Affinage

GRIA3

Glutamate receptor 3 · UniProt P42263

Length
894 aa
Mass
101.2 kDa
Annotated
2026-06-10
61 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

GRIA3 encodes GluA3, an AMPA-type glutamate receptor subunit that mediates fast excitatory synaptic transmission and assembles into both Ca2+-permeable homomers and GluA2/3 heteromers at central and sensory synapses (PMID:28762944, PMID:28397107). Its extracellular architecture is distinctive: cryo-EM of Ca2+-permeable GluA3 homomers reveals tightly coupled NTD and LBD tiers stabilized by an Arg163 stacking interaction whose rupture remodels the extracellular region and increases heteromer trafficking to synapses, defining a mammalian-specific trafficking checkpoint (PMID:40592473), while the NTD adopts a uniquely flexible set of conformations (PMID:30528594). GluA3 homomers traffic poorly because Tyr-454/Arg-461 in the LBD drive nonproductive assembly and aggregation, a defect rescued by co-assembly with GluA2 (PMID:26912664). Functionally, GluA2/3 receptors rest in a low-conductance state and convert to high conductance through cAMP/PKA/Ras and Epac signaling, generating a gating-based form of potentiation that underlies hippocampal and cerebellar parallel-fiber LTP and vestibulo-ocular reflex adaptation independently of GluA1 trafficking (PMID:28762944, PMID:28103481). At auditory nerve-bushy cell synapses GluA3 organizes central AMPAR clustering, promotes fast-desensitizing flop-containing receptors that confer ultrafast, rate-invariant kinetics, and is required for normal presynaptic function and auditory processing (PMID:28397107, PMID:32051325, PMID:28011083). GluA3 surface delivery and stability are controlled by interacting proteins: ABHD6 binds the GluA C-terminus to suppress membrane delivery and currents (PMID:28303090), and α2δ-1 drives K861 ubiquitination and proteasomal degradation of GluA3 to shift spinal AMPAR composition toward Ca2+-permeable homomers during neuropathic pain (PMID:41129242). In disease, Aβ oligomers trigger PDZ-motif-dependent endocytosis and endolysosomal degradation of GluA3, and GluA3 is required for Aβ-driven synaptic depression and spine loss (PMID:27708157, PMID:39779375). Distinct gain-of-function and loss-of-function GRIA3 variants alter channel gating and surface expression and cause genetically defined neurodevelopmental encephalopathies with divergent clinical features (PMID:38038360, PMID:34161333, PMID:32369665), and anti-GluA3 autoantibodies delocalize the receptor from synapses, contributing to glutamatergic dysfunction in frontotemporal dementia (PMID:28751743, PMID:31784278).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2010 High

    Establishing the intrinsic single-channel behavior of GluA3 was needed to define how this subunit gates; recordings showed homomeric GluA3 opens to three conductance levels with agonist-dependent open probabilities, framing the receptor as a multi-state channel.

    Evidence Single-channel patch-clamp of homomeric GluA3 with agonist series and kinetic modeling

    PMID:20816055

    Open questions at the time
    • Did not address heteromeric GluA2/3 gating
    • No link to modulation by intracellular signaling
  2. 2010 High

    To understand subtype- and isoform-selective pharmacology, crystallography of the GluA3 LBD with the modulator PEPA revealed that flop selectivity arises from bidentate hydrogen bonding at N754, mapping a druggable allosteric surface.

    Evidence X-ray crystallography of GluA2 and GluA3 flop LBD-PEPA complexes

    PMID:20199107

    Open questions at the time
    • Static LBD-only structures lack full-receptor context
    • Functional consequences in native synapses not tested
  3. 2010 Medium

    A non-neuronal role was probed by placing GRIA3 in a cancer pathway; it was identified as a CUX1 transcriptional target whose knockdown reduces pancreatic tumor cell proliferation and xenograft growth.

    Evidence RNAi/overexpression, xenograft model, AMPAR antagonist treatment in pancreatic cancer cells

    PMID:20689760

    Open questions at the time
    • Mechanism by which AMPAR signaling drives proliferation unclear
    • Single-context finding outside neural biology
  4. 2016 High

    The longstanding question of why GluA3 homomers express poorly at the surface was resolved by identifying LBD residues Tyr-454 and Arg-461 that drive nonproductive assembly and aggregation, with GluA2 co-assembly rescuing trafficking.

    Evidence Biochemical fractionation, surface expression assays, and LBD mutagenesis

    PMID:26912664

    Open questions at the time
    • Did not resolve the structural basis of the aggregation-prone conformation
    • Cellular chaperone/QC machinery not identified
  5. 2016 High

    Whether GluA3 is required for amyloid-driven synaptic damage was tested genetically; GluA3-deficient neurons and mice were resistant to Aβ-mediated synaptic depression, spine loss, and memory impairment, placing GluA3 downstream of Aβ pathology.

    Evidence GluA3 KO crossed with Aβ-overproducing mice; electrophysiology, spine imaging, behavior

    PMID:27708157

    Open questions at the time
    • Molecular route of Aβ-to-GluA3 coupling not yet defined
    • Did not distinguish homomeric vs heteromeric GluA3
  6. 2017 High

    How basal GluA2/3 receptors contribute to plasticity was clarified by showing they sit in a low-conductance state and switch to high conductance via cAMP/PKA/Ras, defining a gating-based, non-trafficking form of potentiation.

    Evidence Hippocampal electrophysiology, cAMP/PKA/Ras pharmacology, GluA3 KO

    PMID:28762944

    Open questions at the time
    • Molecular target of PKA/Ras on the receptor not mapped
    • Physiological triggers in vivo not fully defined
  7. 2017 High

    Cerebellar LTP and motor learning were shown to depend on GluA3, not GluA1, via Epac/cAMP-driven changes in open-channel probability, establishing a subunit-specific plasticity mechanism distinct from receptor insertion.

    Evidence GluA1 and GluA3 KO mice, electrophysiology, VOR behavior, cAMP/Epac pharmacology

    PMID:28103481

    Open questions at the time
    • Direct demonstration of conductance switch at PF-PC synapse incomplete
    • Epac downstream effectors on GluA3 unknown
  8. 2017 Medium

    Negative regulators of GluA3 surface delivery were identified; ABHD6 binds GluA C-termini directly and suppresses membrane delivery and currents, with C-terminal deletion abolishing both binding and inhibition.

    Evidence HEK293T expression, electrophysiology, surface biotinylation, pull-down with deletion constructs

    PMID:28303090

    Open questions at the time
    • Native neuronal stoichiometry of ABHD6-GluA3 not established
    • Reciprocal in vivo validation limited
  9. 2017 High

    At auditory synapses GluA3 was assigned a structural organizing role; it concentrates AMPARs at the center of AN-bushy cell synapses, and its loss randomizes intrasynaptic distribution.

    Evidence Quantitative freeze-fracture replica immunogold labeling in WT and GluA3 KO mice

    PMID:28397107

    Open questions at the time
    • Molecular interactions driving central clustering not identified
    • Link to physiological signaling speed not addressed here
  10. 2017 Medium

    The first evidence that anti-GluA3 autoimmunity is synaptotoxic came from patient CSF reducing GluA3 synaptic localization and causing spine loss with increased Tau, linking GluA3 dysfunction to FTD.

    Evidence Rat hippocampal and hiPSC-derived neurons treated with patient CSF; immunofluorescence and spine counting

    PMID:28751743

    Open questions at the time
    • Antibody epitope and binding mode not defined
    • Causal contribution to human disease not established
  11. 2016 Medium

    GluA3 was shown to be required for normal auditory processing and experience-dependent plasticity, with KO causing reduced postsynaptic densities and impaired ABR recovery after earplugging.

    Evidence ABR and electron microscopy in WT vs GluA3 KO mice with monaural earplugging

    PMID:28011083

    Open questions at the time
    • Mechanism connecting GluA3 loss to PSD reduction unclear
    • Activity-dependent regulation only partly characterized
  12. 2011 Medium

    Activity-dependent control of GluA3-containing receptor composition at auditory synapses was demonstrated by increased GluA2/3 labeling after conductive hearing loss, implicating GluA3 in homeostatic plasticity.

    Evidence Monaural earplugging in rats with quantitative subunit-specific immunohistochemistry

    PMID:22044924

    Open questions at the time
    • Signaling driving subunit switching not identified
    • Functional consequence at single-synapse level not measured
  13. 2017 High

    The first GRIA3 disease variant mechanism was defined; pore mutation A653T stabilizes a closed channel and produces altered sleep/activity in knock-in mice, linking GluA3 gating to circadian and arousal phenotypes.

    Evidence In vitro electrophysiology of A653T plus CRISPR knock-in mouse actigraphy

    PMID:29016847

    Open questions at the time
    • Circuit basis of sleep phenotype not mapped
    • Single-variant scope
  14. 2020 Medium

    A loss-of-function disease mechanism was established for the TM4 variant G826D, which reduces agonist responses and surface expression, broadening the variant spectrum.

    Evidence Two-electrode voltage clamp in oocytes and β-lactamase surface reporter in HEK293

    PMID:32369665

    Open questions at the time
    • No in vivo model of this variant
    • Synaptic consequences not tested
  15. 2021 High

    Gain-of-function variant biology was demonstrated; R660T slows desensitization/deactivation in homomers and heteromers and slows neuronal EPSCs, showing how GOF prolongs glutamatergic signaling.

    Evidence Voltage clamp in oocytes, patch clamp in HEK and neurons, in utero electroporation

    PMID:34161333

    Open questions at the time
    • Behavioral consequence in a mammalian model untested
    • Structural basis of kinetic slowing not resolved
  16. 2022 High

    Complete loss-of-function variants were tied to a circuit-level behavioral phenotype; G630R and E787G abolish channel function, and mPFC GluA3 re-expression rescues aggression in KO mice.

    Evidence Patch-clamp of mutants, GluA3 KO with AAV mPFC rescue, aggression assays

    PMID:35697757

    Open questions at the time
    • Human causality limited to small patient cohort
    • mPFC circuit mechanism only partly defined
  17. 2022 Medium

    A partial gain-of-function variant A615V was characterized with kinetic slowing and a Drosophila epistasis model, and clinical seizure/hypertonia response to carbamazepine connected GOF to presynaptic glutamate release.

    Evidence Patch-clamp of mutants, Drosophila genetic epistasis, clinical pharmacology

    PMID:35031858

    Open questions at the time
    • Limited replication of Drosophila result
    • Mammalian validation absent
  18. 2022 Medium

    The GluA3 native interactome was resolved using KO-controlled proteomics, showing GluA2/3 receptors preferentially associate with CNIH-2, TARP-γ2, and Noelin1, distinguishing them from GluA1/2 complexes.

    Evidence Affinity purification mass spectrometry from Gria1/Gria3 KO hippocampi with co-IP validation

    PMID:36429079

    Open questions at the time
    • Functional role of each interactor on GluA3 not dissected
    • Single-lab interactome
  19. 2023 High

    Systematic functional classification of NDD variants established two mechanistic disease classes; 31 of 43 variants altered function as LOF or GOF, and each class mapped onto distinct clinical phenotypes.

    Evidence Electrophysiology of 44 variants in heterologous cells with clinical correlation across patients

    PMID:38038360

    Open questions at the time
    • In vivo phenotype-genotype mechanism not modeled for most variants
    • Heteromeric context not always tested
  20. 2019 Medium

    Anti-GluA3 autoantibodies were linked to functional glutamatergic deficits in FTD, decreasing glutamate release and altering GluA3 and scaffolding protein levels in patient brain with TMS confirmation.

    Evidence Neurochemistry of FTLD-tau brain specimens, TMS, CSF glutamate/serine measurement

    PMID:31784278

    Open questions at the time
    • Causal versus correlative role of autoantibodies unresolved
    • Antibody epitope not mapped
  21. 2025 High

    The structural basis of GluA3 trafficking control was defined by cryo-EM showing tightly coupled NTD-LBD tiers and an Arg163 stack whose rupture increases synaptic heteromer trafficking, identifying a mammalian-specific checkpoint.

    Evidence Cryo-EM across gating states with mutagenesis and trafficking assays

    PMID:40592473

    Open questions at the time
    • Signaling that engages this checkpoint in vivo unknown
    • Link to disease variants not directly tested
  22. 2025 High

    The molecular route of Aβ-driven GluA3 loss was pinned to the PDZ-binding motif; Aβ triggers endocytosis and endolysosomal degradation of GluA3, and a single PDZ-motif mutation renders synapses Aβ-resistant.

    Evidence Imaging endocytosis, PDZ-motif mutagenesis, electrophysiology, APP/PS1 synaptosome proteomics

    PMID:39779375

    Open questions at the time
    • PDZ partner mediating degradation not identified
    • Therapeutic targeting in vivo not demonstrated
  23. 2025 High

    A degradation pathway controlling spinal AMPAR composition in pain was defined; α2δ-1 drives K861 ubiquitination and proteasomal degradation of GluA3, and intrathecal Gria3 delivery reverses nerve-injury hypersensitivity.

    Evidence Co-expression, proteasome inhibition, K861 mutagenesis, nerve-injury model with Gria3 gene therapy

    PMID:41129242

    Open questions at the time
    • E3 ligase acting on K861 not identified
    • Generalizability beyond spinal cord untested
  24. 2025 Medium

    Chronic anti-GluA3 IgG exposure was shown to delocalize GluA3 extrasynaptically and remodel dendrites with enhanced NMDA Ca2+ currents and elevated phospho-CREB, detailing downstream synaptic consequences of GluA3 autoimmunity.

    Evidence Primary rat hippocampal neurons with immunofluorescence, dendritic morphology, Ca2+ imaging, phospho-CREB staining

    PMID:39954743

    Open questions at the time
    • In vivo relevance to human FTD not established
    • Antibody mechanism of delocalization not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally defined Arg163 trafficking checkpoint, signaling-driven conductance switching, and the degradation pathways (PDZ-motif/endolysosomal, ABHD6, α2δ-1/K861) are integrated in vivo to set GluA3 abundance, composition, and conductance state across synapse types remains unresolved.
  • No unified model linking structural checkpoint to disease variant classes
  • E3 ligases and PDZ partners mediating GluA3 degradation unidentified
  • In vivo coupling of conductance-state switching to specific signaling inputs incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0005198 structural molecule activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2
Partners
ABHD6CACNA2D1CACNG2CNIH2GRIA2OLFM1
Complex memberships
AMPA receptor (GluA2/3 heteromer)GluA3 homomer

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2025 Cryo-EM structures of Ca2+-permeable GluA3 homomers reveal a unique architecture where the N-terminal domain (NTD) and ligand-binding domain (LBD) tiers are closely coupled throughout gating states. A stacking interaction between two Arg163 residues in the NTD dimer interface traps a unique NTD dimer conformation enabling close NTD-LBD contacts. Rupture of the Arg163 stack alters extracellular region structure/dynamics and increases GluA3 heteromer trafficking to synapses. A mammalian-specific GluA3 trafficking checkpoint determines LBD tier conformational stability. Cryo-electron microscopy with functional validation (mutagenesis, trafficking assays) Nature High 40592473
2017 GluA2/3-containing AMPARs are in a low-conductance state under basal conditions and contribute little to synaptic currents despite being present at synapses. When intracellular cAMP levels rise (e.g., via β-adrenergic receptor activation), GluA2/3 channels shift to a high-conductance state, producing synaptic potentiation. This cAMP-driven potentiation requires both PKA and the GTPase Ras activation. Electrophysiology in mouse hippocampal neurons (CA1), pharmacological manipulation of cAMP/PKA/Ras pathways, GluA3 knockout comparison eLife High 28762944
2017 Cerebellar LTP at the parallel-fiber-to-Purkinje-cell synapse and vestibulo-ocular reflex adaptation depend on GluA3-containing AMPARs, not GluA1-containing AMPARs. This LTP does not require GluA1 AMPAR trafficking but instead requires changes in open-channel probability of GluA3-AMPARs mediated by cAMP signaling and Epac activation. GluA3 and GluA1 knockout mice, electrophysiology, VOR behavioral assay, pharmacological cAMP/Epac manipulation Neuron High 28103481
2016 Aβ oligomer-mediated synaptic depression, spine loss, and blockade of LTP all require the presence of GluA3-containing AMPARs. Hippocampal neurons lacking GluA3 are resistant to Aβ-mediated synaptic depression and spine loss. Aβ-overproducing mice show memory impairment that is absent in GluA3-deficient congenics. GluA3 knockout mice crossed with Aβ-overproducing AD mouse model; electrophysiology, spine imaging, behavioral memory tests Proceedings of the National Academy of Sciences of the United States of America High 27708157
2025 Aβ oligomers trigger endocytosis of GluA3-containing AMPARs and promote their translocation to endolysosomal compartments for degradation. These effects critically depend on the PDZ-binding motif of GluA3; a single point mutation in the GluA3 PDZ-binding motif prevents Aβ-driven endocytosis and renders synapses fully resistant to Aβ. Proteomics of APP/PS1 transgenic mouse synaptosomes confirmed selective early reduction of GluA3. Electrophysiology, AMPAR imaging, site-directed mutagenesis of PDZ-binding motif, live-cell endocytosis assays, synaptosome proteomics from APP/PS1 mice The Journal of neuroscience High 39779375
2010 Single-channel analysis of homomeric GluA3 receptors shows activation by glutamate and the partial agonist fluorowillardiine to the same three open conductance levels but with different open probabilities. Five modes of channel activity were identified, analyzable with a kinetic model of three closed states and two open states per conductance level. Single-channel electrophysiology (patch clamp) with agonist concentration series and X-means algorithm sorting Biophysical journal High 20816055
2010 Crystal structures of the flop-selective allosteric modulator PEPA bound to the ligand-binding domains of GluA2 and GluA3 flop isoforms reveal that flop selectivity is conferred by bidentate hydrogen bonding between PEPA and N754 (asparagine in flop; serine in flip). Five subsites on the binding surface contribute to stoichiometry, orientation, and functional outcome of modulator binding. X-ray crystallography of GluA2 and GluA3 LBD-PEPA complexes Biochemistry High 20199107
2018 Druggability simulations identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), arising from its unique conformational flexibility. Crystal structures of GluA3 NTD were trapped in vastly different conformational states, revealing pharmacophoric features not present in other AMPAR subunits. Molecular dynamics druggability simulations plus X-ray crystallography of GluA3 NTD in multiple conformations Structure High 30528594
2016 Poor surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation, driven by residues Tyr-454 and Arg-461 in the ligand-binding domain. Co-assembly with GluA2 (but not stargazin) rescues surface expression. GluA3 homomers show a Tyr-454/Arg-461-dependent tendency to aggregate detectable by detergent solubility and density-gradient centrifugation. Biochemical fractionation (nonionic detergent solubility, density gradient centrifugation, native gel electrophoresis), surface expression assays, site-directed mutagenesis of LBD residues The Journal of biological chemistry High 26912664
2017 ABHD6 suppresses membrane delivery and glutamate-induced currents of GluA2- and GluA3-containing AMPA receptors. Pull-down experiments show ABHD6 binds directly to GluA1-3 via their C-terminal domains; deletion of the GluA C-terminus abolishes both ABHD6 binding and its inhibitory effects on surface expression and currents. HEK293T overexpression, electrophysiology, surface biotinylation assays, pull-down (ABHD6 binding to GluA C-termini), C-terminal deletion constructs Frontiers in molecular neuroscience Medium 28303090
2022 Interaction proteomics on hippocampi from wildtype vs. Gria3 knockout mice shows that GluA2/3-containing AMPARs preferentially co-purify CNIH-2, TARP-γ2, and Noelin1 (Olfactomedin-1), whereas GluA1/2 receptors preferentially co-purify TARP-γ8, SynDIG4, and CNIH-2. TARP-γ8 and SynDIG4 interact directly and co-assemble into an AMPAR subcomplex at synaptic sites. Affinity purification mass spectrometry (interaction proteomics) from Gria1- or Gria3-KO mouse hippocampi; co-immunoprecipitation and fractionation for TARP-γ8/SynDIG4 interaction Cells Medium 36429079
2017 In cochlear nucleus, GluA3 subunits are concentrated at the center of auditory nerve-bushy cell (AN-BC) synapses at higher density than GluA4, whereas GluA4 is more abundant at AN-fusiform cell synapses. In GluA3-knockout mice, the central intrasynaptic distribution of AMPARs is lost and gold particles distribute evenly, demonstrating GluA3 specifically organizes the central clustering of AMPARs at AN-BC synapses. Quantitative freeze-fracture replica immunogold labeling (FRIL) of cochlear nucleus synapses in wildtype and GluA3-KO mice Brain structure & function High 28397107
2020 GluA3 determines the ultrafast kinetics of endbulb-bushy cell synapse glutamatergic currents by promoting insertion of postsynaptic AMPARs containing fast-desensitizing flop subunits. GluA3 is also required for normal presynaptic terminal function, structure, and development: GluA3 KO mice show altered short-term depression, increased vesicle release probability, impaired vesicle replenishment, and reduced readily-releasable pool. GluA3 makes the speed of synaptic depression rate-invariant. Patch-clamp electrophysiology at endbulb synapses in wildtype vs. GluA3 KO mice, electron microscopy of presynaptic terminals The Journal of neuroscience High 32051325
2016 Deletion of GluA3 leads to impaired auditory signaling (decreased ABR peak amplitudes, increased peak 2 latency, early hearing loss), reduced number and size of postsynaptic densities at AN-BC synapses, and hampered ABR threshold recovery after transient ear plugging, demonstrating GluA3 is required for normal auditory processing and experience-dependent synaptic plasticity. Auditory brainstem responses (ABR) and electron microscopy of AN-BC synapses in wildtype vs. GluA3-KO mice, with transient monaural earplugging paradigm Hearing research Medium 28011083
2017 A missense variant A653T in the GRIA3 ion conduction pore (transmembrane domain) stabilizes the channel in a closed conformation in vitro, opposite to the Lurcher mutation effect. Knock-in of the orthologous mutation in mice by CRISPR-Cas9 causes significantly altered sleep/activity structure with fewer brief bouts and enhanced period lengthening under constant light. In vitro electrophysiology of A653T mutant channels; CRISPR-Cas9 knock-in mouse model with actigraphy/sleep analysis Human molecular genetics High 29016847
2021 A gain-of-function variant R660T in GRIA3 causes slower desensitization and deactivation kinetics with substantial non-desensitized steady-state currents in homomeric GluA3 and in GluA2/GluA3 heteromers expressed in HEK cells. In cultured cerebellar granule neurons and hippocampal CA1 neurons expressing R660T, mEPSCs and evoked EPSCs are significantly slower than wildtype. Two-electrode voltage clamp in Xenopus oocytes, patch clamp in HEK cells and primary neurons, in utero electroporation into hippocampal CA1 neurons PLoS genetics High 34161333
2024 Electrophysiological assays of 43 GRIA3 missense variants found in NDD patients showed 31 alter receptor function: some are loss-of-function (reduced currents) and some are gain-of-function (increased/prolonged currents). GOF variants associate with earlier seizure onset, hypertonia, and movement disorders; LOF variants associate with later seizure onset, hypotonia, and sleep disturbances, establishing distinct NDD phenotypes for each functional class. Electrophysiological assays (patch clamp/voltage clamp) of 44 variants expressed in heterologous cells; clinical correlation across 25 patients Brain High 38038360
2020 The GRIA3 missense variant Gly826Asp (c.2477G>A) in transmembrane domain 4 causes decreased current response to agonists (kainic acid and glutamate) and reduced cell-surface expression, consistent with a loss-of-function mechanism, as shown by two-electrode voltage clamp in Xenopus oocytes and a β-lactamase reporter assay in HEK293 cells. Two-electrode voltage clamp in Xenopus laevis oocytes; β-lactamase reporter assay in HEK293 cells for surface expression Movement disorders Medium 32369665
2022 Two GRIA3 missense variants, G630R and E787G, found in male patients with aggressive behavior, completely abolish GluA3 ion channel function. In GluA3 KO mice, excitatory neurotransmission and neuronal activity in the medial prefrontal cortex (mPFC) are impaired, and viral re-expression of GluA3 in the mPFC alleviates aggressive behavior. Patch-clamp electrophysiology of mutant channels in heterologous cells; GluA3 KO mice with viral rescue (AAV-mediated GluA3 re-expression in mPFC); aggression behavioral assays Molecular psychiatry High 35697757
2022 A gain-of-function GRIA3 variant (p.Ala615Val) causes slower desensitization and deactivation kinetics in patch-clamp recordings. In a Drosophila model, expression of a double mutant (Ala615Val + Lurcher, which makes channels leaky) caused developmental defects, while either single variant alone did not, confirming partial GOF. The patient's seizures and hypertonia were ameliorated by carbamazepine, which inhibits glutamate release from presynapses. Patch-clamp recordings of mutant GluA3 in heterologous cells; Drosophila genetic model with epistasis; clinical pharmacological intervention Human genetics Medium 35031858
2025 α2δ-1 (but not α2δ-2 or α2δ-3) co-expression diminishes GluA3 AMPAR currents and protein levels via ubiquitin-proteasome-mediated degradation. K861 at the GluA3 C-terminus is identified as a key ubiquitination site. Nerve injury increases GluA3 ubiquitination and reduces GluA3 and GluA2/GluA3 heteromer levels in spinal cord. Intrathecal Gria3 gene delivery reverses nerve injury-induced nociceptive hypersensitivity and restores GluA2/GluA3 heteromers. Co-expression in heterologous cells, proteasome inhibition, ubiquitination assays, site-directed mutagenesis of K861, nerve injury mouse model with intrathecal Gria3 gene delivery, electrophysiology The Journal of clinical investigation High 41129242
2010 GRIA3 is a downstream transcriptional target of CUX1 in pancreatic cancer cells. Knockdown of GRIA3 reduces proliferation and migration and enhances apoptosis; overexpression has the opposite effects. GRIA3 knockdown reduces xenograft tumor growth in vivo. AMPAR antagonists (GYKI52466, SYM2206) decrease pancreatic cancer cell survival. RNAi loss-of-function screen, GRIA3 overexpression/knockdown in vitro, xenograft mouse model, AMPAR antagonist treatment Neoplasia Medium 20689760
2019 Anti-GluA3 autoantibodies in FTD patients decrease glutamate release and alter levels of GluA3-containing AMPAR, accompanied by changes in scaffolding proteins involved in receptor synaptic retention/internalization, as shown in FTD patient brain specimens and confirmed by TMS measures of glutamatergic neurotransmission. Molecular/neurochemical analyses on patient brain specimens (FTLD-tau neuropathology); transcranial magnetic stimulation; CSF glutamate/serine measurements Neurobiology of aging Medium 31784278
2017 CSF containing anti-GluA3 antibodies from FTD patients decreases GluA3 subunit synaptic localization of AMPARs and causes loss of dendritic spines in rat hippocampal primary cultures and hiPSC-derived neurons. Reduced GluA3 in the postsynaptic fraction is accompanied by increased neuronal Tau levels. Rat hippocampal primary neuronal cultures and hiPSC-derived neurons incubated with patient CSF; immunofluorescence for GluA3 synaptic localization; dendritic spine counting Scientific reports Medium 28751743
2025 Long-term exposure to human anti-GluA3 IgGs causes delocalization of GluA3-containing AMPARs to extrasynaptic sites, dendritic arbor reorganization, increased dendritic spine number with altered morphology, enhancement of NMDA receptor-mediated postsynaptic Ca2+ currents, and increased nuclear phospho-CREB levels in primary rat hippocampal neurons. Primary rat hippocampal neurons, immunofluorescence for GluA3 localization, dendritic morphology analysis, Ca2+ imaging, phospho-CREB immunostaining Neurobiology of disease Medium 39954743
2011 After 7 days of monaural conductive hearing loss (earplugging), immunolabeling for GluA2/3 (but not GluA2 alone) increases on bushy cells and fusiform cells of both ipsilateral and contralateral cochlear nuclei, while GlyRα1 is downregulated in the same cells, indicating activity-dependent regulation of GluA3-containing AMPAR composition at auditory synapses. Monaural earplugging in rats, quantitative immunohistochemistry and biochemistry with subunit-specific antibodies Neuroscience Medium 22044924
2024 Loss-of-function of Gria3 in mice profoundly alters synapse protein composition, and transcriptomic analysis shows activity-regulated genes are downregulated in cortical regions while immune/glia-related pathways show brain-region-specific changes, distinct from Grin2a mutant mice despite both encoding glutamate receptor subunits associated with schizophrenia risk. Gria3 protein-truncating knock-in mouse model; transcriptomics (RNA-seq); synaptosome proteomics bioRxivpreprint Medium
2024 ABHD6 accelerates the deactivation and desensitization of GluA2(R)/GluA3(R) heteromeric receptors in the presence of TARP γ-2 (but not in its absence), as shown by ultra-fast glutamate application and outside-out patch recordings. Ultra-fast agonist application, outside-out patch recordings in HEK cells expressing GluA2/GluA3 heteromers with/without TARP γ-2 and ABHD6; ABHD6-KO neurons bioRxivpreprint Medium

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3. Proceedings of the National Academy of Sciences of the United States of America 113 27708157
2006 Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 16436610
2017 Motor Learning Requires Purkinje Cell Synaptic Potentiation through Activation of AMPA-Receptor Subunit GluA3. Neuron 88 28103481
2017 MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway. Journal of hematology & oncology 77 28629431
1999 Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation. Genomics 74 10644433
2012 GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum. Behavioural brain research 68 22285418
2017 Synaptic plasticity through activation of GluA3-containing AMPA-receptors. eLife 62 28762944
2019 MicroRNA-330-3p promotes brain metastasis and epithelial-mesenchymal transition via GRIA3 in non-small cell lung cancer. Aging 52 31498117
2019 Anti-GluA3 antibodies in frontotemporal dementia: effects on glutamatergic neurotransmission and synaptic failure. Neurobiology of aging 43 31784278
2018 Chaihu-Shugan-San exerts an antidepressive effect by downregulating miR-124 and releasing inhibition of the MAPK14 and Gria3 signaling pathways. Neural regeneration research 40 29863014
2021 Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3. Molecular and cellular biochemistry 39 34652536
2010 Glutamate receptor GRIA3--target of CUX1 and mediator of tumor progression in pancreatic cancer. Neoplasia (New York, N.Y.) 39 20689760
2017 A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability. Human molecular genetics 38 29016847
2012 Evaluation of hypermethylation and expression pattern of GMR2, GMR5, GMR8, and GRIA3 in patients with schizophrenia. Gene 38 23149219
2010 Characterizing single-channel behavior of GluA3 receptors. Biophysical journal 37 20816055
2017 Anti-AMPA GluA3 antibodies in Frontotemporal dementia: a new molecular target. Scientific reports 35 28751743
2010 Common variants in the regulative regions of GRIA1 and GRIA3 receptor genes are associated with migraine susceptibility. BMC medical genetics 35 20579352
2010 Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA. Biochemistry 34 20199107
2009 Aberrant GRIA3 transcripts with multi-exon duplications in a family with X-linked mental retardation. American journal of medical genetics. Part A 34 19449417
2020 GRIA3 missense mutation is cause of an x-linked developmental and epileptic encephalopathy. Seizure 29 32977175
2011 Monaural conductive hearing loss alters the expression of the GluA3 AMPA and glycine receptor α1 subunits in bushy and fusiform cells of the cochlear nucleus. Neuroscience 27 22044924
2008 Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 27 18163426
2017 The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells. Brain structure & function 26 28397107
2007 Partial tandem duplication of GRIA3 in a male with mental retardation. American journal of medical genetics. Part A 26 17568425
2020 Role of GluA3 AMPA Receptor Subunits in the Presynaptic and Postsynaptic Maturation of Synaptic Transmission and Plasticity of Endbulb-Bushy Cell Synapses in the Cochlear Nucleus. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 32051325
2021 GluA3-containing AMPA receptors: From physiology to synaptic dysfunction in brain disorders. Neurobiology of disease 21 34743951
2013 Xq25 duplications encompassing GRIA3 and STAG2 genes in two families convey recognizable X-linked intellectual disability with distinctive facial appearance. American journal of medical genetics. Part A 21 23637084
2024 Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes. Brain : a journal of neurology 20 38038360
2021 X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3. PLoS genetics 20 34161333
2016 Impaired auditory processing and altered structure of the endbulb of Held synapse in mice lacking the GluA3 subunit of AMPA receptors. Hearing research 20 28011083
2022 Expression and Interaction Proteomics of GluA1- and GluA3-Subunit-Containing AMPARs Reveal Distinct Protein Composition. Cells 18 36429079
2022 Dysfunction of AMPA receptor GluA3 is associated with aggressive behavior in human. Molecular psychiatry 17 35697757
2020 The GRIA3 c.2477G > A Variant Causes an Exaggerated Startle Reflex, Chorea, and Multifocal Myoclonus. Movement disorders : official journal of the Movement Disorder Society 17 32369665
2018 Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain. Structure (London, England : 1993) 17 30528594
2017 The Inhibitory Effect of α/β-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors. Frontiers in molecular neuroscience 17 28303090
2013 Association of a GRIA3 gene polymorphism with migraine in an Australian case-control cohort. Headache 17 23772601
2016 Case-control study of GRIA1 and GRIA3 gene variants in migraine. The journal of headache and pain 15 26800698
2011 Shared genetic background for regulation of mood and sleep: association of GRIA3 with sleep duration in healthy Finnish women. Sleep 15 21966062
2011 Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5' of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability. Human mutation 14 22124977
2016 Aggregation Limits Surface Expression of Homomeric GluA3 Receptors. The Journal of biological chemistry 12 26912664
2018 Genetic variation of GRIA3 gene is associated with vulnerability to methamphetamine dependence and its associated psychosis. Journal of psychopharmacology (Oxford, England) 10 29338492
2025 Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors. Nature 7 40592473
2022 The p.Glu787Lys variant in the GRIA3 gene causes developmental and epileptic encephalopathy mimicking structural epilepsy in a female patient. European journal of medical genetics 7 35093607
2021 Myoclonic status epilepticus and cerebellar hypoplasia associated with a novel variant in the GRIA3 gene. Neurogenetics 7 34731330
2020 Retraction Note to: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway. Journal of hematology & oncology 7 33092612
2018 Correction to: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway. Journal of hematology & oncology 7 29316954
2023 The Expression of Epac2 and GluA3 in an Alzheimer's Disease Experimental Model and Postmortem Patient Samples. Biomedicines 6 37626593
2022 Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant. Human genetics 6 35031858
2025 Amyloid-β-Driven Synaptic Deficits Are Mediated by Synaptic Removal of GluA3-Containing AMPA Receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 5 39779375
2023 GRIA3 p.Met661Thr variant in a female with developmental epileptic encephalopathy. Human genome variation 5 36726007
2023 Novel crosstalk mechanisms between GluA3 and Epac2 in synaptic plasticity and memory in Alzheimer's disease. Neurobiology of disease 4 38142840
2017 Learning about Synaptic GluA3. Neuron 3 28103474
2025 Long-term exposure to anti-GluA3 antibodies triggers functional and structural changes in hippocampal neurons. Neurobiology of disease 2 39954743
2025 Mixed functional consequences of the N651D GRIA3 variant: a case of early-onset developmental and epileptic encephalopathy with parkinsonism. Journal of medical genetics 2 40930967
2025 Spinal α2δ-1 induces GluA3 degradation to regulate assembly of calcium-permeable AMPA receptors and pain hypersensitivity. The Journal of clinical investigation 2 41129242
2019 [X-linked mental retardation combined with autism caused by a novel hemizygous mutation of GRIA3 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 31400139
2025 Effects of LMW-GS Allelic Variations at the Glu-A3 Locus on Fresh Wet Noodle and Frozen Cooked Noodle Quality. Foods (Basel, Switzerland) 1 40361628
2020 TRAILR1 (rs20576) and GRIA3 (rs12557782) are not associated with interferon-β response in multiple sclerosis patients. Molecular biology reports 1 33269432
2010 [Analyzing GRIA3 gene mutations located in AUNX1 locus in a Chinese pedigree with auditory neuropathy]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 20564826
2001 [Linkage analysis and mutation detection of GRIA3 in Smith--Fineman--Myers syndrome]. Yi chuan xue bao = Acta genetica Sinica 1 11725645
2025 Non-Convulsive Status Epilepticus and Mild Neurodevelopmental Phenotype in a Female with a Novel p.Thr657Ala Variant in the GRIA3 Gene. Children (Basel, Switzerland) 0 41462794

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