-NMDARs during a critical developmental window, providing a lateral diffusion mechanism for the GluN2B-to-GluN2A developmental switch.

    Evidence Single-particle tracking, confocal imaging, biochemistry, electrophysiology in developing rodent neurons

    PMID:37149869

    Open questions at the time
    • Molecular determinant of selective GluN2A (but not GluN2B) regulation by GluN3A not identified
    • Whether this diffusion-based mechanism operates in adult brain regions that retain GluN3A
  17. 2024 High

    Showing that GluN3A persists at synaptic and extrasynaptic sites in adult ventral hippocampus and regulates GluN2B content, Ca²⁺ influx, and LTP in CA1 pyramidal cells extended the eGlyR and plasticity-braking functions to a hippocampal subregion critical for anxiety and emotional memory.

    Evidence Patch-clamp, ifenprodil pharmacology, Ca²⁺ imaging, GluN3A KO mice in adult hippocampal slices

    PMID:39256046

    Open questions at the time
    • Behavioral consequences of enhanced ventral hippocampal LTP in GluN3A KO not tested
    • Whether GluN3A regulates GluN2B content directly or via altered trafficking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of native triheteromeric GluN1/GluN2/GluN3A complexes, the identity of endogenous modulators acting through the GluN3A NTD, how GluN3A's ionotropic and non-ionotropic (GIT1/mTOR, p38/MEF2C) functions are differentially engaged by physiological stimuli, and whether selective pharmacological modulation of eGlyRs in specific circuits can treat neuropsychiatric conditions.
  • No high-resolution structure of native triheteromeric receptor from mammalian brain
  • Endogenous allosteric modulators of the NTD gate unknown
  • Relative contribution of ionotropic versus non-ionotropic GluN3A signaling to behavioral phenotypes not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2
Partners
AP2A1GIT1GRIN1GRIN2AGRIN2BMTORPACSIN1RPTOR
Complex memberships
GluN1/GluN2/GluN3A triheteromeric NMDARGluN1/GluN3A diheteromeric eGlyRGluN3A/GIT1/mTOR/Raptor signaling complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Cocaine drives insertion of GluN3A/GluN2B-containing NMDARs that are quasi-Ca2+-impermeable into VTA dopamine neurons; these GluN3A-containing NMDARs are necessary for cocaine-evoked AMPAR plasticity, and an mGluR1-dependent mechanism requiring Homer/Shank interaction and protein synthesis removes them. Ex vivo patch-clamp recordings, mouse genetics, subcellular Ca2+ imaging, GluN3A knockout mice Neuron High 24183704
2013 Mutant huntingtin sequesters and disrupts subcellular localization of the endocytic adaptor PACSIN1 (which is specific for GluN3A), thereby redirecting an intracellular store of GluN3A-containing NMDARs to the surface of striatal neurons, causing aberrant synapse pruning; genetic deletion of GluN3A prevented synapse degeneration in HD mouse models. Mouse genetics (GluN3A KO, YAC128 HD model), immunofluorescence, electrophysiology, behavioral assays Nature Medicine High 23852340
2019 GluN1/GluN3A receptors are functional excitatory glycine receptors (activated by glycine alone, not glutamate) in adult medial habenula neurons; glial cells tune neuronal activity via these receptors, and reducing GluN1/GluN3A levels in the MHb prevents place-aversion conditioning. Electrophysiology (patch-clamp in brain slices), pharmacology, viral knockdown, behavioral conditioning assays in mice Science High 31601771
2018 CGP-78608 (a GluN1 glycine-site antagonist) greatly enhances GluN1/GluN3A responses by converting small desensitizing currents into large stable responses; an endogenous GluN3A disulfide bond confers distinct redox modulation affecting agonist sensitivity and gating kinetics; under reducing conditions, ambient glycine generates tonic GluN1/GluN3A activation. GluN1/GluN3A NMDARs are functionally expressed as excitatory glycine receptors in juvenile hippocampal neurons. Recombinant receptor electrophysiology in HEK cells, mutagenesis, redox chemistry, native hippocampal slice recordings Nature Communications High 30425244
2022 GluN3A forms excitatory glycine GluN1/GluN3A receptors (eGlyRs) that are mostly extrasynaptic, tonically activated by extracellular glycine, present in BLA principal cells and SST-positive neocortical interneurons; tonic eGlyR currents in BLA are modulated by dopamine and fear-conditioning protocols and control fear memory stability; in neocortex, eGlyRs control SST interneuron spiking and behavior-dependent cortical activity. Patch-clamp electrophysiology, pharmacology, mouse genetics, in vivo recordings, behavioral assays Neuron High 35700736
2013 GluN3A binds GIT1 (a postsynaptic scaffold that assembles actin regulatory complexes including βPIX), limiting GIT1 synaptic localization and its ability to complex βPIX, leading to decreased Rac1 activation and reduced spine density and size; GluN3A knockout favors GIT1/βPIX complex formation and increases Rac1 and PAK activation; GluN3A-GIT1 binding is regulated by synaptic activity. Co-immunoprecipitation, pulldown, primary cultured neurons, KO mouse biochemistry, spine morphology analysis PNAS High 24297929
2013 GluN3A endocytosis is mediated by a novel YWL endocytic motif in its cytoplasmic C-terminal tail that binds the clathrin adaptor AP2; tyrosine phosphorylation of this motif by Src family kinases promotes internalization and reduces cell-surface GluN3A expression. Alanine and phosphomimetic mutagenesis, immunocytochemistry, electrophysiology, biotinylation surface assays in recombinant systems and primary rat neurons Journal of Neuroscience High 23447623
2014 GluN3A overexpression reduces spine density, increases spine elimination and decreases spine stability in hippocampal neurons; an endocytosis-deficient GluN3A mutant enhances this effect; silencing PACSIN1 (which prevents GluN3A endocytosis) phenocopies GluN3A overexpression; GluN3A's destabilizing effect depends on its ability to bind GIT1. Confocal time-lapse imaging, organotypic slices, overexpression and shRNA knockdown, endocytosis-deficient mutants Journal of Neuroscience High 25009255
2021 GluN3A forms neuronal signaling complexes with GIT1, mTOR kinase, and Raptor; GluN3A acts as a key negative regulator of GIT1 binding to mTOR. Disrupting GIT1/mTOR complexes (by GluN3A overexpression or GIT1 silencing) inhibits synaptic mTOR activation and restricts mTOR-dependent translation of activity-regulated mRNAs (Bdnf, Arc). GluN3A removal potentiates mTOR-dependent protein synthesis and facilitates consolidation of associative and spatial memories. Co-immunoprecipitation, overexpression and KO mouse genetics, two-photon glutamate uncaging with Ca2+ imaging, behavioral memory assays, reporter assays eLife High 34787081
2016 Extracellular acidification strongly potentiates GluN1/GluN3A glycine-gated currents (half-maximal effect in physiological pH range) primarily by slowing desensitization and accelerating recovery from desensitization; this is mediated by residues at the heterodimer interface of the ligand-binding domain. Whole-cell electrophysiology of recombinant GluN1/GluN3A in heterologous expression system, site-directed mutagenesis Scientific Reports High 27000430
2016 The N-terminal domain (NTD) of GluN3A is a crucial regulatory determinant of GluN1/GluN3A receptor efficacy; deletion of GluN3A NTD causes large increase in glycine-inducible current amplitude with impaired GluN1-antagonist potentiation; oxidative crosslinking of the GluN3A NTD homophilic intersubunit interface decreases glycine-induced current and increases GluN1-antagonist potentiation. Xenopus oocyte expression, affinity purification/surface labeling, oxidative crosslinking mutagenesis, two-electrode voltage clamp Neuropharmacology High 26777280
2017 Residues in the GluN1 C-terminal alternatively spliced cassettes control the level of steady-state activity of GluN1/GluN3A receptors and the degree to which activity is facilitated by zinc and protons; phosphorylation status of splice-variant-specific sites further modulates channel activity. Whole-cell electrophysiology of recombinant GluN1/GluN3A in HEK293 cells differing in GluN1 C-terminal tail sequence, phosphorylation state manipulation Neuropharmacology Medium 28365212
2012 GluN3A deletion in adult mice enhances hippocampal LTP compared to wild-type; this enhancement is associated with increased CaMKII expression in forebrain and higher phosphorylated CaMKII upon LTP induction; CaMKII inhibition abolishes the enhanced LTP in GluN3A KO mice. GluN3A KO mice, hippocampal slice electrophysiology (LTP), Western blot, CaMKII inhibitor pharmacology Journal of Physiology High 23006484
2020 GluN3A knockdown in rat hippocampal neurons promotes synaptic activity-induced transcription of NMDAR-sensitive genes (Bdnf, Arc) via accumulation of phosphorylated p38 MAPK in the nucleus and activation of the transcription factor MEF2C. shRNA knockdown in primary rat hippocampal neurons, qRT-PCR, immunostaining, reporter gene assays, RNA-seq, two-photon glutamate uncaging with Ca2+ imaging Journal of Biological Chemistry High 32393578
2018 N-glycosylation at specific asparagine residues (N203 and N368 in GluN1; N145, N264, N275 in GluN3A) is required for surface delivery of GluN3A-containing NMDARs; GluN3A subunits carry extensively modified hybrid/complex N-glycan structures; altering N-glycan remodeling with inhibitors increases surface mobility of GluN3A-containing NMDARs in hippocampal neurons. Mutagenesis, microscopy, biochemistry (deglycosylation, lectin analysis), electrophysiology in HEK cells and rat hippocampal neurons, patient fibroblasts from CDG disorder Frontiers in Molecular Neuroscience High 29915530
2019 Glycine-binding site structural features in both GluN1 and GluN3A subunits regulate forward trafficking and surface delivery of GluN3A-containing NMDARs; a clinically relevant mutation in the human GluN3A glycine-binding site significantly reduces NMDAR surface delivery. Mutagenesis of glycine-binding site residues, surface delivery assays in mammalian cell lines and primary rat hippocampal neurons, electrophysiology Scientific Reports High 31444392
2014 GluN1/GluN3A receptors are activated by glycine or d-serine but not glutamate; agonist binding causes a ~1 nm reduction in height of the extracellular domain as measured by AFM imaging; GluN1 and GluN3A subunits interact intimately within transfected cells. Atomic force microscopy (AFM) imaging of isolated GluN1/GluN3A receptors in lipid bilayers, co-expression in tsA201 cells Biochemical and Biophysical Research Communications Medium 25017909
2012 Triheteromeric NMDARs containing GluN2 and GluN3A subunits exist at layer 1 cortical inputs onto L5 pyramidal neurons in somatosensory cortex; these receptors show threshold-like activation at hyperpolarized potentials with strong outward rectification, are activated by glutamate (unlike diheteromeric GluN1/GluN3), are Ca2+-permeable, and are pharmacologically distinct from GluN1/GluN2 and GluN1/GluN3 receptors. Ex vivo patch-clamp electrophysiology, pharmacological characterization in acute brain slices Neuroscience Medium 22814002
2012 GluN3A subunit inclusion in NMDARs reduces Mg2+ and memantine sensitivity (IC50 for Mg2+ block increased from 4.2 to 22.4 µM; for memantine from 2.5 to 7.5 µM); mutations at N and N+1 channel pore sites of GluN3A partially restore blocking activity, indicating that GluN3A alters channel pore properties at and beyond the deep pore region. Two-electrode voltage clamp in Xenopus oocytes expressing defined NMDAR subunit combinations, site-directed pore mutagenesis European Journal of Pharmacology High 22564863
2013 Mild GluN3A overexpression protects striatal neurons from 3-nitropropionic acid excitotoxic lesions; neuroprotection correlates with 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, neurotoxin lesion model, Western blot for calpain substrates (fodrin, STEP), immunohistochemistry Neurobiology of Disease Medium 22801082
2016 In the YAC128 HD mouse model, GluN3A reactivation enhances both AMPAR- and NMDAR-mediated synaptic responses in striatal spiny projection neurons; suppressing GluN3A prevents this synaptic transmission phenotype; GluN3A mediates a lower threshold for NMDA spikes (electrogenic upstate events), which is restored by GluN3A suppression or memantine; NMDA spikes rather than glutamate spillover account for previously attributed extrasynaptic NMDAR activation. Ex vivo patch-clamp electrophysiology in YAC128 and GluN3A-suppressed HD mouse slices, pharmacology Neurobiology of Disease Medium 27072890
2019 Mouse hippocampal glutamatergic nerve endings (synaptosomes) express presynaptic release-regulating NMDARs containing GluN3A subunits; anti-GluN3A antibody prevents NMDA/glycine-evoked glutamate release; incubation with anti-GluN subunit antibodies causes internalization of NMDARs and reduction of GluN1 and GluN2B in synaptosomal plasma membranes. Confocal microscopy of synaptosomes, [3H]D-aspartate release assay, biotinylation surface analysis, pharmacology Molecular Neurobiology Medium 30734226
2023 Surface GluN3A-NMDARs form a highly diffusive receptor pool loosely anchored to synapses; changes in GluN3A expression selectively alter surface diffusion and synaptic anchoring of GluN2A- (but not GluN2B-) NMDARs, possibly through altered interactions with cell surface receptors; these effects are restricted to an early postnatal developmental time window. Single-molecule imaging (single-particle tracking), confocal imaging, biochemistry, electrophysiology in developing rodent neurons Cell Reports High 37149869
2024 GluN3A subunits are enriched in adult ventral hippocampus (VH) at both synaptic and extrasynaptic sites and assemble as functional excitatory glycine receptors (eGlyRs) on CA1 pyramidal cells; GluN3A deletion accelerates NMDAR current decay and reduces ifenprodil sensitivity in VH, indicating GluN3A regulates GluN2B content of conventional NMDARs; GluN3A KO enhances NMDAR-dependent Ca2+ influx and LTP in VH. Patch-clamp electrophysiology, pharmacology (ifenprodil), Ca2+ imaging, GluN3A KO mice, adult hippocampal slices Journal of Neuroscience High 39256046
2025 Cryo-EM structure of purified GluN1-GluN2A-GluN3A triheteromeric NMDARs was determined; these receptors can be activated by co-binding of glycine and glutamate and exhibit two distinct conductance levels in proteoliposome single-channel recordings; photo-crosslinking confirms direct GluN3A-GluN2A and GluN3A-GluN2B subunit interactions in vitro and in vivo. Cryo-EM structural determination, two-step affinity-tag chromatography purification, proteoliposome single-channel recording, photo-crosslinker (AzF) click-chemistry crosslinking bioRxivpreprint High bio_10.1101_2025.08.25.672209
2025 UCM-A86 is a GluN3-selective positive allosteric modulator (PAM) that potentiates GluN1/GluN3A receptors (EC50 ~21 µM) by increasing open probability without affecting mean channel conductance; it has no activity at GluN1/GluN2A-D receptors and selectively potentiates native GluN1/GluN3A responses in SST interneurons of somatosensory cortex. Whole-cell and single-channel patch-clamp electrophysiology in recombinant HEK cells and native cortical interneurons, pharmacological characterization bioRxivpreprint High bio_10.1101_2025.11.14.688378
2025 GluN1/GluN3A excitatory glycine receptors (eGlyRs) are expressed in hippocampal somatostatin interneurons (Sst-INs) and neurogliaform interneurons (NGFCs) from early postnatal through adult ages; in the developing hippocampus, eGlyR-mediated excitation of NGFCs dramatically increases GABAergic tone affecting giant depolarizing potentials; in the 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, pharmacology, GluN3A KO mice, in vivo recordings, non-human primate brain slices bioRxivpreprint High 41473287
2026 Two novel negative allosteric modulators (EU1180-560 and EU1180-590) selectively inhibit GluN1/GluN3A over GluN1/GluN3B receptors (IC50 ~2.6 and 3.7 µM respectively) via noncompetitive, voltage-independent allosteric inhibition with no effect on GluN1/GluN2 NMDARs, AMPA, GABA, glycine, P2X, or kainate receptors. Whole-cell patch-clamp electrophysiology in recombinant expression systems, voltage-dependence analysis, cross-receptor selectivity profiling Molecular Pharmacology High 41713186

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 104 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.) 81 31601771
2018 Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nature communications 80 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 54 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
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
2022 GluN3A excitatory glycine receptors control adult cortical and amygdalar circuits. Neuron 44 35700736
2012 A population-specific uncommon variant in GRIN3A associated with schizophrenia. Biological psychiatry 43 23237318
2014 GluN3A promotes dendritic spine pruning and destabilization during postnatal development. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 25009255
2023 Excitatory GluN1/GluN3A glycine receptors (eGlyRs) in brain signaling. Trends in neurosciences 38 37248111
2013 Glutamatergic receptors at developing synapses: the role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors. European journal of pharmacology 35 23872415
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 35 24297929
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 GluN3A NMDA receptor subunits: more enigmatic than ever? The Journal of physiology 31 33942912
2021 Temporal Dynamics and Neuronal Specificity of Grin3a Expression in the Mouse Forebrain. Cerebral cortex (New York, N.Y. : 1991) 30 33290502
2012 The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation. Neurobiology of disease 27 22801082
2016 Protons Potentiate GluN1/GluN3A Currents by Attenuating Their Desensitisation. Scientific reports 26 27000430
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
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
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
2018 Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit. Experimental neurology 24 29554474
2016 GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models. Neurobiology of disease 24 27072890
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
2018 N-Glycosylation Regulates the Trafficking and Surface Mobility of GluN3A-Containing NMDA Receptors. Frontiers in molecular neuroscience 19 29915530
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
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
2012 Open-channel blockade is less effective on GluN3B than GluN3A subunit-containing NMDA receptors. European journal of pharmacology 15 22564863
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
2016 The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors. Neuropharmacology 12 26777280
2017 Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N-methyl-d-aspartate receptors. Neuropharmacology 11 28365212
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
2025 AI-enhanced virtual screening approach to hit identification for GluN1/GluN3A NMDA receptor. Acta pharmacologica Sinica 4 40858884
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
2024 Hippocampal tau-induced GRIN3A deficiency in Alzheimer's disease. FEBS open bio 3 39396906
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 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 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 1 41255364
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 A subunit-selective negative allosteric modulator of GluN1/GluN3A glycine-activated receptor. Molecular pharmacology 0 41713186
2025 Discrete interneuron subsets participate in GluN1/GluN3A excitatory glycine receptor (eGlyR)-mediated regulation of hippocampal network activity throughout development and evolution. Research square 0 41472680
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