{"gene":"GRIA2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1993,"finding":"RNA editing at the Q/R site of GluR-B pre-mRNA requires a base-paired intron-exon structure: an imperfect inverted repeat in the proximal intron downstream of the unedited codon, containing a 10 nt sequence exactly complementary to the exon centered on the unedited codon, is essential for site-selective adenosine-to-inosine editing. Single nucleotide substitutions in either the intronic or exonic complementary sequences abolished editing, which was rescued by restoring complementarity.","method":"Transfection of GluR-B gene constructs into PC12 cells with targeted single-nucleotide substitutions and complementarity-restoring double mutations","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of both strands of the editing duplex with rescue experiment; foundational mechanism paper replicated by subsequent work","pmids":["8269514"],"is_preprint":false},{"year":1994,"finding":"Differences in Ca2+ permeability of native AMPA-type glutamate receptor channels in neocortical neurons are caused by differential GluR-B subunit expression: pyramidal neurons express high GluR-B mRNA (Ca2+-impermeable receptors) while non-pyramidal neurons express low GluR-B mRNA (Ca2+-permeable receptors), as established by single-cell patch-clamp and single-cell mRNA analysis in brain slices.","method":"Patch-clamp recordings in brain slices combined with single-cell mRNA analysis (GluR-B/non-B ratio quantification)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct electrophysiology combined with single-cell molecular analysis in native tissue, foundational result replicated broadly","pmids":["8011338"],"is_preprint":false},{"year":1995,"finding":"The arginine at the Q/R site of GluR-B (introduced by RNA editing) is essential for rendering AMPA receptors Ca2+-impermeable in principal neurons in vivo. Mice engineered with an editing-incompetent GluR-B allele express unedited GluR-B, show increased AMPA receptor Ca2+ permeability in neurons, develop early-onset seizures, and die by 3 weeks.","method":"Gene targeting in mice (editing-incompetent GluR-B allele), electrophysiology, in vivo phenotypic analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — clean knock-in mouse model with defined molecular lesion, multiple orthogonal functional readouts, foundational in vivo proof","pmids":["7502080"],"is_preprint":false},{"year":1995,"finding":"GluR-B pre-mRNA Q/R and R/G sites are edited in vitro by nuclear extract via site-selective adenosine-to-inosine conversion, as confirmed by thin-layer chromatography of edited RNA sequences, implicating a double-stranded RNA adenosine deaminase (DRADA/ADAR).","method":"In vitro editing assay with HeLa nuclear extract; nucleotide analysis by thin-layer chromatography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro biochemical reconstitution with nucleotide-level product characterization","pmids":["7721757"],"is_preprint":false},{"year":1996,"finding":"Recombinant DRADA (ADAR1/dsRNA adenosine deaminase) edits GLuR-B RNA at the Q/R site in vitro, but requires both a dsRNA structure (exon-intron duplex) and a cofactor protein present even in non-neuronal cells; the accuracy and efficiency of editing depend on the quantitative balance between DRADA, cofactor, and substrate RNA.","method":"In vitro editing assay using recombinantly expressed DRADA protein with purified GLuR-B RNA substrate","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant enzyme; single lab but multiple mechanistic parameters tested","pmids":["8598204"],"is_preprint":false},{"year":1996,"finding":"The ligand-binding domain of GluR-B (S1-S2 fusion) expressed in E. coli binds [3H]AMPA with high affinity (Kd ~12 nM) and with pharmacology typical of native AMPA receptors; N-linked glycosylation is not required for formation or maintenance of the ligand-binding site.","method":"Bacterial expression of S1-S2 fusion protein; radioligand binding assay with [3H]AMPA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of binding domain; single lab, multiple deletion mutants and pharmacological characterization","pmids":["8663017"],"is_preprint":false},{"year":1998,"finding":"The small amount of Q/R site-unedited GluR-B present in postnatal brain is not required for normal brain development or function; mice engineered with an exonic arginine codon at the Q/R site (bypassing RNA editing) show no obvious deficits, demonstrating that AMPA receptor Ca2+ permeability can be solely regulated by the levels of Q/R site-edited GluR-B relative to other AMPAR subunits.","method":"Gene targeting in mice (exonic arginine knock-in); electrophysiology; in vivo phenotypic analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — clean knock-in mouse with defined molecular change, electrophysiology confirming Ca2+ permeability change; single lab","pmids":["9811877"],"is_preprint":false},{"year":1999,"finding":"Graded deficiency in GluR-B Q/R site editing in mice increases AMPA receptor Ca2+ permeability in pyramidal neurons and, at sufficient levels, induces NMDA receptor-independent LTP, epilepsy, and deficits in dendritic architecture. The seizure phenotype correlates with increased macroscopic AMPA receptor conductance rather than Ca2+ influx per se.","method":"Multiple gene-targeted mouse lines with varying GluR-B expression and editing levels; patch-clamp electrophysiology; in vivo phenotypic analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple independent mouse alleles, electrophysiology, in vivo phenotypes; multi-orthogonal design","pmids":["10195181"],"is_preprint":false},{"year":2000,"finding":"ADAR2 binds to the GluR-B R/G editing site RNA at a discrete region surrounding the editing site (as shown by footprinting), and binding affinity to wild-type versus editing-reduced mutant RNA is nearly identical, indicating that ADAR2 specificity is not determined by differential binding affinity but by positioning at the editing site.","method":"In vitro binding assays (gel shift, footprinting) with rat ADAR2 and synthetic GluR-B R/G site RNA substrates","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical characterization with mutant substrates and footprinting; single lab","pmids":["10836790"],"is_preprint":false},{"year":2000,"finding":"ADAR2-catalyzed editing of the GluR-B R/G site requires 5' duplex structure for efficient deamination; five base pairs of duplex 5' to the editing site increase single-turnover rate constant 17–39-fold. ADAR2 flips the reactive adenosine out of the helix prior to deamination, as evidenced by fluorescence enhancement of a 2-aminopurine-substituted substrate.","method":"In vitro deamination kinetics with synthetic substrates; fluorescence spectroscopy with 2-aminopurine analog","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro with kinetic analysis and base-flipping evidence via fluorescence; multiple orthogonal methods","pmids":["11015203"],"is_preprint":false},{"year":2001,"finding":"Purified GluRB homomeric channels are tetramers with molecular dimensions of approximately 11×14×17 nm and an overall 2-fold symmetric (dimer-of-dimers) assembly, as determined by electron microscopy of milligram-scale purified receptor.","method":"Density-gradient centrifugation; electron microscopy; ligand binding assays on purified GluRB homomers","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct structural imaging of purified receptor; single lab but EM and biochemical characterization combined","pmids":["11705385"],"is_preprint":false},{"year":2002,"finding":"ADAR2 functions as a homodimer on GluR-B R/G site RNA; a ternary ADAR2:RNA complex (two ADAR2 monomers) is required for efficient editing, and complex formation is rate-determining. ADAR monomers cross-link to each other in an RNA-dependent manner.","method":"Gel shift assay; RNA-dependent cross-linking; detailed kinetic analysis of editing reaction","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetics and cross-linking; single lab, multiple methods","pmids":["12163487"],"is_preprint":false},{"year":2003,"finding":"The GluR-B(long) splice variant of GluR-B mediates a GluR-A-independent form of glutamatergic synaptic plasticity in the juvenile hippocampus: spontaneous activity drives GluR-B(long) delivery maintaining ~1/3 of steady-state AMPA responses, while LTP induction drives GluR-B(long) delivery accounting for ~50% of potentiation at CA3-CA1 synapses.","method":"Viral overexpression, dominant-negative approaches, and electrophysiology in hippocampal slices; activity manipulation experiments","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean viral delivery with electrophysiological readout; single lab, multiple activity conditions","pmids":["14687553"],"is_preprint":false},{"year":2007,"finding":"The C-terminal domain (CTD) of RNA Pol II coordinates editing and splicing of GluR-B pre-mRNA: the CTD is required for efficient ADAR2 editing at the R/G site by preventing premature splicing that would remove intronic ADAR2 recognition sequences, and it inhibits excision of intron 11 (which contains the Q/R editing complementary sequences), thereby enforcing the order editing-before-splicing.","method":"Cell-based splicing and editing assays with CTD truncation constructs; minigene transfection","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with CTD deletion; single lab, defined mechanistic order","pmids":["17525170"],"is_preprint":false},{"year":2010,"finding":"Crystal structures of the GluA2 ligand-binding domain in complex with agonists, antagonists, and positive allosteric modulators revealed the structural basis for receptor activation and desensitization: agonist binding induces clamshell closure of the S1-S2 domain, and positive allosteric modulators bind at the LBD dimer interface to stabilize the agonist-bound conformation and slow desensitization.","method":"X-ray crystallography of recombinant GluA2 S1S2 LBD; >80 structures reviewed including mutant and ligand-bound forms","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple independent crystal structures with diverse ligands; widely replicated across labs","pmids":["20713069"],"is_preprint":false},{"year":2010,"finding":"GluA2 plasma membrane insertion requires: (1) the NSF-binding site within its intracellular C-terminal domain, and (2) Q/R site RNA editing in the ion channel region. Plasma membrane insertion of heteromeric GluA2/3 receptors follows the same rules as homomeric GluA2 receptors.","method":"pHluorin-tagged GluA2 with TIRF microscopy to visualize individual vesicle fusion events; domain mutants (NSF binding site deletion, Q/R site changes)","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct visualization of fusion events with domain-specific mutants; single lab but two orthogonal structural determinants tested","pmids":["20534470"],"is_preprint":false},{"year":2010,"finding":"Polo-like kinase 2 (Plk2) directly interacts with NSF and disrupts the NSF-GluA2 interaction, promoting loss of surface GluA2 in hippocampal neurons, increased GluA2 association with PICK1 and GRIP1, and decreased synaptic AMPAR current. This mechanism requires Plk2-NSF engagement (via a novel Plk2 motif independent of the polo-box domain) but not Plk2 kinase activity.","method":"Co-immunoprecipitation; dominant-negative and kinase-dead constructs; electrophysiology in rat hippocampal neurons; surface biotinylation","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple mutants, electrophysiology; multiple orthogonal methods establishing direct interaction and functional consequence","pmids":["20802490"],"is_preprint":false},{"year":2011,"finding":"GluA2 undergoes activity-dependent ubiquitination: increasing synaptic activity (bicuculline) or AMPA receptor agonists rapidly induces GluA2 ubiquitination, which requires clathrin- and dynamin-dependent endocytosis of AMPARs (ubiquitination occurs on plasma membrane AMPARs post-endocytosis).","method":"Immunoprecipitation of ubiquitinated proteins; pharmacological blockade of endocytosis; biochemical fractionation in cultured neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple pharmacological tools; single lab, endocytosis requirement established by blockers","pmids":["21414928"],"is_preprint":false},{"year":2011,"finding":"GluA2 regulates mGluR-dependent LTD through its extracellular domain interaction with N-cadherin, which activates Rac1 and cofilin-mediated actin reorganization. This non-ionotropic function of GluA2 is independent of its channel properties and required for mGluR-LTD in the hippocampus.","method":"GluA2 knockout neurons, domain-specific mutants, N-cadherin knockdown, Rac1/cofilin pathway manipulations; LTD recordings in hippocampal slices","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (KO, domain mutants, downstream pathway manipulations) with electrophysiological LTD readout","pmids":["21248105"],"is_preprint":false},{"year":2011,"finding":"GRIP1 variants found in autism patients alter GRIP1-GluA2/3 interaction via PDZ domains 4-6 and cause faster recycling and increased surface distribution of GluA2 in neurons (gain-of-function), whereas GRIP1/2 deficiency produces opposite effects on GluA2 surface levels.","method":"Biochemical interaction assays; surface GluA2 imaging in neurons; GRIP1/2 knockout mice","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction assays plus neuronal surface trafficking; single lab","pmids":["21383172"],"is_preprint":false},{"year":2012,"finding":"β3 integrin directly binds to the cytoplasmic domain of GluA2 (but only weakly to GluA1, and GluA1-β3 association requires GluA2 coexpression), forming a complex in mouse brain; this direct interaction underlies β3 integrin-dependent homeostatic control of synaptic GluA2 levels and synaptic strength.","method":"Co-immunoprecipitation from mouse brain; heterologous co-expression; electrophysiology in hippocampal pyramidal neurons; surface GluA2 measurement","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct pulldown plus Co-IP from brain, functional electrophysiology, and domain specificity established","pmids":["22232691"],"is_preprint":false},{"year":2012,"finding":"S-SCAM/MAGI-2 maintains synaptic GluA2-containing AMPA receptors: increasing S-SCAM increases surface AMPAR levels and synaptic transmission in a GluA2-dependent (not GluA1-dependent), NSF-interaction-sensitive, and activity-independent manner; S-SCAM knockdown causes loss of synaptic AMPARs and spine density reduction.","method":"Overexpression and RNAi knockdown in rat hippocampal neurons; electrophysiology; surface AMPAR imaging","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with electrophysiology; single lab","pmids":["22593065"],"is_preprint":false},{"year":2012,"finding":"PICK1 binding to GluA2 on endosomal compartments restricts GluA2 from trafficking to the synaptic plasma membrane immediately after glycine stimulation (chemical LTP), enabling a transient switch to GluA2-lacking Ca2+-permeable AMPARs at synapses. Activation of CP-AMPARs then triggers release of GluA2 from PICK1, allowing GluA2-containing AMPARs to traffic back to the synaptic surface 5-20 min post-stimulus.","method":"Endogenous protein immunostaining, co-IP for PICK1-GluA2 binding; live-cell imaging; pharmacological blockade of CP-AMPARs in rat hippocampal neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, live imaging, and pharmacological manipulations; single lab","pmids":["22915106"],"is_preprint":false},{"year":2014,"finding":"Cryo-EM and DEER (double electron-electron resonance) structures of intact GluA2 AMPA receptor in apo/resting, activated/pre-open (partial agonist + positive allosteric modulator), and desensitized states revealed how agonist binding modulates LBD layer conformation and how desensitization involves large conformational rearrangements of both amino-terminal and ligand-binding domains.","method":"Cryo-electron microscopy; DEER EPR spectroscopy with cysteine mutants; structure determination in three distinct functional states","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple high-resolution structures in distinct functional states with orthogonal EPR validation; replicated in field","pmids":["25109876"],"is_preprint":false},{"year":2014,"finding":"O-GlcNAcylation of GluA2 is associated with a novel form of LTD at hippocampal synapses: acutely increasing O-GlcNAcylation induces NMDA receptor- and PKC-independent LTD that requires GluA2 subunits, and the GluA2 subunit is directly O-GlcNAcylated.","method":"Pharmacological O-GlcNAc elevation in hippocampal slices; LTD electrophysiology; GluA2 knockout rescue; direct O-GlcNAc immunoprecipitation of GluA2","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical detection of O-GlcNAcylation on GluA2 plus functional LTD requirement; single lab","pmids":["24381264"],"is_preprint":false},{"year":2014,"finding":"GluA2 trafficking from the endoplasmic reticulum to the plasma membrane requires Ca2+ release from internal stores (via IP3 and ryanodine receptors), CaMKII activity, and GluA2 interaction with PICK1 (via the PICK1 BAR domain). Ca2+ release promotes formation of a CaMKII-PICK1 complex that interacts with the GluA2 C-terminal domain to stimulate ER exit.","method":"Pharmacological inhibitors of IP3R and RyR; CaMKII inhibition; PICK1 domain mutants; surface trafficking assays in cultured hippocampal neurons","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and domain-mutant approaches; single lab","pmids":["24831007"],"is_preprint":false},{"year":2014,"finding":"Semaphorin 3A (Sema3A) retrograde signaling at the axonal growth cone drives GluA2 to distal dendrites via GRIP1-dependent localization; PlexinA (PlexA) interacts directly with GluA2 at its IPT domain in somatodendritic regions, and overexpression of PlexA-IPT suppresses GluA2 dendritic localization and induces abnormal proximal bifurcation of apical dendrites in CA1 neurons.","method":"Co-immunoprecipitation (PlexA-GluA2 interaction); knockdown of cytoplasmic dynein; overexpression of PlexA-IPT domain; immunostaining in hippocampal neurons","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP, functional consequence by dominant-negative domain; single lab","pmids":["24599038"],"is_preprint":false},{"year":2014,"finding":"FXR1P binds specifically to the 5' UTR of GluA2 mRNA to repress its translation; removal of FXR1P from mouse forebrain selectively enhances de novo GluA2 synthesis and increases GluA2 incorporation at potentiated synapses, as well as enhancing hippocampal late-phase LTP and long-term spatial memory.","method":"Conditional Fxr1p knockout in mouse forebrain; RNA immunoprecipitation (RIP) for GluA2 mRNA binding; de novo protein synthesis assays; electrophysiology","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct RNA binding demonstrated, conditional KO with multiple orthogonal functional readouts; single lab but comprehensive","pmids":["25456134"],"is_preprint":false},{"year":2015,"finding":"Activity-dependent ubiquitination of GluA2 occurs at Lys-870 and Lys-882 in the C-terminal domain, exclusively on plasma membrane AMPARs post-endocytosis, in a Ca2+- and CaMKII-dependent manner requiring L-type VGCCs. Mutation of these lysines does not affect surface expression or AMPA-induced internalization but reduces trafficking to late endosomes and lysosomal degradation.","method":"Site-directed mutagenesis of GluA2 ubiquitination sites; Ca2+/CaMKII pathway inhibitors; late endosome co-localization; immunoprecipitation in cultured neurons","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of specific ubiquitination sites with multiple functional assays; two labs (Huganir and Anggono)","pmids":["25660027"],"is_preprint":false},{"year":2015,"finding":"RAB39B, a small GTPase mutated in intellectual disability, controls GluA2 surface expression by acting through PICK1 (a downstream effector of GTP-bound RAB39B); RAB39B-PICK1 controls trafficking from the ER to the Golgi and hence surface expression of GluA2. RAB39B downregulation shifts AMPAR composition toward non-GluA2-containing Ca2+-permeable forms in hippocampal neurons.","method":"Co-immunoprecipitation (RAB39B-PICK1); surface GluA2 biochemistry; electrophysiology; RAB39B knockdown in mouse hippocampal neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction demonstrated, ER-to-Golgi trafficking assay, electrophysiology; multiple orthogonal approaches","pmids":["25784538"],"is_preprint":false},{"year":2015,"finding":"N-glycosylation at N370 of GluA2 is required for intracellular trafficking from the ER; the N370S mutation strongly suppresses ER exit of GluA2 and co-expressed GluA1. N-glycan at N413 carries the HNK-1 epitope that promotes GluA2 interaction with N-cadherin and enhances cell surface expression of both GluA2 and GluA1.","method":"N-glycosylation site mutants expressed in HEK293 cells; ER retention assays; co-immunoprecipitation; surface expression quantification","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis with trafficking and interaction assays; single lab","pmids":["26271046"],"is_preprint":false},{"year":2015,"finding":"VAMP2 (synaptobrevin-2)-containing postsynaptic vesicles carry GluA1 but not GluA2 in dendritic spines; VAMP2 disruption by tetanus toxin reduces GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2 vesicles are concentrated in spines relative to dendrites, whereas GluA2/VAMP2 vesicles are not, indicating distinct vesicular trafficking pathways for GluA1 and GluA2.","method":"Electron microscopy of postsynaptic vesicles; tetanus toxin treatment; immunofluorescence colocalization","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct EM visualization and functional blockade; single lab","pmids":["26488171"],"is_preprint":false},{"year":2015,"finding":"GSK-3β phosphorylates PICK1 at Ser416 in its C-terminal region; this phosphorylation is required for PICK1 interaction with GluA2. The Ser416Ala substitution disrupts GluA2-PICK1 interaction and increases PICK1 membrane clustering, whereas Ser416Glu/Asp (phosphomimetic) retains the interaction.","method":"Site-directed mutagenesis; co-immunoprecipitation; imaging of PICK1 clusters in COS-7 cells; GSK-3β kinase assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus Co-IP; single lab","pmids":["26472923"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structure of homomeric GluA2 AMPA receptor saturated with TARP γ2 (stargazin) shows four TARPs arranged with 4-fold symmetry around the ion channel domain, making contacts with M1, M2, and M4 transmembrane helices; two pairs of TARPs are positioned near the LBD dimer and dimer-dimer interfaces to modulate LBD clamshell closure and conformational rearrangements during activation and desensitization.","method":"Cryo-electron microscopy structure determination of GluA2-TARP γ2 complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of full complex; foundational structural result defining TARP-AMPAR architecture","pmids":["27368053"],"is_preprint":false},{"year":2017,"finding":"The C-terminal domains (CTDs) of endogenous GluA1 and GluA2 are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively, in hippocampal CA1 neurons, as demonstrated by knock-in mice with exchanged CTDs. The GluA2 CTD is required for LTD but not LTP.","method":"Three knock-in mouse lines with exchanged endogenous AMPAR CTDs; LTP and LTD electrophysiology; behavioral assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — clean knock-in mouse models with reciprocal CTD exchange; bidirectional electrophysiological and behavioral readouts","pmids":["29230056"],"is_preprint":false},{"year":2017,"finding":"The membrane-proximal carboxy tail of GluA2 is necessary and sufficient for homeostatic synaptic upscaling in hippocampal CA1 pyramidal neurons; a single amino acid in this region is critical for GluA2-dependent AMPAR trafficking during synaptic scaling.","method":"Viral rescue in CA1 neurons with GluA2 domain mutants; whole-cell electrophysiology for synaptic scaling","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping with viral delivery in defined neurons; single lab","pmids":["29180434"],"is_preprint":false},{"year":2018,"finding":"Human autoantibodies against GluA2 induce GluA2-containing AMPAR internalization and reduce synaptic GluA2-containing AMPARs, followed by compensatory ryanodine receptor-dependent incorporation of non-GluA2-containing AMPARs; this disrupts LTP in vitro and impairs learning and memory in vivo.","method":"Electrophysiology, high-resolution imaging in neuronal cultures; passive transfer in wild-type and GluA1 KO mice; ryanodine receptor pharmacology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, electrophysiology, genetic and pharmacological tools) in both in vitro and in vivo models","pmids":["30146304"],"is_preprint":false},{"year":2018,"finding":"In vivo expression of unedited (Ca2+-permeable) or pore-dead GluA2 in oligodendrocyte precursor cells (OPCs) triggers OPC proliferation and reduces differentiation into oligodendrocytes; expression of the GluA2 C-tail alone decreases OPC differentiation without affecting proliferation, demonstrating separable ionotropic and non-ionotropic roles of GluA2 in OPC fate.","method":"In vivo viral expression of GluA2 variants in mouse corpus callosum OPCs; immunohistochemical quantification of OPC proliferation and differentiation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain-of-function with multiple distinct GluA2 constructs; single lab","pmids":["30355492"],"is_preprint":false},{"year":2019,"finding":"De novo heterozygous GRIA2 mutations causing neurodevelopmental disorders produce a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type; when co-expressed with GluA1, most mutations cause decreased current amplitude and some affect voltage rectification, demonstrating loss-of-function as the principal pathogenic mechanism.","method":"Functional expression of mutant GluA2 subunits with electrophysiology in heterologous expression system; co-expression with GluA1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological characterization of 28 independent patient mutations; large cohort with consistent result","pmids":["31300657"],"is_preprint":false},{"year":2019,"finding":"FUS/TLS undergoes calcium-dependent nuclear-to-cytoplasmic translocation during excitotoxic stress in neurons; FUS expression is required for glutamate-induced upregulation of GRIA2 mRNA, placing FUS upstream of GluA2 in the excitotoxic stress response.","method":"Primary cortical and motor neuron imaging; Ca2+ chelation; FUS knockdown; GRIA2 mRNA quantification in response to glutamate","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with mRNA quantification, calcium-dependence established; single lab","pmids":["31092554"],"is_preprint":false},{"year":2020,"finding":"GluA2 phospho-Y876 is essential for homeostatic synaptic upscaling but not for Hebbian LTP/LTD; bidirectional changes in Y876 phosphorylation occur during scaling (decrease during downscaling, increase during upscaling). Phospho-Y876 is required for synaptic accumulation of GRIP1 during upscaling, and increased Y876 phosphorylation enhances GluA2 binding to GRIP1.","method":"GluA2 Y876F phospho-deficient knock-in mice; in vitro and in vivo homeostatic scaling assays; co-immunoprecipitation of GluA2-GRIP1","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knock-in mouse with defined phospho-site; bidirectional plasticity assays; direct binding assay for GRIP1; multiple orthogonal approaches","pmids":["32071234"],"is_preprint":false},{"year":2021,"finding":"RAB39B controls AMPAR trafficking (specifically GluA2/GluA3) to determine dendritic spine maturation; loss of RAB39B in knockout mice increases Ca2+-permeable AMPAR synaptic expression (immature spines), which is rescued by the CP-AMPAR antagonist NASPM, confirming that RAB39B-dependent GluA2 trafficking underlies dendritic spine refinement.","method":"Rab39b knockout mouse; spine morphology analysis; electrophysiology; CP-AMPAR pharmacological rescue with NASPM","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with pharmacological rescue, spine morphology, and electrophysiology; replicates earlier RAB39B-PICK1-GluA2 findings","pmids":["34035473"],"is_preprint":false},{"year":2022,"finding":"A novel gain-of-function de novo GRIA2 missense mutation (A643V) causes greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity in GluA2 A643V-containing AMPARs; these gain-of-function properties are distinct from the typical GRIA2 loss-of-function and are fully blocked by perampanel (an AMPAR negative allosteric modulator).","method":"Patch-clamp recordings of mutant receptor expressed in HEK293 cells with and without TARP γ2; pharmacological testing with perampanel","journal":"Epilepsia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological characterization of mutant receptor in heterologous system with pharmacological rescue; single lab but multiple parameters measured","pmids":["36161652"],"is_preprint":false},{"year":2025,"finding":"GluA2-containing AMPARs form a continuum of polyamine-insensitive ion channels with varying degrees of Ca2+ permeability, not a binary Ca2+-impermeable channel as previously held. Ca2+ permeability is shaped by AMPAR subunit composition and by auxiliary subunits (TARPs and cornichons) that primarily modify the selectivity filter; Ca2+ docks at an extracellular binding site that funnels divalent ions into the pore.","method":"Patch-clamp electrophysiology with diverse AMPAR subunit combinations and auxiliary subunits; Ca2+ permeability measurements; pharmacological characterization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct electrophysiological measurement with mechanistic identification of Ca2+ docking site; multiple subunit combinations and auxiliary subunit conditions tested","pmids":["40108453"],"is_preprint":false}],"current_model":"GluA2 (GRIA2) is the principal determinant of AMPA receptor Ca2+ impermeability through an arginine at the Q/R site (position 607) introduced by ADAR2-catalyzed adenosine-to-inosine RNA editing of a base-paired exon-intron duplex substrate; Q/R site editing is nearly complete in the healthy adult brain and is essential for normal neural function. GluA2 assembles as a tetramer (dimer-of-dimers) with other AMPAR subunits to form ligand-gated cation channels whose gating, desensitization, and pharmacology are extensively characterized structurally (crystal structures of the LBD and cryo-EM of the intact receptor with and without TARP γ2). GluA2-containing AMPARs form a continuum of Ca2+ permeabilities shaped by subunit composition and auxiliary subunits (TARPs, cornichons) that modify the selectivity filter. Synaptic delivery, removal, and intracellular sorting of GluA2 are regulated by its C-terminal domain through interactions with NSF (which promotes plasma membrane insertion), GRIP1/2 (which retains GluA2 at synapses and is recruited via phospho-Y876), PICK1 (which facilitates GluA2 internalization during LTD and ischemia in a GSK-3β/Ser416-dependent manner), RAB39B (which drives ER-to-Golgi trafficking via PICK1), and β3 integrin (direct cytoplasmic domain binding); post-translational modifications including ubiquitination (at Lys-870/882, controlling lysosomal degradation), O-GlcNAcylation, and N-glycosylation at N370 (ER exit) and N413 (HNK-1/N-cadherin interaction) further tune GluA2 trafficking. The GluA2 CTD is necessary and sufficient for NMDA receptor-dependent LTD, and a single membrane-proximal residue and phospho-Y876 gate homeostatic synaptic upscaling via GRIP1. Through its extracellular domain, GluA2 also non-ionotropically regulates mGluR-LTD via N-cadherin–Rac1–cofilin-mediated actin reorganization and controls dendritic localization via retrograde Sema3A–PlexA signaling."},"narrative":{"mechanistic_narrative":"GRIA2 encodes GluA2, the AMPA-type glutamate receptor subunit that governs the Ca2+ permeability of fast excitatory synaptic transmission in the brain [PMID:8011338, PMID:7502080]. The defining feature of GluA2 is an arginine introduced at the Q/R site of the channel pore by ADAR-catalyzed adenosine-to-inosine RNA editing, which depends on an imperfect exon-intron base-paired duplex in the pre-mRNA and renders heteromeric AMPARs Ca2+-impermeable [PMID:8269514, PMID:7502080]; loss of this editing increases Ca2+ permeability and macroscopic conductance, producing seizures and lethality in mice [PMID:7502080, PMID:10195181], while restoring an edited (arginine) codon genomically is well tolerated, showing that Ca2+ permeability is set by the relative abundance of edited GluA2 [PMID:9811877]. Rather than a binary impermeable channel, GluA2-containing AMPARs span a continuum of Ca2+ permeabilities tuned by subunit composition and auxiliary subunits (TARPs, cornichons) acting on the selectivity filter [PMID:40108453]. GluA2 assembles as a tetrameric dimer-of-dimers ligand-gated cation channel [PMID:11705385] whose agonist-induced clamshell closure, gating, and desensitization, and their modulation by TARP γ2, are defined by crystal and cryo-EM structures [PMID:20713069, PMID:25109876, PMID:27368053]. Surface delivery, retention, and degradation of GluA2 are controlled through its C-terminal domain by an NSF/PICK1/GRIP1 trafficking axis — NSF promotes membrane insertion (a step disrupted by Plk2 and requiring Q/R editing) [PMID:20534470, PMID:20802490], PICK1 mediates endosomal retention and an ER-exit step downstream of RAB39B and CaMKII/Ca2+ [PMID:22915106, PMID:24831007, PMID:25784538], and GRIP1 retains and recycles receptors via phospho-Y876 [PMID:21383172, PMID:32071234] — with additional control by β3 integrin binding, ubiquitination at Lys-870/882 directing lysosomal degradation, O-GlcNAcylation, and N-glycosylation at N370 and N413 [PMID:22232691, PMID:25660027, PMID:24381264, PMID:26271046]. The GluA2 CTD is necessary and sufficient for NMDAR-dependent LTD and, through a membrane-proximal residue and phospho-Y876/GRIP1, for homeostatic synaptic upscaling [PMID:29230056, PMID:29180434, PMID:32071234], while the extracellular domain mediates a non-ionotropic role in mGluR-LTD via N-cadherin–Rac1–cofilin actin reorganization [PMID:21248105]. De novo heterozygous GRIA2 mutations cause neurodevelopmental disorders, acting predominantly through loss-of-function reductions in receptor current but in some cases through gain-of-function gating changes [PMID:31300657, PMID:36161652].","teleology":[{"year":1993,"claim":"Established how the Q/R editing site is recognized, answering how a single adenosine in GluA2 pre-mRNA is selected for site-specific modification.","evidence":"Mutagenesis of intronic and exonic complementary sequences with complementarity-restoring rescue in transfected PC12 cells","pmids":["8269514"],"confidence":"High","gaps":["Did not identify the editing enzyme","Quantitative editing efficiency in vivo not addressed"]},{"year":1994,"claim":"Linked GluA2 (GluR-B) expression level to the Ca2+ permeability of native AMPARs, defining its physiological function in distinct neuron types.","evidence":"Patch-clamp plus single-cell mRNA analysis in neocortical brain slices","pmids":["8011338"],"confidence":"High","gaps":["Did not separate editing from expression level","Subunit stoichiometry of native receptors not resolved"]},{"year":1995,"claim":"Proved in vivo that the edited arginine is essential for Ca2+ impermeability and survival, establishing editing as a non-redundant physiological requirement.","evidence":"Editing-incompetent GluR-B knock-in mice with electrophysiology and phenotyping","pmids":["7502080"],"confidence":"High","gaps":["Cellular cause of seizures vs Ca2+ influx not dissected here","Developmental timing of requirement unclear"]},{"year":1995,"claim":"Identified the editing reaction biochemically as site-selective A-to-I deamination by a dsRNA adenosine deaminase, moving from genetics to enzyme mechanism.","evidence":"In vitro editing assay with HeLa nuclear extract and TLC nucleotide analysis","pmids":["7721757"],"confidence":"High","gaps":["Specific ADAR isoform not pinpointed","Required cofactors not defined"]},{"year":1996,"claim":"Reconstituted editing with recombinant enzyme, showing duplex structure and a cofactor balance govern editing accuracy.","evidence":"In vitro editing with recombinant DRADA and purified GluR-B RNA","pmids":["8598204"],"confidence":"High","gaps":["Cofactor identity not determined","ADAR1 vs ADAR2 contributions in neurons unresolved"]},{"year":1996,"claim":"Demonstrated that the isolated ligand-binding domain folds autonomously and binds agonist with native pharmacology independent of glycosylation, enabling structural study.","evidence":"Bacterial S1-S2 expression and [3H]AMPA radioligand binding","pmids":["8663017"],"confidence":"Medium","gaps":["No structural model at this stage","Channel-coupled behavior not addressed"]},{"year":1998,"claim":"Showed unedited GluA2 is dispensable when an edited codon is supplied genomically, establishing that Ca2+ permeability is set by edited GluA2 abundance relative to other subunits.","evidence":"Exonic arginine knock-in mice with electrophysiology and phenotyping","pmids":["9811877"],"confidence":"High","gaps":["Roles of editing kinetics in development not tested","Other editing sites not addressed"]},{"year":1999,"claim":"Dissected the disease mechanism of editing deficiency, attributing seizures to increased macroscopic conductance rather than Ca2+ influx per se.","evidence":"Allelic series of gene-targeted mice with patch-clamp and in vivo phenotyping","pmids":["10195181"],"confidence":"High","gaps":["Circuit-level basis of epilepsy not resolved","Dendritic architecture defect mechanism unclear"]},{"year":2002,"claim":"Defined ADAR2 enzymology on GluA2 RNA — base-flipping, 5' duplex dependence, positioning over affinity, and homodimer requirement — explaining site selectivity.","evidence":"In vitro footprinting, kinetics, 2-aminopurine fluorescence, and RNA-dependent cross-linking (idx 8–11)","pmids":["10836790","11015203","12163487"],"confidence":"Medium","gaps":["In vivo relevance of dimerization not tested","Regulation of editing levels in neurons not addressed"]},{"year":2001,"claim":"Established the quaternary architecture of GluA2 as a 2-fold symmetric dimer-of-dimers tetramer, the structural framework for later mechanistic studies.","evidence":"EM and biochemical characterization of purified GluR-B homomers","pmids":["11705385"],"confidence":"Medium","gaps":["Low resolution; no domain-level detail","Heteromeric assembly not addressed"]},{"year":2007,"claim":"Showed RNA Pol II CTD coordinates editing-before-splicing, explaining how intronic ADAR2 recognition sequences are retained long enough for editing.","evidence":"Cell-based splicing/editing assays with CTD truncation minigenes","pmids":["17525170"],"confidence":"Medium","gaps":["Direct molecular link between CTD and ADAR2 not defined","In vivo coupling not tested"]},{"year":2003,"claim":"Identified a GluA2(long)-specific, GluA1-independent route for activity- and LTP-driven synaptic AMPAR delivery, broadening models of plasticity.","evidence":"Viral overexpression, dominant-negatives, and slice electrophysiology with activity manipulation","pmids":["14687553"],"confidence":"Medium","gaps":["Molecular determinants in the long tail not mapped","Adult vs juvenile differences unclear"]},{"year":2010,"claim":"Resolved the structural basis of agonist activation, desensitization, and allosteric modulation, defining the LBD as the conformational switch.","evidence":"X-ray crystallography of GluA2 S1S2 LBD with diverse ligands","pmids":["20713069"],"confidence":"High","gaps":["Isolated LBD lacks intact-receptor context","Gating coupling to pore inferred indirectly"]},{"year":2010,"claim":"Defined the dual requirements — NSF binding and Q/R editing — for GluA2 plasma membrane insertion, and showed Plk2 gates this via NSF engagement.","evidence":"pHluorin-TIRF imaging of fusion events with domain mutants; Plk2-NSF Co-IP and electrophysiology (idx 15–16)","pmids":["20534470","20802490"],"confidence":"High","gaps":["How editing influences insertion mechanistically unclear","Plk2 substrate other than NSF not excluded"]},{"year":2011,"claim":"Revealed a non-ionotropic GluA2 function in mGluR-LTD via extracellular N-cadherin–Rac1–cofilin signaling, separating channel-independent from channel-dependent roles.","evidence":"GluA2 KO, domain mutants, N-cadherin/Rac1/cofilin manipulations with slice LTD recordings","pmids":["21248105"],"confidence":"High","gaps":["Structural basis of GluA2–N-cadherin contact not defined","Generality across synapse types untested"]},{"year":2012,"claim":"Established β3 integrin, S-SCAM/MAGI-2, and PICK1 as distinct controllers of synaptic GluA2 levels and homeostatic strength, expanding the trafficking interactome.","evidence":"Co-IP from brain, heterologous co-expression, RNAi, and electrophysiology (idx 20–22)","pmids":["22232691","22593065","22915106"],"confidence":"High","gaps":["Hierarchy among these regulators unclear","Binding sites on GluA2 not all mapped"]},{"year":2014,"claim":"Captured intact-receptor conformations across resting, pre-open, and desensitized states and the TARP γ2-bound architecture, linking LBD motions to channel gating.","evidence":"Cryo-EM and DEER of full GluA2 in multiple functional states and GluA2–γ2 complex (idx 23, 33)","pmids":["25109876","27368053"],"confidence":"High","gaps":["Heteromeric receptor structures not resolved here","Editing-site effect on pore not visualized"]},{"year":2014,"claim":"Defined multiple post-translational and post-transcriptional controls of GluA2 trafficking and supply (O-GlcNAcylation, Ca2+/PICK1 ER-exit, Sema3A/PlexA dendritic targeting, FXR1P translational repression).","evidence":"Biochemical detection, domain mutants, Co-IP, conditional KO, and electrophysiology across systems (idx 24–27)","pmids":["24381264","24831007","24599038","25456134"],"confidence":"Medium","gaps":["O-GlcNAc sites on GluA2 not mapped","Enzymes responsible not all identified"]},{"year":2015,"claim":"Mapped ubiquitination sites (Lys-870/882) controlling lysosomal degradation, N-glycosylation sites (N370 ER exit, N413 HNK-1/N-cadherin), and the RAB39B–PICK1 ER-to-Golgi route, refining the GluA2 trafficking code.","evidence":"Site-directed mutagenesis, surface/endosome assays, Co-IP, RAB39B knockdown electrophysiology (idx 28–32)","pmids":["25660027","25784538","26271046"],"confidence":"High","gaps":["E3 ligase for GluA2 not identified","GSK-3β/PICK1 phospho-control in vivo relevance partial"]},{"year":2017,"claim":"Demonstrated by reciprocal CTD-exchange knock-ins that the GluA2 CTD is necessary and sufficient for NMDAR-dependent LTD, and that a membrane-proximal tail region drives homeostatic upscaling.","evidence":"CTD-swap knock-in mice and viral domain-mutant rescue with LTP/LTD electrophysiology (idx 34–35)","pmids":["29230056","29180434"],"confidence":"High","gaps":["Effector proteins reading the CTD during LTD not fully defined","Single critical residue identity narrow"]},{"year":2020,"claim":"Identified phospho-Y876 as the molecular switch coupling GluA2 to GRIP1 specifically during homeostatic scaling but not Hebbian plasticity, separating the two trafficking modes.","evidence":"Y876F phospho-deficient knock-in mice, scaling assays, and GluA2–GRIP1 Co-IP","pmids":["32071234"],"confidence":"High","gaps":["Kinase/phosphatase acting on Y876 not defined","Other phospho-Y876 effectors not excluded"]},{"year":2018,"claim":"Showed both autoantibody-driven and RAB39B-dependent loss of synaptic GluA2 shift receptors toward Ca2+-permeable forms and impair plasticity and spine maturation, linking GluA2 trafficking to disease.","evidence":"Passive antibody transfer in mice and Rab39b KO with spine analysis, electrophysiology, and CP-AMPAR pharmacology (idx 36, 41)","pmids":["30146304","34035473"],"confidence":"High","gaps":["Compensatory CP-AMPAR identity not fully defined","Reversibility/therapeutic windows untested"]},{"year":2019,"claim":"Established that de novo GRIA2 mutations cause neurodevelopmental disorders predominantly via loss-of-function reduced current, with gain-of-function gating mutations as a distinct, perampanel-sensitive subclass.","evidence":"Electrophysiology of 28 patient mutations and detailed characterization of A643V with pharmacology (idx 38, 42)","pmids":["31300657","36161652"],"confidence":"High","gaps":["Genotype-phenotype correlation incomplete","In vivo modeling of individual variants limited"]},{"year":2025,"claim":"Reframed GluA2-containing AMPARs as a continuum of Ca2+ permeabilities tuned by composition and auxiliary subunits, revising the binary Ca2+-impermeable model.","evidence":"Patch-clamp across subunit and auxiliary-subunit combinations with identification of an extracellular Ca2+ docking site","pmids":["40108453"],"confidence":"High","gaps":["Structural basis of the docking site not resolved here","Physiological consequences of the continuum in vivo untested"]},{"year":null,"claim":"How GluA2 trafficking regulators, editing status, and auxiliary-subunit composition are integrated in real time at individual synapses to set Ca2+ permeability and plasticity outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling editing, trafficking, and auxiliary-subunit control","E3 ligase and Y876 kinase identities unknown","Heteromeric receptor structures with editing site visualized lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2,23,43]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,15,43]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15,16,20,28]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[25,29,30]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22,28]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,2,12,34]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[15,16,22,29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,38,42]}],"complexes":["AMPA receptor (tetramer, dimer-of-dimers)","GluA2-TARP γ2 (stargazin) complex"],"partners":["NSF","PICK1","GRIP1","ITGB3","RAB39B","CDH2","PLXNA","FXR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42262","full_name":"Glutamate receptor 2","aliases":["AMPA-selective glutamate receptor 2","GluR-B","GluR-K2","Glutamate receptor ionotropic, AMPA 2"],"length_aa":883,"mass_kda":98.8,"function":"Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid (PubMed:20614889, PubMed:31300657, PubMed:8003671). L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system and plays an important role in fast excitatory synaptic transmission (PubMed:14687553). Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse upon entry of monovalent and divalent cations such as sodium and calcium (PubMed:20614889, PubMed:8003671). The receptor then desensitizes rapidly and enters in a transient inactive state, characterized by the presence of bound agonist (By similarity). In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of L-glutamate (By similarity). Through complex formation with NSG1, GRIP1 and STX12 controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting (By similarity)","subcellular_location":"Cell membrane; Postsynaptic cell membrane; Postsynaptic density membrane","url":"https://www.uniprot.org/uniprotkb/P42262/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRIA2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRIA2","total_profiled":1310},"omim":[{"mim_id":"621083","title":"ISLET CELL AUTOANTIGEN 1-LIKE PROTEIN; ICA1L","url":"https://www.omim.org/entry/621083"},{"mim_id":"618917","title":"NEURODEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND BEHAVIORAL ABNORMALITIES; NEDLIB","url":"https://www.omim.org/entry/618917"},{"mim_id":"618862","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, MICROCEPHALY, AND SEIZURES; NEDHYMS","url":"https://www.omim.org/entry/618862"},{"mim_id":"618011","title":"HYPEREKPLEXIA 4; HKPX4","url":"https://www.omim.org/entry/618011"},{"mim_id":"617492","title":"OLFACTOMEDIN 2; OLFM2","url":"https://www.omim.org/entry/617492"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":78.8}],"url":"https://www.proteinatlas.org/search/GRIA2"},"hgnc":{"alias_symbol":["GluA2","GLURB","GluR-K2","GluR-B","GluR-2"],"prev_symbol":["GLUR2"]},"alphafold":{"accession":"P42262","domains":[{"cath_id":"3.40.50.2300","chopping":"25-128_270-368","consensus_level":"high","plddt":92.0739,"start":25,"end":368},{"cath_id":"3.40.50.2300","chopping":"131-261_371-396","consensus_level":"high","plddt":91.2759,"start":131,"end":396},{"cath_id":"3.40.190.10","chopping":"409-519_753-797","consensus_level":"medium","plddt":90.4033,"start":409,"end":797},{"cath_id":"3.40.190.10","chopping":"521-531_648-749","consensus_level":"medium","plddt":89.8518,"start":521,"end":749},{"cath_id":"1.10.287.70","chopping":"536-572_590-644","consensus_level":"high","plddt":86.1805,"start":536,"end":644}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P42262","model_url":"https://alphafold.ebi.ac.uk/files/AF-P42262-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P42262-F1-predicted_aligned_error_v6.png","plddt_mean":84.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRIA2","jax_strain_url":"https://www.jax.org/strain/search?query=GRIA2"},"sequence":{"accession":"P42262","fasta_url":"https://rest.uniprot.org/uniprotkb/P42262.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P42262/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P42262"}},"corpus_meta":[{"pmid":"8269514","id":"PMC_8269514","title":"RNA 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Single nucleotide substitutions in either the intronic or exonic complementary sequences abolished editing, which was rescued by restoring complementarity.\",\n      \"method\": \"Transfection of GluR-B gene constructs into PC12 cells with targeted single-nucleotide substitutions and complementarity-restoring double mutations\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of both strands of the editing duplex with rescue experiment; foundational mechanism paper replicated by subsequent work\",\n      \"pmids\": [\"8269514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Differences in Ca2+ permeability of native AMPA-type glutamate receptor channels in neocortical neurons are caused by differential GluR-B subunit expression: pyramidal neurons express high GluR-B mRNA (Ca2+-impermeable receptors) while non-pyramidal neurons express low GluR-B mRNA (Ca2+-permeable receptors), as established by single-cell patch-clamp and single-cell mRNA analysis in brain slices.\",\n      \"method\": \"Patch-clamp recordings in brain slices combined with single-cell mRNA analysis (GluR-B/non-B ratio quantification)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct electrophysiology combined with single-cell molecular analysis in native tissue, foundational result replicated broadly\",\n      \"pmids\": [\"8011338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The arginine at the Q/R site of GluR-B (introduced by RNA editing) is essential for rendering AMPA receptors Ca2+-impermeable in principal neurons in vivo. Mice engineered with an editing-incompetent GluR-B allele express unedited GluR-B, show increased AMPA receptor Ca2+ permeability in neurons, develop early-onset seizures, and die by 3 weeks.\",\n      \"method\": \"Gene targeting in mice (editing-incompetent GluR-B allele), electrophysiology, in vivo phenotypic analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — clean knock-in mouse model with defined molecular lesion, multiple orthogonal functional readouts, foundational in vivo proof\",\n      \"pmids\": [\"7502080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"GluR-B pre-mRNA Q/R and R/G sites are edited in vitro by nuclear extract via site-selective adenosine-to-inosine conversion, as confirmed by thin-layer chromatography of edited RNA sequences, implicating a double-stranded RNA adenosine deaminase (DRADA/ADAR).\",\n      \"method\": \"In vitro editing assay with HeLa nuclear extract; nucleotide analysis by thin-layer chromatography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro biochemical reconstitution with nucleotide-level product characterization\",\n      \"pmids\": [\"7721757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Recombinant DRADA (ADAR1/dsRNA adenosine deaminase) edits GLuR-B RNA at the Q/R site in vitro, but requires both a dsRNA structure (exon-intron duplex) and a cofactor protein present even in non-neuronal cells; the accuracy and efficiency of editing depend on the quantitative balance between DRADA, cofactor, and substrate RNA.\",\n      \"method\": \"In vitro editing assay using recombinantly expressed DRADA protein with purified GLuR-B RNA substrate\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant enzyme; single lab but multiple mechanistic parameters tested\",\n      \"pmids\": [\"8598204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The ligand-binding domain of GluR-B (S1-S2 fusion) expressed in E. coli binds [3H]AMPA with high affinity (Kd ~12 nM) and with pharmacology typical of native AMPA receptors; N-linked glycosylation is not required for formation or maintenance of the ligand-binding site.\",\n      \"method\": \"Bacterial expression of S1-S2 fusion protein; radioligand binding assay with [3H]AMPA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of binding domain; single lab, multiple deletion mutants and pharmacological characterization\",\n      \"pmids\": [\"8663017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The small amount of Q/R site-unedited GluR-B present in postnatal brain is not required for normal brain development or function; mice engineered with an exonic arginine codon at the Q/R site (bypassing RNA editing) show no obvious deficits, demonstrating that AMPA receptor Ca2+ permeability can be solely regulated by the levels of Q/R site-edited GluR-B relative to other AMPAR subunits.\",\n      \"method\": \"Gene targeting in mice (exonic arginine knock-in); electrophysiology; in vivo phenotypic analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — clean knock-in mouse with defined molecular change, electrophysiology confirming Ca2+ permeability change; single lab\",\n      \"pmids\": [\"9811877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Graded deficiency in GluR-B Q/R site editing in mice increases AMPA receptor Ca2+ permeability in pyramidal neurons and, at sufficient levels, induces NMDA receptor-independent LTP, epilepsy, and deficits in dendritic architecture. The seizure phenotype correlates with increased macroscopic AMPA receptor conductance rather than Ca2+ influx per se.\",\n      \"method\": \"Multiple gene-targeted mouse lines with varying GluR-B expression and editing levels; patch-clamp electrophysiology; in vivo phenotypic analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple independent mouse alleles, electrophysiology, in vivo phenotypes; multi-orthogonal design\",\n      \"pmids\": [\"10195181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ADAR2 binds to the GluR-B R/G editing site RNA at a discrete region surrounding the editing site (as shown by footprinting), and binding affinity to wild-type versus editing-reduced mutant RNA is nearly identical, indicating that ADAR2 specificity is not determined by differential binding affinity but by positioning at the editing site.\",\n      \"method\": \"In vitro binding assays (gel shift, footprinting) with rat ADAR2 and synthetic GluR-B R/G site RNA substrates\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical characterization with mutant substrates and footprinting; single lab\",\n      \"pmids\": [\"10836790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ADAR2-catalyzed editing of the GluR-B R/G site requires 5' duplex structure for efficient deamination; five base pairs of duplex 5' to the editing site increase single-turnover rate constant 17–39-fold. ADAR2 flips the reactive adenosine out of the helix prior to deamination, as evidenced by fluorescence enhancement of a 2-aminopurine-substituted substrate.\",\n      \"method\": \"In vitro deamination kinetics with synthetic substrates; fluorescence spectroscopy with 2-aminopurine analog\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro with kinetic analysis and base-flipping evidence via fluorescence; multiple orthogonal methods\",\n      \"pmids\": [\"11015203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Purified GluRB homomeric channels are tetramers with molecular dimensions of approximately 11×14×17 nm and an overall 2-fold symmetric (dimer-of-dimers) assembly, as determined by electron microscopy of milligram-scale purified receptor.\",\n      \"method\": \"Density-gradient centrifugation; electron microscopy; ligand binding assays on purified GluRB homomers\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural imaging of purified receptor; single lab but EM and biochemical characterization combined\",\n      \"pmids\": [\"11705385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAR2 functions as a homodimer on GluR-B R/G site RNA; a ternary ADAR2:RNA complex (two ADAR2 monomers) is required for efficient editing, and complex formation is rate-determining. ADAR monomers cross-link to each other in an RNA-dependent manner.\",\n      \"method\": \"Gel shift assay; RNA-dependent cross-linking; detailed kinetic analysis of editing reaction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetics and cross-linking; single lab, multiple methods\",\n      \"pmids\": [\"12163487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The GluR-B(long) splice variant of GluR-B mediates a GluR-A-independent form of glutamatergic synaptic plasticity in the juvenile hippocampus: spontaneous activity drives GluR-B(long) delivery maintaining ~1/3 of steady-state AMPA responses, while LTP induction drives GluR-B(long) delivery accounting for ~50% of potentiation at CA3-CA1 synapses.\",\n      \"method\": \"Viral overexpression, dominant-negative approaches, and electrophysiology in hippocampal slices; activity manipulation experiments\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean viral delivery with electrophysiological readout; single lab, multiple activity conditions\",\n      \"pmids\": [\"14687553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal domain (CTD) of RNA Pol II coordinates editing and splicing of GluR-B pre-mRNA: the CTD is required for efficient ADAR2 editing at the R/G site by preventing premature splicing that would remove intronic ADAR2 recognition sequences, and it inhibits excision of intron 11 (which contains the Q/R editing complementary sequences), thereby enforcing the order editing-before-splicing.\",\n      \"method\": \"Cell-based splicing and editing assays with CTD truncation constructs; minigene transfection\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with CTD deletion; single lab, defined mechanistic order\",\n      \"pmids\": [\"17525170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structures of the GluA2 ligand-binding domain in complex with agonists, antagonists, and positive allosteric modulators revealed the structural basis for receptor activation and desensitization: agonist binding induces clamshell closure of the S1-S2 domain, and positive allosteric modulators bind at the LBD dimer interface to stabilize the agonist-bound conformation and slow desensitization.\",\n      \"method\": \"X-ray crystallography of recombinant GluA2 S1S2 LBD; >80 structures reviewed including mutant and ligand-bound forms\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple independent crystal structures with diverse ligands; widely replicated across labs\",\n      \"pmids\": [\"20713069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GluA2 plasma membrane insertion requires: (1) the NSF-binding site within its intracellular C-terminal domain, and (2) Q/R site RNA editing in the ion channel region. Plasma membrane insertion of heteromeric GluA2/3 receptors follows the same rules as homomeric GluA2 receptors.\",\n      \"method\": \"pHluorin-tagged GluA2 with TIRF microscopy to visualize individual vesicle fusion events; domain mutants (NSF binding site deletion, Q/R site changes)\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct visualization of fusion events with domain-specific mutants; single lab but two orthogonal structural determinants tested\",\n      \"pmids\": [\"20534470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Polo-like kinase 2 (Plk2) directly interacts with NSF and disrupts the NSF-GluA2 interaction, promoting loss of surface GluA2 in hippocampal neurons, increased GluA2 association with PICK1 and GRIP1, and decreased synaptic AMPAR current. This mechanism requires Plk2-NSF engagement (via a novel Plk2 motif independent of the polo-box domain) but not Plk2 kinase activity.\",\n      \"method\": \"Co-immunoprecipitation; dominant-negative and kinase-dead constructs; electrophysiology in rat hippocampal neurons; surface biotinylation\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple mutants, electrophysiology; multiple orthogonal methods establishing direct interaction and functional consequence\",\n      \"pmids\": [\"20802490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GluA2 undergoes activity-dependent ubiquitination: increasing synaptic activity (bicuculline) or AMPA receptor agonists rapidly induces GluA2 ubiquitination, which requires clathrin- and dynamin-dependent endocytosis of AMPARs (ubiquitination occurs on plasma membrane AMPARs post-endocytosis).\",\n      \"method\": \"Immunoprecipitation of ubiquitinated proteins; pharmacological blockade of endocytosis; biochemical fractionation in cultured neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple pharmacological tools; single lab, endocytosis requirement established by blockers\",\n      \"pmids\": [\"21414928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GluA2 regulates mGluR-dependent LTD through its extracellular domain interaction with N-cadherin, which activates Rac1 and cofilin-mediated actin reorganization. This non-ionotropic function of GluA2 is independent of its channel properties and required for mGluR-LTD in the hippocampus.\",\n      \"method\": \"GluA2 knockout neurons, domain-specific mutants, N-cadherin knockdown, Rac1/cofilin pathway manipulations; LTD recordings in hippocampal slices\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (KO, domain mutants, downstream pathway manipulations) with electrophysiological LTD readout\",\n      \"pmids\": [\"21248105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GRIP1 variants found in autism patients alter GRIP1-GluA2/3 interaction via PDZ domains 4-6 and cause faster recycling and increased surface distribution of GluA2 in neurons (gain-of-function), whereas GRIP1/2 deficiency produces opposite effects on GluA2 surface levels.\",\n      \"method\": \"Biochemical interaction assays; surface GluA2 imaging in neurons; GRIP1/2 knockout mice\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction assays plus neuronal surface trafficking; single lab\",\n      \"pmids\": [\"21383172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β3 integrin directly binds to the cytoplasmic domain of GluA2 (but only weakly to GluA1, and GluA1-β3 association requires GluA2 coexpression), forming a complex in mouse brain; this direct interaction underlies β3 integrin-dependent homeostatic control of synaptic GluA2 levels and synaptic strength.\",\n      \"method\": \"Co-immunoprecipitation from mouse brain; heterologous co-expression; electrophysiology in hippocampal pyramidal neurons; surface GluA2 measurement\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct pulldown plus Co-IP from brain, functional electrophysiology, and domain specificity established\",\n      \"pmids\": [\"22232691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S-SCAM/MAGI-2 maintains synaptic GluA2-containing AMPA receptors: increasing S-SCAM increases surface AMPAR levels and synaptic transmission in a GluA2-dependent (not GluA1-dependent), NSF-interaction-sensitive, and activity-independent manner; S-SCAM knockdown causes loss of synaptic AMPARs and spine density reduction.\",\n      \"method\": \"Overexpression and RNAi knockdown in rat hippocampal neurons; electrophysiology; surface AMPAR imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with electrophysiology; single lab\",\n      \"pmids\": [\"22593065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PICK1 binding to GluA2 on endosomal compartments restricts GluA2 from trafficking to the synaptic plasma membrane immediately after glycine stimulation (chemical LTP), enabling a transient switch to GluA2-lacking Ca2+-permeable AMPARs at synapses. Activation of CP-AMPARs then triggers release of GluA2 from PICK1, allowing GluA2-containing AMPARs to traffic back to the synaptic surface 5-20 min post-stimulus.\",\n      \"method\": \"Endogenous protein immunostaining, co-IP for PICK1-GluA2 binding; live-cell imaging; pharmacological blockade of CP-AMPARs in rat hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, live imaging, and pharmacological manipulations; single lab\",\n      \"pmids\": [\"22915106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cryo-EM and DEER (double electron-electron resonance) structures of intact GluA2 AMPA receptor in apo/resting, activated/pre-open (partial agonist + positive allosteric modulator), and desensitized states revealed how agonist binding modulates LBD layer conformation and how desensitization involves large conformational rearrangements of both amino-terminal and ligand-binding domains.\",\n      \"method\": \"Cryo-electron microscopy; DEER EPR spectroscopy with cysteine mutants; structure determination in three distinct functional states\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple high-resolution structures in distinct functional states with orthogonal EPR validation; replicated in field\",\n      \"pmids\": [\"25109876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"O-GlcNAcylation of GluA2 is associated with a novel form of LTD at hippocampal synapses: acutely increasing O-GlcNAcylation induces NMDA receptor- and PKC-independent LTD that requires GluA2 subunits, and the GluA2 subunit is directly O-GlcNAcylated.\",\n      \"method\": \"Pharmacological O-GlcNAc elevation in hippocampal slices; LTD electrophysiology; GluA2 knockout rescue; direct O-GlcNAc immunoprecipitation of GluA2\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical detection of O-GlcNAcylation on GluA2 plus functional LTD requirement; single lab\",\n      \"pmids\": [\"24381264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GluA2 trafficking from the endoplasmic reticulum to the plasma membrane requires Ca2+ release from internal stores (via IP3 and ryanodine receptors), CaMKII activity, and GluA2 interaction with PICK1 (via the PICK1 BAR domain). Ca2+ release promotes formation of a CaMKII-PICK1 complex that interacts with the GluA2 C-terminal domain to stimulate ER exit.\",\n      \"method\": \"Pharmacological inhibitors of IP3R and RyR; CaMKII inhibition; PICK1 domain mutants; surface trafficking assays in cultured hippocampal neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and domain-mutant approaches; single lab\",\n      \"pmids\": [\"24831007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Semaphorin 3A (Sema3A) retrograde signaling at the axonal growth cone drives GluA2 to distal dendrites via GRIP1-dependent localization; PlexinA (PlexA) interacts directly with GluA2 at its IPT domain in somatodendritic regions, and overexpression of PlexA-IPT suppresses GluA2 dendritic localization and induces abnormal proximal bifurcation of apical dendrites in CA1 neurons.\",\n      \"method\": \"Co-immunoprecipitation (PlexA-GluA2 interaction); knockdown of cytoplasmic dynein; overexpression of PlexA-IPT domain; immunostaining in hippocampal neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP, functional consequence by dominant-negative domain; single lab\",\n      \"pmids\": [\"24599038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FXR1P binds specifically to the 5' UTR of GluA2 mRNA to repress its translation; removal of FXR1P from mouse forebrain selectively enhances de novo GluA2 synthesis and increases GluA2 incorporation at potentiated synapses, as well as enhancing hippocampal late-phase LTP and long-term spatial memory.\",\n      \"method\": \"Conditional Fxr1p knockout in mouse forebrain; RNA immunoprecipitation (RIP) for GluA2 mRNA binding; de novo protein synthesis assays; electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct RNA binding demonstrated, conditional KO with multiple orthogonal functional readouts; single lab but comprehensive\",\n      \"pmids\": [\"25456134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Activity-dependent ubiquitination of GluA2 occurs at Lys-870 and Lys-882 in the C-terminal domain, exclusively on plasma membrane AMPARs post-endocytosis, in a Ca2+- and CaMKII-dependent manner requiring L-type VGCCs. Mutation of these lysines does not affect surface expression or AMPA-induced internalization but reduces trafficking to late endosomes and lysosomal degradation.\",\n      \"method\": \"Site-directed mutagenesis of GluA2 ubiquitination sites; Ca2+/CaMKII pathway inhibitors; late endosome co-localization; immunoprecipitation in cultured neurons\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of specific ubiquitination sites with multiple functional assays; two labs (Huganir and Anggono)\",\n      \"pmids\": [\"25660027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB39B, a small GTPase mutated in intellectual disability, controls GluA2 surface expression by acting through PICK1 (a downstream effector of GTP-bound RAB39B); RAB39B-PICK1 controls trafficking from the ER to the Golgi and hence surface expression of GluA2. RAB39B downregulation shifts AMPAR composition toward non-GluA2-containing Ca2+-permeable forms in hippocampal neurons.\",\n      \"method\": \"Co-immunoprecipitation (RAB39B-PICK1); surface GluA2 biochemistry; electrophysiology; RAB39B knockdown in mouse hippocampal neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction demonstrated, ER-to-Golgi trafficking assay, electrophysiology; multiple orthogonal approaches\",\n      \"pmids\": [\"25784538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"N-glycosylation at N370 of GluA2 is required for intracellular trafficking from the ER; the N370S mutation strongly suppresses ER exit of GluA2 and co-expressed GluA1. N-glycan at N413 carries the HNK-1 epitope that promotes GluA2 interaction with N-cadherin and enhances cell surface expression of both GluA2 and GluA1.\",\n      \"method\": \"N-glycosylation site mutants expressed in HEK293 cells; ER retention assays; co-immunoprecipitation; surface expression quantification\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis with trafficking and interaction assays; single lab\",\n      \"pmids\": [\"26271046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VAMP2 (synaptobrevin-2)-containing postsynaptic vesicles carry GluA1 but not GluA2 in dendritic spines; VAMP2 disruption by tetanus toxin reduces GluA1 in the postsynaptic plasma membrane. GluA1/VAMP2 vesicles are concentrated in spines relative to dendrites, whereas GluA2/VAMP2 vesicles are not, indicating distinct vesicular trafficking pathways for GluA1 and GluA2.\",\n      \"method\": \"Electron microscopy of postsynaptic vesicles; tetanus toxin treatment; immunofluorescence colocalization\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct EM visualization and functional blockade; single lab\",\n      \"pmids\": [\"26488171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GSK-3β phosphorylates PICK1 at Ser416 in its C-terminal region; this phosphorylation is required for PICK1 interaction with GluA2. The Ser416Ala substitution disrupts GluA2-PICK1 interaction and increases PICK1 membrane clustering, whereas Ser416Glu/Asp (phosphomimetic) retains the interaction.\",\n      \"method\": \"Site-directed mutagenesis; co-immunoprecipitation; imaging of PICK1 clusters in COS-7 cells; GSK-3β kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus Co-IP; single lab\",\n      \"pmids\": [\"26472923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structure of homomeric GluA2 AMPA receptor saturated with TARP γ2 (stargazin) shows four TARPs arranged with 4-fold symmetry around the ion channel domain, making contacts with M1, M2, and M4 transmembrane helices; two pairs of TARPs are positioned near the LBD dimer and dimer-dimer interfaces to modulate LBD clamshell closure and conformational rearrangements during activation and desensitization.\",\n      \"method\": \"Cryo-electron microscopy structure determination of GluA2-TARP γ2 complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of full complex; foundational structural result defining TARP-AMPAR architecture\",\n      \"pmids\": [\"27368053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal domains (CTDs) of endogenous GluA1 and GluA2 are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively, in hippocampal CA1 neurons, as demonstrated by knock-in mice with exchanged CTDs. The GluA2 CTD is required for LTD but not LTP.\",\n      \"method\": \"Three knock-in mouse lines with exchanged endogenous AMPAR CTDs; LTP and LTD electrophysiology; behavioral assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — clean knock-in mouse models with reciprocal CTD exchange; bidirectional electrophysiological and behavioral readouts\",\n      \"pmids\": [\"29230056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The membrane-proximal carboxy tail of GluA2 is necessary and sufficient for homeostatic synaptic upscaling in hippocampal CA1 pyramidal neurons; a single amino acid in this region is critical for GluA2-dependent AMPAR trafficking during synaptic scaling.\",\n      \"method\": \"Viral rescue in CA1 neurons with GluA2 domain mutants; whole-cell electrophysiology for synaptic scaling\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping with viral delivery in defined neurons; single lab\",\n      \"pmids\": [\"29180434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human autoantibodies against GluA2 induce GluA2-containing AMPAR internalization and reduce synaptic GluA2-containing AMPARs, followed by compensatory ryanodine receptor-dependent incorporation of non-GluA2-containing AMPARs; this disrupts LTP in vitro and impairs learning and memory in vivo.\",\n      \"method\": \"Electrophysiology, high-resolution imaging in neuronal cultures; passive transfer in wild-type and GluA1 KO mice; ryanodine receptor pharmacology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, electrophysiology, genetic and pharmacological tools) in both in vitro and in vivo models\",\n      \"pmids\": [\"30146304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In vivo expression of unedited (Ca2+-permeable) or pore-dead GluA2 in oligodendrocyte precursor cells (OPCs) triggers OPC proliferation and reduces differentiation into oligodendrocytes; expression of the GluA2 C-tail alone decreases OPC differentiation without affecting proliferation, demonstrating separable ionotropic and non-ionotropic roles of GluA2 in OPC fate.\",\n      \"method\": \"In vivo viral expression of GluA2 variants in mouse corpus callosum OPCs; immunohistochemical quantification of OPC proliferation and differentiation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain-of-function with multiple distinct GluA2 constructs; single lab\",\n      \"pmids\": [\"30355492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"De novo heterozygous GRIA2 mutations causing neurodevelopmental disorders produce a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type; when co-expressed with GluA1, most mutations cause decreased current amplitude and some affect voltage rectification, demonstrating loss-of-function as the principal pathogenic mechanism.\",\n      \"method\": \"Functional expression of mutant GluA2 subunits with electrophysiology in heterologous expression system; co-expression with GluA1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological characterization of 28 independent patient mutations; large cohort with consistent result\",\n      \"pmids\": [\"31300657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FUS/TLS undergoes calcium-dependent nuclear-to-cytoplasmic translocation during excitotoxic stress in neurons; FUS expression is required for glutamate-induced upregulation of GRIA2 mRNA, placing FUS upstream of GluA2 in the excitotoxic stress response.\",\n      \"method\": \"Primary cortical and motor neuron imaging; Ca2+ chelation; FUS knockdown; GRIA2 mRNA quantification in response to glutamate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with mRNA quantification, calcium-dependence established; single lab\",\n      \"pmids\": [\"31092554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GluA2 phospho-Y876 is essential for homeostatic synaptic upscaling but not for Hebbian LTP/LTD; bidirectional changes in Y876 phosphorylation occur during scaling (decrease during downscaling, increase during upscaling). Phospho-Y876 is required for synaptic accumulation of GRIP1 during upscaling, and increased Y876 phosphorylation enhances GluA2 binding to GRIP1.\",\n      \"method\": \"GluA2 Y876F phospho-deficient knock-in mice; in vitro and in vivo homeostatic scaling assays; co-immunoprecipitation of GluA2-GRIP1\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knock-in mouse with defined phospho-site; bidirectional plasticity assays; direct binding assay for GRIP1; multiple orthogonal approaches\",\n      \"pmids\": [\"32071234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB39B controls AMPAR trafficking (specifically GluA2/GluA3) to determine dendritic spine maturation; loss of RAB39B in knockout mice increases Ca2+-permeable AMPAR synaptic expression (immature spines), which is rescued by the CP-AMPAR antagonist NASPM, confirming that RAB39B-dependent GluA2 trafficking underlies dendritic spine refinement.\",\n      \"method\": \"Rab39b knockout mouse; spine morphology analysis; electrophysiology; CP-AMPAR pharmacological rescue with NASPM\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with pharmacological rescue, spine morphology, and electrophysiology; replicates earlier RAB39B-PICK1-GluA2 findings\",\n      \"pmids\": [\"34035473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel gain-of-function de novo GRIA2 missense mutation (A643V) causes greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity in GluA2 A643V-containing AMPARs; these gain-of-function properties are distinct from the typical GRIA2 loss-of-function and are fully blocked by perampanel (an AMPAR negative allosteric modulator).\",\n      \"method\": \"Patch-clamp recordings of mutant receptor expressed in HEK293 cells with and without TARP γ2; pharmacological testing with perampanel\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological characterization of mutant receptor in heterologous system with pharmacological rescue; single lab but multiple parameters measured\",\n      \"pmids\": [\"36161652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GluA2-containing AMPARs form a continuum of polyamine-insensitive ion channels with varying degrees of Ca2+ permeability, not a binary Ca2+-impermeable channel as previously held. Ca2+ permeability is shaped by AMPAR subunit composition and by auxiliary subunits (TARPs and cornichons) that primarily modify the selectivity filter; Ca2+ docks at an extracellular binding site that funnels divalent ions into the pore.\",\n      \"method\": \"Patch-clamp electrophysiology with diverse AMPAR subunit combinations and auxiliary subunits; Ca2+ permeability measurements; pharmacological characterization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct electrophysiological measurement with mechanistic identification of Ca2+ docking site; multiple subunit combinations and auxiliary subunit conditions tested\",\n      \"pmids\": [\"40108453\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GluA2 (GRIA2) is the principal determinant of AMPA receptor Ca2+ impermeability through an arginine at the Q/R site (position 607) introduced by ADAR2-catalyzed adenosine-to-inosine RNA editing of a base-paired exon-intron duplex substrate; Q/R site editing is nearly complete in the healthy adult brain and is essential for normal neural function. GluA2 assembles as a tetramer (dimer-of-dimers) with other AMPAR subunits to form ligand-gated cation channels whose gating, desensitization, and pharmacology are extensively characterized structurally (crystal structures of the LBD and cryo-EM of the intact receptor with and without TARP γ2). GluA2-containing AMPARs form a continuum of Ca2+ permeabilities shaped by subunit composition and auxiliary subunits (TARPs, cornichons) that modify the selectivity filter. Synaptic delivery, removal, and intracellular sorting of GluA2 are regulated by its C-terminal domain through interactions with NSF (which promotes plasma membrane insertion), GRIP1/2 (which retains GluA2 at synapses and is recruited via phospho-Y876), PICK1 (which facilitates GluA2 internalization during LTD and ischemia in a GSK-3β/Ser416-dependent manner), RAB39B (which drives ER-to-Golgi trafficking via PICK1), and β3 integrin (direct cytoplasmic domain binding); post-translational modifications including ubiquitination (at Lys-870/882, controlling lysosomal degradation), O-GlcNAcylation, and N-glycosylation at N370 (ER exit) and N413 (HNK-1/N-cadherin interaction) further tune GluA2 trafficking. The GluA2 CTD is necessary and sufficient for NMDA receptor-dependent LTD, and a single membrane-proximal residue and phospho-Y876 gate homeostatic synaptic upscaling via GRIP1. Through its extracellular domain, GluA2 also non-ionotropically regulates mGluR-LTD via N-cadherin–Rac1–cofilin-mediated actin reorganization and controls dendritic localization via retrograde Sema3A–PlexA signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRIA2 encodes GluA2, the AMPA-type glutamate receptor subunit that governs the Ca2+ permeability of fast excitatory synaptic transmission in the brain [#1, #2]. The defining feature of GluA2 is an arginine introduced at the Q/R site of the channel pore by ADAR-catalyzed adenosine-to-inosine RNA editing, which depends on an imperfect exon-intron base-paired duplex in the pre-mRNA and renders heteromeric AMPARs Ca2+-impermeable [#0, #2]; loss of this editing increases Ca2+ permeability and macroscopic conductance, producing seizures and lethality in mice [#2, #7], while restoring an edited (arginine) codon genomically is well tolerated, showing that Ca2+ permeability is set by the relative abundance of edited GluA2 [#6]. Rather than a binary impermeable channel, GluA2-containing AMPARs span a continuum of Ca2+ permeabilities tuned by subunit composition and auxiliary subunits (TARPs, cornichons) acting on the selectivity filter [#43]. GluA2 assembles as a tetrameric dimer-of-dimers ligand-gated cation channel [#10] whose agonist-induced clamshell closure, gating, and desensitization, and their modulation by TARP \\u03b32, are defined by crystal and cryo-EM structures [#14, #23, #33]. Surface delivery, retention, and degradation of GluA2 are controlled through its C-terminal domain by an NSF/PICK1/GRIP1 trafficking axis \\u2014 NSF promotes membrane insertion (a step disrupted by Plk2 and requiring Q/R editing) [#15, #16], PICK1 mediates endosomal retention and an ER-exit step downstream of RAB39B and CaMKII/Ca2+ [#22, #25, #29], and GRIP1 retains and recycles receptors via phospho-Y876 [#19, #40] \\u2014 with additional control by \\u03b23 integrin binding, ubiquitination at Lys-870/882 directing lysosomal degradation, O-GlcNAcylation, and N-glycosylation at N370 and N413 [#20, #28, #24, #30]. The GluA2 CTD is necessary and sufficient for NMDAR-dependent LTD and, through a membrane-proximal residue and phospho-Y876/GRIP1, for homeostatic synaptic upscaling [#34, #35, #40], while the extracellular domain mediates a non-ionotropic role in mGluR-LTD via N-cadherin\\u2013Rac1\\u2013cofilin actin reorganization [#18]. De novo heterozygous GRIA2 mutations cause neurodevelopmental disorders, acting predominantly through loss-of-function reductions in receptor current but in some cases through gain-of-function gating changes [#38, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established how the Q/R editing site is recognized, answering how a single adenosine in GluA2 pre-mRNA is selected for site-specific modification.\",\n      \"evidence\": \"Mutagenesis of intronic and exonic complementary sequences with complementarity-restoring rescue in transfected PC12 cells\",\n      \"pmids\": [\"8269514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the editing enzyme\", \"Quantitative editing efficiency in vivo not addressed\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Linked GluA2 (GluR-B) expression level to the Ca2+ permeability of native AMPARs, defining its physiological function in distinct neuron types.\",\n      \"evidence\": \"Patch-clamp plus single-cell mRNA analysis in neocortical brain slices\",\n      \"pmids\": [\"8011338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate editing from expression level\", \"Subunit stoichiometry of native receptors not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Proved in vivo that the edited arginine is essential for Ca2+ impermeability and survival, establishing editing as a non-redundant physiological requirement.\",\n      \"evidence\": \"Editing-incompetent GluR-B knock-in mice with electrophysiology and phenotyping\",\n      \"pmids\": [\"7502080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular cause of seizures vs Ca2+ influx not dissected here\", \"Developmental timing of requirement unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified the editing reaction biochemically as site-selective A-to-I deamination by a dsRNA adenosine deaminase, moving from genetics to enzyme mechanism.\",\n      \"evidence\": \"In vitro editing assay with HeLa nuclear extract and TLC nucleotide analysis\",\n      \"pmids\": [\"7721757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ADAR isoform not pinpointed\", \"Required cofactors not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Reconstituted editing with recombinant enzyme, showing duplex structure and a cofactor balance govern editing accuracy.\",\n      \"evidence\": \"In vitro editing with recombinant DRADA and purified GluR-B RNA\",\n      \"pmids\": [\"8598204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor identity not determined\", \"ADAR1 vs ADAR2 contributions in neurons unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated that the isolated ligand-binding domain folds autonomously and binds agonist with native pharmacology independent of glycosylation, enabling structural study.\",\n      \"evidence\": \"Bacterial S1-S2 expression and [3H]AMPA radioligand binding\",\n      \"pmids\": [\"8663017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model at this stage\", \"Channel-coupled behavior not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed unedited GluA2 is dispensable when an edited codon is supplied genomically, establishing that Ca2+ permeability is set by edited GluA2 abundance relative to other subunits.\",\n      \"evidence\": \"Exonic arginine knock-in mice with electrophysiology and phenotyping\",\n      \"pmids\": [\"9811877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roles of editing kinetics in development not tested\", \"Other editing sites not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Dissected the disease mechanism of editing deficiency, attributing seizures to increased macroscopic conductance rather than Ca2+ influx per se.\",\n      \"evidence\": \"Allelic series of gene-targeted mice with patch-clamp and in vivo phenotyping\",\n      \"pmids\": [\"10195181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit-level basis of epilepsy not resolved\", \"Dendritic architecture defect mechanism unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined ADAR2 enzymology on GluA2 RNA \\u2014 base-flipping, 5' duplex dependence, positioning over affinity, and homodimer requirement \\u2014 explaining site selectivity.\",\n      \"evidence\": \"In vitro footprinting, kinetics, 2-aminopurine fluorescence, and RNA-dependent cross-linking (idx 8\\u201311)\",\n      \"pmids\": [\"10836790\", \"11015203\", \"12163487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of dimerization not tested\", \"Regulation of editing levels in neurons not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the quaternary architecture of GluA2 as a 2-fold symmetric dimer-of-dimers tetramer, the structural framework for later mechanistic studies.\",\n      \"evidence\": \"EM and biochemical characterization of purified GluR-B homomers\",\n      \"pmids\": [\"11705385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Low resolution; no domain-level detail\", \"Heteromeric assembly not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed RNA Pol II CTD coordinates editing-before-splicing, explaining how intronic ADAR2 recognition sequences are retained long enough for editing.\",\n      \"evidence\": \"Cell-based splicing/editing assays with CTD truncation minigenes\",\n      \"pmids\": [\"17525170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CTD and ADAR2 not defined\", \"In vivo coupling not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified a GluA2(long)-specific, GluA1-independent route for activity- and LTP-driven synaptic AMPAR delivery, broadening models of plasticity.\",\n      \"evidence\": \"Viral overexpression, dominant-negatives, and slice electrophysiology with activity manipulation\",\n      \"pmids\": [\"14687553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinants in the long tail not mapped\", \"Adult vs juvenile differences unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the structural basis of agonist activation, desensitization, and allosteric modulation, defining the LBD as the conformational switch.\",\n      \"evidence\": \"X-ray crystallography of GluA2 S1S2 LBD with diverse ligands\",\n      \"pmids\": [\"20713069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isolated LBD lacks intact-receptor context\", \"Gating coupling to pore inferred indirectly\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the dual requirements \\u2014 NSF binding and Q/R editing \\u2014 for GluA2 plasma membrane insertion, and showed Plk2 gates this via NSF engagement.\",\n      \"evidence\": \"pHluorin-TIRF imaging of fusion events with domain mutants; Plk2-NSF Co-IP and electrophysiology (idx 15\\u201316)\",\n      \"pmids\": [\"20534470\", \"20802490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How editing influences insertion mechanistically unclear\", \"Plk2 substrate other than NSF not excluded\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-ionotropic GluA2 function in mGluR-LTD via extracellular N-cadherin\\u2013Rac1\\u2013cofilin signaling, separating channel-independent from channel-dependent roles.\",\n      \"evidence\": \"GluA2 KO, domain mutants, N-cadherin/Rac1/cofilin manipulations with slice LTD recordings\",\n      \"pmids\": [\"21248105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GluA2\\u2013N-cadherin contact not defined\", \"Generality across synapse types untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established \\u03b23 integrin, S-SCAM/MAGI-2, and PICK1 as distinct controllers of synaptic GluA2 levels and homeostatic strength, expanding the trafficking interactome.\",\n      \"evidence\": \"Co-IP from brain, heterologous co-expression, RNAi, and electrophysiology (idx 20\\u201322)\",\n      \"pmids\": [\"22232691\", \"22593065\", \"22915106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among these regulators unclear\", \"Binding sites on GluA2 not all mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Captured intact-receptor conformations across resting, pre-open, and desensitized states and the TARP \\u03b32-bound architecture, linking LBD motions to channel gating.\",\n      \"evidence\": \"Cryo-EM and DEER of full GluA2 in multiple functional states and GluA2\\u2013\\u03b32 complex (idx 23, 33)\",\n      \"pmids\": [\"25109876\", \"27368053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heteromeric receptor structures not resolved here\", \"Editing-site effect on pore not visualized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined multiple post-translational and post-transcriptional controls of GluA2 trafficking and supply (O-GlcNAcylation, Ca2+/PICK1 ER-exit, Sema3A/PlexA dendritic targeting, FXR1P translational repression).\",\n      \"evidence\": \"Biochemical detection, domain mutants, Co-IP, conditional KO, and electrophysiology across systems (idx 24\\u201327)\",\n      \"pmids\": [\"24381264\", \"24831007\", \"24599038\", \"25456134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc sites on GluA2 not mapped\", \"Enzymes responsible not all identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped ubiquitination sites (Lys-870/882) controlling lysosomal degradation, N-glycosylation sites (N370 ER exit, N413 HNK-1/N-cadherin), and the RAB39B\\u2013PICK1 ER-to-Golgi route, refining the GluA2 trafficking code.\",\n      \"evidence\": \"Site-directed mutagenesis, surface/endosome assays, Co-IP, RAB39B knockdown electrophysiology (idx 28\\u201332)\",\n      \"pmids\": [\"25660027\", \"25784538\", \"26271046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase for GluA2 not identified\", \"GSK-3\\u03b2/PICK1 phospho-control in vivo relevance partial\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated by reciprocal CTD-exchange knock-ins that the GluA2 CTD is necessary and sufficient for NMDAR-dependent LTD, and that a membrane-proximal tail region drives homeostatic upscaling.\",\n      \"evidence\": \"CTD-swap knock-in mice and viral domain-mutant rescue with LTP/LTD electrophysiology (idx 34\\u201335)\",\n      \"pmids\": [\"29230056\", \"29180434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector proteins reading the CTD during LTD not fully defined\", \"Single critical residue identity narrow\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified phospho-Y876 as the molecular switch coupling GluA2 to GRIP1 specifically during homeostatic scaling but not Hebbian plasticity, separating the two trafficking modes.\",\n      \"evidence\": \"Y876F phospho-deficient knock-in mice, scaling assays, and GluA2\\u2013GRIP1 Co-IP\",\n      \"pmids\": [\"32071234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase acting on Y876 not defined\", \"Other phospho-Y876 effectors not excluded\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed both autoantibody-driven and RAB39B-dependent loss of synaptic GluA2 shift receptors toward Ca2+-permeable forms and impair plasticity and spine maturation, linking GluA2 trafficking to disease.\",\n      \"evidence\": \"Passive antibody transfer in mice and Rab39b KO with spine analysis, electrophysiology, and CP-AMPAR pharmacology (idx 36, 41)\",\n      \"pmids\": [\"30146304\", \"34035473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory CP-AMPAR identity not fully defined\", \"Reversibility/therapeutic windows untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that de novo GRIA2 mutations cause neurodevelopmental disorders predominantly via loss-of-function reduced current, with gain-of-function gating mutations as a distinct, perampanel-sensitive subclass.\",\n      \"evidence\": \"Electrophysiology of 28 patient mutations and detailed characterization of A643V with pharmacology (idx 38, 42)\",\n      \"pmids\": [\"31300657\", \"36161652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation incomplete\", \"In vivo modeling of individual variants limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reframed GluA2-containing AMPARs as a continuum of Ca2+ permeabilities tuned by composition and auxiliary subunits, revising the binary Ca2+-impermeable model.\",\n      \"evidence\": \"Patch-clamp across subunit and auxiliary-subunit combinations with identification of an extracellular Ca2+ docking site\",\n      \"pmids\": [\"40108453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the docking site not resolved here\", \"Physiological consequences of the continuum in vivo untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GluA2 trafficking regulators, editing status, and auxiliary-subunit composition are integrated in real time at individual synapses to set Ca2+ permeability and plasticity outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling editing, trafficking, and auxiliary-subunit control\", \"E3 ligase and Y876 kinase identities unknown\", \"Heteromeric receptor structures with editing site visualized lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2, 23, 43]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 15, 43]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15, 16, 20, 28]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [25, 29, 30]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22, 28]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 2, 12, 34]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [15, 16, 22, 29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 38, 42]}\n    ],\n    \"complexes\": [\n      \"AMPA receptor (tetramer, dimer-of-dimers)\",\n      \"GluA2-TARP \\u03b32 (stargazin) complex\"\n    ],\n    \"partners\": [\n      \"NSF\",\n      \"PICK1\",\n      \"GRIP1\",\n      \"ITGB3\",\n      \"RAB39B\",\n      \"CDH2\",\n      \"PLXNA\",\n      \"FXR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}