{"gene":"GRIK2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"PKC-mediated phosphorylation of GluK2 at serine 868 promotes GluK2 SUMOylation at lysine 886; both modifications are required for internalization of GluK2-containing KARs during long-term depression at hippocampal mossy fiber synapses. Phosphorylation at S868 without SUMOylation instead increases KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane.","method":"Phosphomimetic and non-phosphorylatable mutagenesis, SUMO-1 infusion, patch-clamp electrophysiology, surface biotinylation in neurons","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, electrophysiology, surface biotinylation) in two complementary papers from same group establishing the same mechanism","pmids":["22522402","22089239"],"is_preprint":false},{"year":2011,"finding":"Kainate stimulation causes rapid PKC-dependent phosphorylation of GluK2 at both S846 and S868; only S868 phosphorylation is required to enhance GluK2 SUMOylation and promote endocytosis. SUMO-1 infusion reduces KAR-mediated currents in WT or S846A GluK2 but not in S868A mutant GluK2.","method":"Phosphomimetic mutagenesis (S846A, S868A), SUMO-1 intracellular infusion, whole-cell patch-clamp in HEK293 cells and neurons, surface biotinylation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and electrophysiology, multiple orthogonal methods within single rigorous study","pmids":["22089239"],"is_preprint":false},{"year":2012,"finding":"Brain ischemia evokes sustained GluK2 SUMOylation in hippocampal CA1; SUMOylated GluK2 promotes its interaction with MLK3, thereby activating the MLK3-JNK3 apoptotic signaling pathway. Inhibiting GluK2 endocytosis decreases MLK3-JNK3 activation and GluK2-MLK3 binding.","method":"Overexpression of WT vs. SUMOylation-deficient GluK2 mutant, co-immunoprecipitation, kinase activity assay in cultured cortical neurons and rat brain ischemia model","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with mutant overexpression and functional kinase assay, single lab","pmids":["22483987"],"is_preprint":false},{"year":2014,"finding":"Src family kinases phosphorylate GluK2 at tyrosine 590 (Y590) in response to brain ischemia/reperfusion. GluK2-Y590 phosphorylation increases whole-cell currents and calcium influx in response to kainate, facilitates GluK2 endocytosis, and activates JNK3 and c-Jun downstream proapoptotic signaling.","method":"Site-directed mutagenesis (Y590), whole-cell patch-clamp, calcium imaging, co-immunoprecipitation of GluK2 with Src, rat ischemia/reperfusion model with biochemical assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with electrophysiology, calcium imaging, and co-IP, single lab with multiple orthogonal methods","pmids":["25201974"],"is_preprint":false},{"year":2014,"finding":"Parkin interacts with the GluK2 subunit of kainate receptors; loss of parkin function causes GluK2 protein accumulation in the plasma membrane, potentiates KAR currents, and increases KAR-dependent excitotoxicity in neurons and in mouse brain.","method":"Co-immunoprecipitation, surface biotinylation, whole-cell patch-clamp, parkin knockout/loss-of-function in primary cultured neurons and in vivo mouse brain expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, surface biotinylation, electrophysiology, and in vivo model all in one study","pmids":["25316086"],"is_preprint":false},{"year":2012,"finding":"GluK2 and GluK5 assemble as heterotetramers with 2:2 stoichiometry in the plasma membrane of live cells, as directly counted by single-molecule imaging.","method":"Single-molecule imaging (fluorescence subunit counting) in live cell plasma membranes","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct single-molecule counting in live cells, rigorous quantitative method, single lab","pmids":["22509486"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of the GluK2/GluK5 heteromeric kainate receptor in apo, antagonist-bound, and desensitized states show the receptor assembles with two copies of each subunit, GluK5 subunits proximal to the channel, and that during desensitization GluK2 (but not GluK5) subunits undergo major structural rearrangements facilitating channel closure.","method":"Cryo-electron microscopy structural determination in multiple states","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures in multiple states, direct structural determination, single study","pmids":["33724189"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures show BPAM344 (positive allosteric modulator) binds at the ligand-binding domain dimer interface (two molecules per dimer) and stabilizes GluK2 in the closed state in the absence of agonist; perampanel (negative allosteric modulator) binds to extracellular collar sites of the ion channel in two out of four GluK2 subunits and also stabilizes the closed state.","method":"Cryo-electron microscopy structural determination of GluK2 complexes with BPAM344, DNQX, and perampanel","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with bound ligands, direct visualization of binding sites, single rigorous study","pmids":["36857176"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GluK2 in complex with Neto2 in apo closed and open (agonist kainate + BPAM344) states show that Neto2 binding prevents tightening of the LBD dimer-dimer interface during activation and slows deactivation kinetics, while not changing individual LBD or ion channel behavior.","method":"Time-resolved cryo-electron microscopy, electrophysiology","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures in multiple states combined with electrophysiology, single rigorous study","pmids":["40846810"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of homomeric GluK2 in apo and partial agonist (domoate)-bound states reveal that the apo state is captured in a desensitized conformation, confirming KAR desensitization prior to activation; domoate-bound GluK2 populates intermediate and desensitized states. N-glycans at the ATD-LBD interface modulate receptor gating by interfering with cation binding at the LBD dimer interface.","method":"Cryo-electron microscopy, electrophysiology (functional validation of N-glycan mutants)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures in multiple states with electrophysiological functional validation, single rigorous study","pmids":["40442317"],"is_preprint":false},{"year":2019,"finding":"The N-terminal domain (NTD) of GluK2 binds the first CUB domain of Neto1/Neto2 (NTD-CUB1 interaction), and the GluK2 core binds Neto proteins through domains other than CUB1. The NTD-CUB1 interaction mediates Neto1/Neto2 differential regulation of GluK2 gating kinetics and recovery from desensitization; the NTD itself stabilizes the GluK2 desensitized state.","method":"Electrophysiology in HEK293T cells with deletion mutants, chimeric constructs, and charge-neutralization mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — systematic mutagenesis and chimeric receptor analysis with functional electrophysiology, multiple orthogonal approaches in single study","pmids":["31628192"],"is_preprint":false},{"year":2010,"finding":"Cysteine mutant cross-linking experiments in full-length GluK2 established that the ATD and LBD extracellular domains assemble as a dimer of dimers with subunit partner-swapping between ATD and LBD layers, and that cross-linking either the ATD or LBD inhibits GluK2 activation.","method":"Cysteine mutant cross-linking in full-length GluK2, non-reducing SDS-PAGE, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-type biochemical cross-linking combined with functional electrophysiology in single study","pmids":["20404149"],"is_preprint":false},{"year":1998,"finding":"The kainate-binding site of GluR-6 (GluK2) is formed exclusively by two discontinuous extracellular segments S1 and S2 homologous to bacterial amino-acid-binding proteins; both S1 and S2 contribute to agonist selectivity.","method":"Expression of recombinant GluR-6 fragments in insect cells, deletion analysis, S1-S2 chimeras between GluR-6 and GluR-D, [3H]kainate binding assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic deletion and chimera analysis with direct ligand-binding assays, single rigorous study","pmids":["9494120"],"is_preprint":false},{"year":2018,"finding":"ADAR2-dependent Q/R editing of GluK2 mRNA (converting glutamine to arginine) regulates KAR surface expression. Suppression of synaptic activity induces proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing; because GluK2(Q)-containing KARs assemble and exit the ER more efficiently, this leads to KAR upscaling. Partial ADAR2 knockdown phenocopies and occludes KAR upscaling.","method":"Proteasome inhibition, ADAR2 knockdown (siRNA), surface biotinylation, activity suppression (TTX treatment) in hippocampal neurons","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (KD, inhibitor, surface biotinylation, occlusion experiment) in single study","pmids":["30559217"],"is_preprint":false},{"year":2010,"finding":"Scanning mutagenesis of the pore-loop, M1, and M3 helices identified three abutting surfaces along M1-M2-M3 where substitutions render GluK2(Q) channels susceptible to fatty acid inhibition. Arginine substitutions at M3 positions F611, L614, S618, and T621 increase chloride permeability and eliminate polyamine block, demonstrating the importance of the central cavity in ionic selectivity.","method":"Scanning mutagenesis of GluK2, whole-cell patch-clamp electrophysiology, fatty acid application, polyamine block assays","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional electrophysiology across multiple residues, single rigorous study","pmids":["20805577"],"is_preprint":false},{"year":2020,"finding":"Seizure protein 6 (SEZ6) interacts with GluK2 through its ectodomain and promotes post-ER transport of GluK2 in the secretory pathway; loss of SEZ6 reduces GluK2/3 surface levels, reduces kainate-evoked currents, and prevents HNK-1 glycosylation modification of GluK2/3.","method":"Co-immunoprecipitation, surface biotinylation in neurons, electrophysiology in hippocampal slices, in vitro and in vivo glycan analysis (HNK-1), SEZ6 knockout","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, electrophysiology, surface biotinylation, and in vivo KO, multiple orthogonal methods in single study","pmids":["32567721"],"is_preprint":false},{"year":2020,"finding":"GluK2 interacts with the K-Cl cotransporter KCC2 to regulate structural maturation of dendritic spines. GluK2 silencing in CA3 hippocampal neurons alters dendritic spine morphology and reduces mEPSC frequency; this is associated with redistribution of KCC2, reduction of 4.1N and cofilin expression, and increased F-actin stability (measured by FRAP). Overexpression of KCC2 rescues the aberrant spine morphology caused by GluK2 deficiency.","method":"In vivo lentiviral knockdown of GluK2, co-immunoprecipitation, FRAP of β-actin, mEPSC recordings, KCC2 rescue overexpression","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, FRAP, electrophysiology, and rescue experiment in single study from one lab","pmids":["33005130"],"is_preprint":false},{"year":2016,"finding":"TTBK2 (tau tubulin kinase 2) downregulates GluK2 activity by decreasing receptor protein abundance at the cell membrane via RAB5-dependent endocytosis; this effect requires TTBK2 kinase activity and is absent with truncated TTBK2(450), which lacks the C-terminal region mutated in SCA11 patients.","method":"Xenopus oocyte expression, dual-electrode voltage clamp, confocal microscopy of EGFP-tagged GluK2, overexpression of dominant-negative RAB5(N133I)","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional electrophysiology with localization imaging and RAB5 epistasis in heterologous system, single lab","pmids":["27607061"],"is_preprint":false},{"year":2013,"finding":"Double mutant cycle analysis of GluK2 demonstrated strong energetic coupling between the Q/R site residue in the pore loop (M2) and L614 in the M3 helix at the central cavity; replacement of L614 with smaller side chains reverses fatty acid effects on edited GluK2(R) channels from inhibition to potentiation.","method":"Double mutant cycle analysis, whole-cell patch-clamp electrophysiology, scanning mutagenesis in GluK2","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — thermodynamic double mutant cycle analysis with functional electrophysiology, rigorous quantitative approach","pmids":["23940260"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of GluK1 and GluK2 ligand-binding domains bound to dysiherbaine analogues identified three amino acids (Thr503, Ser706, Ser726 in GluK1 vs. Ala487, Asn690, Thr710 in GluK2) generating differences in binding mode and receptor selectivity. All ligands induced full domain closure regardless of agonist efficacy.","method":"X-ray crystallography of ligand-binding domains with multiple bound ligands","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with multiple ligands defining binding pocket residues, single rigorous study","pmids":["21893069"],"is_preprint":false},{"year":2018,"finding":"Cysteine substitutions at A657C (within SYTANLAAF motif) and adjacent L659C in the GluK2 M3 bundle-crossing gate allow direct channel activation by Cd2+; activation by Cd2+ requires substitution at only two of four subunits in the tetramer, and occurs similarly for either the A/C or B/D conformations. This demonstrates rapid and reversible channel activation independent of agonist-site occupancy.","method":"Cysteine mutagenesis, Cd2+ application, whole-cell patch-clamp, MTSEA modification, heteromeric and chimeric receptor analysis","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis combined with chemical gating and functional electrophysiology, rigorous mechanistic study","pmids":["30498132"],"is_preprint":false},{"year":2024,"finding":"GluK2 is expressed in dorsal root ganglion somatosensory neurons and functions as a cold-temperature sensor in the periphery; GluK2 knockout mice exhibit a specific deficit in sensing cold (but not cool, hot, or mechanical) temperatures in behavioral assays. This identifies a role for GluK2 as a thermoreceptor co-opted from its function as a glutamate chemoreceptor.","method":"GluK2 knockout mouse behavioral analysis (cold/heat/mechanical sensitivity tests), DRG neuron analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific behavioral phenotype and cellular localization analysis, published in high-tier journal","pmids":["38467901"],"is_preprint":false},{"year":2023,"finding":"GluK2 functions as a metabotropic receptor coupled to phospholipase D (PLD) in primary mechanosensory spindle terminals, independent of its ionotropic function. Immunofluorescence and western blotting showed GluK2 is the only glutamate receptor subunit present in these terminals; in a mouse model with ionotropic function ablated in GluK2, spindle glutamatergic responses were still present, confirming purely metabotropic signaling.","method":"Immunofluorescence, western blotting, far-western blotting, electrophysiology in spindle mechanosensory terminals, ionotropic function-ablated mouse model","journal":"Experimental physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple protein detection methods plus functional assay with ablation model, single lab","pmids":["37656490"],"is_preprint":false},{"year":2021,"finding":"Autoantibodies against GluK2 in patients with autoimmune encephalitis internalize GluK2 in HEK293 cells and neurons, causing a significant reduction of GluK2-mediated currents; this antibody-mediated internalization is reversible in neurons.","method":"Cell-based assay, immunoprecipitation, confocal microscopy in neurons, electrophysiology in GluK2-expressing HEK293 cells","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CBA, co-IP, confocal, electrophysiology) in single study","pmids":["33949707"],"is_preprint":false},{"year":2023,"finding":"GluK2 Q/R editing status (edited GluK2(R) vs. unedited GluK2(Q)) controls the balance between ionotropic and metabotropic KAR signaling at mossy fiber-CA3 synapses. GluK2(Q) editing-deficient mice show increased postsynaptic KAR ionotropic function and presynaptic facilitation but reduced metabotropic KAR function; they also display fewer GluA1/GluA3-containing AMPARs and reduced LTP at CA1-Schaffer collateral synapses.","method":"GluK2 editing-deficient knock-in mice, electrophysiology (postsynaptic KAR currents, ISAHP, LTP), western blotting for AMPAR subunits","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with electrophysiology and biochemistry, single lab","pmids":["37720087"],"is_preprint":false},{"year":2015,"finding":"Neto1 and Neto2 have distinct subunit-dependent effects on GluK2 gating: co-expression of Neto2 with GluK2 homomers increases recovery from desensitization and slows desensitization onset at all glutamate concentrations; chimeric analysis showed the extracellular N-terminal CUB domain region is largely responsible for the distinct regulatory effects.","method":"Patch-clamp electrophysiology in HEK-293T cells, Neto1/Neto2 chimeric subunit analysis","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic chimeric analysis with functional electrophysiology, single lab","pmids":["26277340"],"is_preprint":false},{"year":2013,"finding":"Agonist binding to the GluK5 subunit, but not GluK2, is both necessary and sufficient for surface expression of heteromeric GluK2/GluK5 receptors; occupancy of the GluK2 agonist site alone is not sufficient for surface trafficking of the heteromer.","method":"Point mutations reducing agonist affinity in GluK2 or GluK5 subunits, surface expression assays in heterologous cells, rescue with competitive antagonist or WT partner subunit","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mutagenesis with surface expression assays, systematic rescue experiments, single lab","pmids":["23975096"],"is_preprint":false},{"year":2013,"finding":"Mutations K531A and R775A in the GluK2 LBD dimer interface attenuate desensitization; K531A also switches relative efficacies of glutamate and kainate. Crystal structures reveal new dimer contacts with K531 truncation and show that absence of chloride at the dimer-interface anion binding site (R775A) is sufficient to attenuate desensitization, suggesting charge balance at the dimer interface maintains instability required for rapid desensitization.","method":"Site-directed mutagenesis, X-ray crystallography of LBD, patch-clamp electrophysiology","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures combined with mutagenesis and electrophysiology, single study with orthogonal methods","pmids":["23720540"],"is_preprint":false},{"year":2017,"finding":"A de novo gain-of-function point mutation A657T in GluK2 causes constitutive channel activity in nominally glutamate-free media, profoundly altered channel gating, and neurodevelopmental deficits (ataxia, motor and speech delay, intellectual disability) in a human patient.","method":"Whole-exome sequencing to identify de novo variant, whole-cell voltage-clamp recordings of mutant KARs in heterologous expression system","journal":"Neurology. Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional characterization in heterologous system single study; replicated in context of broader cohort study (PMID 34375587)","pmids":["28180184"],"is_preprint":false},{"year":2021,"finding":"Mutations in the M3 transmembrane domain of GluK2 (p.Ala657Thr, p.Thr660Lys, p.Thr660Arg) and the M3-S2 linker (p.Ile668Thr) cause complex alterations in channel gating kinetics of homomeric and heteromeric KARs. p.Thr660Lys and p.Thr660Arg mutations produce markedly slowed gating kinetics similar to p.Ala657Thr, and p.Thr660Lys is associated with severe epilepsy while both p.Thr660Lys and p.Thr660Arg cause hypomyelination.","method":"Whole-exome sequencing, whole-cell voltage-clamp electrophysiology in heterologous expression system, membrane localization assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic electrophysiological characterization of multiple independent mutants, replicated in multiple patients, correlation with clinical phenotype","pmids":["34375587"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GluK2 ion channel pore in complex with polyamine channel blockers (spermine, Kukoamine A, NpTx-8, PhTx-74) reveal that blockers reside inside the pore intracellular to the closed M3 helix bundle-crossing gate, with hydrophobic heads in the central cavity and positively charged polyamine tails spanning the selectivity filter, establishing the trapping mechanism of KAR channel block.","method":"Cryo-electron microscopy structural determination, molecular dynamics simulations","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with four different blockers plus MD simulations, single rigorous study","pmids":["39592599"],"is_preprint":false},{"year":2010,"finding":"The M867I mutation in the C-terminus of human GluK2 (associated with autism) slows the channel desensitization rate by ~1.6-fold at saturating glutamate but does not affect channel-opening or channel-closing rate constants. Wild-type human GluK2 has a ~3-fold smaller channel-opening rate constant than rat GluK2 but an identical channel-closing rate and ~2-fold lower EC50.","method":"Laser-pulse photolysis with whole-cell patch-clamp recording, detailed kinetic mechanism analysis of WT and M867I mutant GluK2","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous kinetic analysis in heterologous system, single lab, single method type","pmids":["20863077"],"is_preprint":false},{"year":2021,"finding":"GluK2 Q/R editing of the calcium permeability gate regulates synapse morphology: overexpression of calcium-permeable GluK2(Q) increases spine length and head area in hippocampal neurons compared to calcium-impermeable GluK2(R); the N-terminal domain (NTD) is responsible for this morphogenic effect, as shown by NTD-swap chimeras between GluK2 and GluK1.","method":"Overexpression of GluK2(Q) vs. GluK2(R) in primary cultured hippocampal neurons, GluK1-GluK2 domain-swap chimeras, confocal imaging of spine morphology","journal":"Synapse","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression with chimeric domain analysis in primary neurons, single lab","pmids":["36121930"],"is_preprint":false},{"year":2017,"finding":"SUMOylation of PKC (not of GluK2 itself) inhibits the binding of 14-3-3τ to GluK2a by decreasing PKC-mediated phosphorylation of GluK2a, establishing a pathway by which PKC SUMOylation regulates the 14-3-3τ–GluK2a complex and may contribute to KAR-EPSC decay kinetics.","method":"Co-immunoprecipitation, overexpression of SUMO-modified PKC, western blotting for GluK2 phosphorylation levels","journal":"Channels","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP study from single lab, no direct electrophysiological validation in this paper","pmids":["28837400"],"is_preprint":false},{"year":2021,"finding":"Postoperative pain (plantar incision) induces synaptic delivery of GluK2 in ipsilateral spinal dorsal horns and increases GluK2-GRIP interaction; knockdown of GRIP with intrathecal siRNA reduces synaptic GluK2 abundance and attenuates postoperative pain hypersensitivity.","method":"Co-immunoprecipitation, synaptic fractionation, intrathecal GRIP siRNA, behavioral pain assays in rats","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with functional siRNA knockdown and behavioral readout, single lab","pmids":["33847855"],"is_preprint":false},{"year":2025,"finding":"NETO2 slows GluK2 channel-opening rate (~7-fold) and channel-closing rate (~3-fold), while NETO1 slows both rates by ~2-fold; this establishes differential kinetic regulation of GluK2 channel gating by the two Neto auxiliary subunits.","method":"Laser-pulse photolysis combined with whole-cell patch-clamp recording in HEK293 cells expressing GluK2 with NETO1 or NETO2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous kinetic analysis in heterologous system, single lab, single method","pmids":["41197725"],"is_preprint":false},{"year":2020,"finding":"GluK2 internalization during kainate excitotoxicity occurs through a clathrin-independent but dynamin-dependent mechanism regulated by intracellular Ca2+/calcineurin signaling; PICK1-GluK2 interaction is regulated by Ca2+/calcineurin, and calcineurin activation is linked to dynamin function.","method":"Surface biotinylation, co-immunoprecipitation, inhibitors of clathrin-independent endocytosis, Ca2+ chelators, calcineurin inhibitors in cultured neurons","journal":"Journal of integrative neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple inhibitor approaches with co-IP and surface biotinylation, single lab","pmids":["33070524"],"is_preprint":false},{"year":2025,"finding":"De novo gain-of-function Grik2 knock-in mouse models (orthologous to human p.Ala657Thr and p.Thr660Lys) exhibit developmental, motor, cognitive, and behavioral impairments; GluK2(T660K) mice additionally show interictal EEG abnormalities and handling-induced seizures, establishing in vivo pathogenicity of these gain-of-function mutations.","method":"CRISPR/Cas9 knock-in mouse generation, behavioral analysis battery, EEG recording","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in models with behavioral and electrophysiological characterization, single study","pmids":["41391686"],"is_preprint":false},{"year":2024,"finding":"GluK2 is selectively expressed on dermal mast cells; GluK2 agonism (SYM2081) inhibits mast cell degranulation in response to MrgprB2 agonism, suppresses expression of Mrgprb2 and mast cell proliferation genes, and reduces skin inflammation in murine dermatitis and rosacea models.","method":"In vitro mast cell degranulation assays, in vivo intradermal and topical administration, transcriptomic analysis, Ki-67 and BrdU incorporation assays, mouse inflammatory models","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo assays, single lab, novel peripheral function","pmids":["39661706"],"is_preprint":false},{"year":2007,"finding":"A homozygous complex mutation in GRIK2 causing loss of the first ligand-binding domain, adjacent transmembrane domain, and pore loop results in complete loss of GLuK6 (GluK2) function and segregates with moderate-to-severe autosomal recessive intellectual disability in a consanguineous Iranian family, establishing that GluK2 is indispensable for higher brain function.","method":"Genetic linkage analysis, mutation identification, electrophysiological characterization of mutant protein (loss of function)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic co-segregation with electrophysiological functional validation, first proof of concept","pmids":["17847003"],"is_preprint":false}],"current_model":"GluK2 (GRIK2) is a kainate-type ionotropic glutamate receptor subunit that assembles as a homotetrameric or 2:2 heteromeric (with GluK5) ligand-gated ion channel; its activity, surface expression, and synaptic plasticity are tightly regulated by PKC-mediated phosphorylation at S868 (which promotes SUMO modification at K886 to drive endocytosis or, without SUMOylation, promotes recycling), by Src-mediated phosphorylation at Y590 (increasing currents and downstream JNK3 apoptotic signaling), by ADAR2-dependent Q/R mRNA editing (controlling calcium permeability, ER exit, and the balance between ionotropic and metabotropic signaling), and by auxiliary subunits Neto1/Neto2 (which bind via CUB domain interactions with the GluK2 NTD to slow gating kinetics and modulate desensitization). GluK2 also acts as a cold thermoreceptor in peripheral somatosensory DRG neurons and as a metabotropic PLD-coupled receptor in mechanosensory spindle terminals, and it plays roles in dendritic spine maturation through interaction with KCC2 and in excitotoxic signaling through SUMOylation-mediated interaction with MLK3-JNK3."},"narrative":{"mechanistic_narrative":"GRIK2 encodes GluK2, a kainate-type ionotropic glutamate receptor subunit that assembles as homotetramers or, with GluK5, as 2:2 heterotetramers with GluK5 subunits positioned proximal to the channel [PMID:22509486, PMID:33724189]. The extracellular domains assemble as a dimer of dimers with subunit partner-swapping between the amino-terminal and ligand-binding domain (LBD) layers, and the kainate-binding site is built from two discontinuous segments, S1 and S2, that together set agonist selectivity [PMID:20404149, PMID:9494120]. Gating is governed by charge balance at the LBD dimer interface, where chloride occupancy and key interface residues maintain the instability required for rapid desensitization; structural studies capture the receptor in apo desensitized, agonist-bound, and antagonist-bound states, with GluK2 subunits undergoing the major rearrangements that close the channel [PMID:23720540, PMID:33724189, PMID:40442317]. The M1–M2–M3 pore region determines ionic selectivity and polyamine block, with the M3 bundle-crossing gate (SYTANLAAF motif) coupling to the central cavity and selectivity filter [PMID:20805577, PMID:30498132, PMID:39592599]. Receptor function is extensively tuned post-transcriptionally and post-translationally: ADAR2-dependent Q/R editing controls calcium permeability, ER exit, surface expression, and the balance between ionotropic and metabotropic signaling [PMID:30559217, PMID:37720087]; PKC phosphorylation at S868 promotes SUMOylation at K886 to drive endocytosis during long-term depression, whereas S868 phosphorylation without SUMOylation favors recycling and surface retention [PMID:22522402, PMID:22089239]; and Src phosphorylation at Y590 augments currents and calcium influx during ischemia [PMID:25201974]. Auxiliary Neto1/Neto2 subunits bind the GluK2 N-terminal domain via their CUB1 domain to slow gating and modulate desensitization [PMID:31628192, PMID:40846810, PMID:41197725], while trafficking partners including parkin, SEZ6, and TTBK2 control surface abundance [PMID:25316086, PMID:32567721, PMID:27607061]. Beyond synaptic transmission, GluK2 acts as a peripheral cold thermoreceptor in dorsal root ganglion neurons, signals metabotropically through phospholipase D in muscle spindle terminals, and regulates dendritic spine maturation via interaction with KCC2 [PMID:38467901, PMID:37656490, PMID:33005130]. Excitotoxic and apoptotic signaling proceeds through SUMOylated GluK2 recruitment of the MLK3–JNK3 cascade [PMID:22483987, PMID:25201974]. Loss-of-function GRIK2 mutation causes autosomal recessive intellectual disability, and de novo gain-of-function mutations in the M3 region cause neurodevelopmental disorders with epilepsy and hypomyelination [PMID:17847003, PMID:28180184, PMID:34375587, PMID:41391686].","teleology":[{"year":1998,"claim":"Establishing where agonist binds was prerequisite to understanding receptor activation; this work localized the kainate-binding pocket to two discontinuous extracellular segments.","evidence":"Recombinant GluR-6 fragment expression, deletion analysis, S1-S2 chimeras, and [3H]kainate binding","pmids":["9494120"],"confidence":"High","gaps":["Did not resolve the atomic structure of the bound site","Did not address subunit stoichiometry or gating coupling"]},{"year":2007,"claim":"Whether GluK2 is essential for human brain function was unknown; a loss-of-function mutation segregating with intellectual disability established its indispensable role.","evidence":"Genetic linkage in a consanguineous family plus electrophysiological characterization of the mutant","pmids":["17847003"],"confidence":"High","gaps":["Did not define the cellular circuit mechanism underlying cognitive impairment","Single family"]},{"year":2010,"claim":"Resolving how the extracellular domains and pore are organized clarified the gating machinery; cross-linking established a dimer-of-dimers architecture with partner swapping, and pore mutagenesis defined the ionic selectivity determinants.","evidence":"Cysteine cross-linking in full-length GluK2 and scanning mutagenesis of M1-M2-M3 with electrophysiology","pmids":["20404149","20805577"],"confidence":"High","gaps":["Did not provide a full-length structural model","Mechanism of desensitization-coupled conformational change not yet resolved"]},{"year":2011,"claim":"How agonist selectivity differs among kainate subunits was unclear; LBD crystal structures with dysiherbaine analogues identified the specific residues governing binding mode.","evidence":"X-ray crystallography of GluK1 and GluK2 LBDs with multiple ligands","pmids":["21893069"],"confidence":"High","gaps":["Isolated LBD does not report full-receptor gating","Did not address auxiliary-subunit effects on the binding pocket"]},{"year":2012,"claim":"The molecular code controlling receptor surface fate was undefined; PKC phosphorylation at S868 was shown to gate a bifurcation between SUMO-driven endocytosis (LTD) and recycling-driven surface retention, and heteromer stoichiometry was directly counted.","evidence":"Phosphomimetic/non-phosphorylatable mutagenesis, SUMO-1 infusion, surface biotinylation, electrophysiology, and single-molecule subunit counting","pmids":["22522402","22089239","22509486"],"confidence":"High","gaps":["SUMO ligase machinery acting on GluK2 not identified","How the phospho/SUMO switch is set in vivo unresolved"]},{"year":2012,"claim":"Whether GluK2 modification links to cell death was unknown; ischemia-induced SUMOylation was shown to recruit MLK3 and activate the JNK3 apoptotic cascade.","evidence":"Mutant overexpression, co-IP, and kinase assays in cortical neurons and a rat ischemia model","pmids":["22483987"],"confidence":"Medium","gaps":["Single lab, co-IP based","Stoichiometry and direct nature of GluK2-MLK3 contact not defined"]},{"year":2013,"claim":"The structural basis of rapid desensitization and Q/R-site pore coupling was unclear; interface mutagenesis with crystallography and double-mutant cycle analysis linked dimer-interface charge balance and the Q/R–L614 axis to gating and lipid modulation.","evidence":"Site-directed mutagenesis, LBD crystallography, double mutant cycle analysis, and patch-clamp","pmids":["23720540","23940260"],"confidence":"High","gaps":["Did not capture full-length desensitized intermediate","In vivo relevance of fatty-acid modulation unaddressed"]},{"year":2013,"claim":"Which subunit controls heteromer surface delivery was unknown; agonist occupancy of GluK5, not GluK2, was found necessary and sufficient for GluK2/GluK5 surface expression.","evidence":"Affinity-reducing point mutations and surface expression rescue assays in heterologous cells","pmids":["23975096"],"confidence":"Medium","gaps":["Trafficking checkpoint sensing agonist occupancy not identified","Single heterologous system"]},{"year":2014,"claim":"Additional regulatory inputs to GluK2 function were sought; Src-mediated Y590 phosphorylation was shown to boost currents and feed proapoptotic signaling, and parkin was identified as a trafficking regulator restraining surface GluK2 and excitotoxicity.","evidence":"Site-directed mutagenesis, electrophysiology, calcium imaging, co-IP, surface biotinylation, and ischemia / parkin-loss models","pmids":["25201974","25316086"],"confidence":"High","gaps":["Whether parkin ubiquitinates GluK2 directly not established","Interplay between Y590 and S868/SUMO pathways unresolved"]},{"year":2015,"claim":"How auxiliary subunits differentially shape gating was unclear; Neto1 and Neto2 were shown to have distinct, CUB-domain-dependent effects on desensitization and recovery.","evidence":"Patch-clamp with Neto1/Neto2 chimeric subunit analysis in HEK-293T cells","pmids":["26277340"],"confidence":"Medium","gaps":["Did not localize the binding interface to a specific GluK2 region","Single heterologous system"]},{"year":2018,"claim":"Whether the gate can be activated independently of agonist occupancy was untested; engineered cysteines in the M3 bundle crossing allowed direct Cd2+ activation requiring only two of four subunits, demonstrating agonist-site-independent gating.","evidence":"Cysteine mutagenesis, Cd2+ application, MTSEA modification, and chimeric receptor electrophysiology","pmids":["30498132"],"confidence":"High","gaps":["Physiological trigger of subunit-asymmetric gating in native receptors unknown"]},{"year":2018,"claim":"How activity scales KAR abundance was unknown; activity-dependent ADAR2 degradation reduces Q/R editing, and the more efficiently ER-exiting GluK2(Q) isoform drives KAR upscaling.","evidence":"Proteasome inhibition, ADAR2 siRNA, TTX activity suppression, surface biotinylation, and occlusion experiments in neurons","pmids":["30559217"],"confidence":"High","gaps":["Mechanism targeting ADAR2 for degradation not detailed","Timescale relative to other scaling pathways unresolved"]},{"year":2019,"claim":"The molecular interface for Neto regulation was undefined; the GluK2 NTD was shown to bind Neto CUB1, mediating differential gating control while stabilizing the desensitized state.","evidence":"Deletion mutants, chimeric constructs, charge-neutralization mutagenesis, and electrophysiology in HEK293T cells","pmids":["31628192"],"confidence":"High","gaps":["Did not provide a structural model of the NTD-CUB1 contact"]},{"year":2020,"claim":"Trafficking and morphogenic roles were broadened; SEZ6 promotes post-ER GluK2 transport and HNK-1 glycosylation, GluK2-KCC2 interaction regulates spine maturation, and TTBK2 downregulates GluK2 via RAB5-dependent endocytosis.","evidence":"Co-IP, surface biotinylation, slice/oocyte electrophysiology, FRAP, glycan analysis, and SEZ6 knockout / RAB5 epistasis","pmids":["32567721","33005130","27607061"],"confidence":"Medium","gaps":["KCC2 and TTBK2 findings rest on single labs","Whether spine and trafficking roles are channel-independent not fully resolved"]},{"year":2021,"claim":"Atomic-resolution mechanism of the intact heteromer and allosteric drug action was lacking; cryo-EM resolved GluK2/GluK5 across functional states and defined positive and negative allosteric modulator binding sites, while Q/R editing was linked to NTD-dependent spine morphogenesis.","evidence":"Cryo-EM in apo/antagonist/desensitized states, cryo-EM with BPAM344/perampanel, and GluK2(Q)/(R) overexpression with chimeras","pmids":["33724189","36857176","36121930"],"confidence":"High","gaps":["Spine morphogenesis study is overexpression-based","Native-state allosteric modulation in vivo not addressed"]},{"year":2021,"claim":"The genetic-physiologic basis of GRIK2 disease was extended beyond loss-of-function; M3-region de novo gain-of-function mutations were shown to slow gating and correlate with epilepsy and hypomyelination, and GluK2 autoantibodies were shown to internalize the receptor in encephalitis.","evidence":"Whole-exome sequencing, voltage-clamp characterization of multiple mutants, and antibody cell-based / neuronal internalization assays","pmids":["34375587","28180184","33949707"],"confidence":"High","gaps":["Mechanism linking gating defects to hypomyelination unresolved","Autoantibody epitope not mapped"]},{"year":2023,"claim":"Whether GluK2 signals non-canonically and how editing tunes signaling mode were addressed; Q/R editing was shown to set the ionotropic/metabotropic balance at mossy fiber synapses, and GluK2 was found to act as a PLD-coupled metabotropic receptor in spindle terminals.","evidence":"Editing-deficient knock-in mice with electrophysiology and biochemistry, plus protein detection and an ionotropic-ablated mouse in spindle terminals","pmids":["37720087","37656490"],"confidence":"Medium","gaps":["Molecular coupling of GluK2 to PLD not defined","Both rest on single labs"]},{"year":2024,"claim":"Peripheral, non-synaptic functions were established; GluK2 acts as a cold thermoreceptor in DRG neurons and an inhibitory regulator of dermal mast cell degranulation.","evidence":"GluK2 knockout mouse behavioral thermosensation assays, and mast cell degranulation/transcriptomic assays in dermatitis and rosacea models","pmids":["38467901","39661706"],"confidence":"Medium","gaps":["Cold-transduction signaling mechanism in DRG not defined","Mast cell pathway mechanism single lab"]},{"year":2025,"claim":"Structural mechanisms of auxiliary regulation, homomeric gating, channel block, and in vivo disease pathogenicity were resolved; cryo-EM defined how Neto2 and N-glycans shape gating, how polyamine blockers are trapped in the pore, kinetic Neto1/Neto2 effects, and knock-in mice confirmed gain-of-function pathogenicity.","evidence":"Time-resolved cryo-EM with electrophysiology, cryo-EM/MD of pore blockers, laser-pulse photolysis kinetics, and CRISPR knock-in behavioral/EEG analysis","pmids":["40846810","40442317","39592599","41197725","41391686"],"confidence":"High","gaps":["In vivo Neto subunit-specific contributions to circuit function not fully resolved","Therapeutic targeting of pore block unaddressed"]},{"year":null,"claim":"How the integrated phospho/SUMO/editing/auxiliary regulatory network coordinates GluK2 surface dynamics across distinct physiological contexts (synaptic plasticity, peripheral sensation, excitotoxicity) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking trafficking regulators (parkin, SEZ6, TTBK2, GRIP, PICK1) to specific physiological states","Mechanism of metabotropic GluK2-PLD coupling unknown","Structural basis of disease mutations in native heteromers not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,6,21,22]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[14,20,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,25,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,5,13,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,17,36]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13,15,26]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,24,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[22,2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,15,17,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[21]}],"complexes":["GluK2/GluK5 heterotetrameric kainate receptor","GluK2 homotetrameric kainate receptor","GluK2-Neto1/Neto2 receptor complex"],"partners":["GRIK5","NETO1","NETO2","PRKN","SEZ6","TTBK2","KCC2","GRIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13002","full_name":"Glutamate receptor ionotropic, kainate 2","aliases":["Excitatory amino acid receptor 4","EAA4","Glutamate receptor 6","GluR-6","GluR6"],"length_aa":908,"mass_kda":102.6,"function":"Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid (PubMed:7536611, PubMed:8730589, PubMed:14511640). L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system (By similarity). Binding of the excitatory neurotransmitter L-glutamate induces a conformational change leading to the opening of the cation channel, converting the chemical signal to an electrical impulse (By similarity). The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist (PubMed:14511640, PubMed:28180184, PubMed:34375587, PubMed:7536611, PubMed:8730589). Modulates cell surface expression of NETO2 (By similarity). In association with GRIK3, involved in presynaptic facilitation of glutamate release at hippocampal mossy fiber synapses (By similarity) Independent of its ionotropic glutamate receptor activity, acts as a thermoreceptor conferring sensitivity to cold temperatures (PubMed:31474366). Functions in dorsal root ganglion neurons (By similarity)","subcellular_location":"Cell membrane; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13002/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRIK2","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/GRIK2","total_profiled":1310},"omim":[{"mim_id":"619580","title":"NEURODEVELOPMENTAL DISORDER WITH IMPAIRED LANGUAGE AND ATAXIA AND WITH OR WITHOUT SEIZURES; NEDLAS","url":"https://www.omim.org/entry/619580"},{"mim_id":"615004","title":"LEUCINE-RICH REPEAT, IMMUNOGLOBULIN-LIKE, AND TRANSMEMBRANE DOMAINS-CONTAINING PROTEIN 3; LRIT3","url":"https://www.omim.org/entry/615004"},{"mim_id":"612691","title":"POLYMICROGYRIA, BILATERAL TEMPOROOCCIPITAL; BTOP","url":"https://www.omim.org/entry/612691"},{"mim_id":"611092","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 6; MRT6","url":"https://www.omim.org/entry/611092"},{"mim_id":"610863","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-4; GNB4","url":"https://www.omim.org/entry/610863"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":10.0},{"tissue":"heart muscle","ntpm":4.0}],"url":"https://www.proteinatlas.org/search/GRIK2"},"hgnc":{"alias_symbol":["GluK2","MRT6","GluR-6","EAA4","GLUK6"],"prev_symbol":["GLUR6"]},"alphafold":{"accession":"Q13002","domains":[{"cath_id":"3.40.50.2300","chopping":"34-137_317-382","consensus_level":"high","plddt":90.1477,"start":34,"end":382},{"cath_id":"3.40.50.2300","chopping":"152-258_261-281_387-412","consensus_level":"high","plddt":89.2353,"start":152,"end":412},{"cath_id":"3.40.190.10","chopping":"426-536_768-795","consensus_level":"high","plddt":90.6617,"start":426,"end":795},{"cath_id":"3.40.190.10","chopping":"540-546_664-760","consensus_level":"high","plddt":89.076,"start":540,"end":760},{"cath_id":"1.10.287.70","chopping":"553-659","consensus_level":"high","plddt":84.7,"start":553,"end":659}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13002","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13002-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13002-F1-predicted_aligned_error_v6.png","plddt_mean":83.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRIK2","jax_strain_url":"https://www.jax.org/strain/search?query=GRIK2"},"sequence":{"accession":"Q13002","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13002.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13002/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13002"}},"corpus_meta":[{"pmid":"18332879","id":"PMC_18332879","title":"Evidence 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Phosphorylation at S868 without SUMOylation instead increases KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane.\",\n      \"method\": \"Phosphomimetic and non-phosphorylatable mutagenesis, SUMO-1 infusion, patch-clamp electrophysiology, surface biotinylation in neurons\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, electrophysiology, surface biotinylation) in two complementary papers from same group establishing the same mechanism\",\n      \"pmids\": [\"22522402\", \"22089239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kainate stimulation causes rapid PKC-dependent phosphorylation of GluK2 at both S846 and S868; only S868 phosphorylation is required to enhance GluK2 SUMOylation and promote endocytosis. SUMO-1 infusion reduces KAR-mediated currents in WT or S846A GluK2 but not in S868A mutant GluK2.\",\n      \"method\": \"Phosphomimetic mutagenesis (S846A, S868A), SUMO-1 intracellular infusion, whole-cell patch-clamp in HEK293 cells and neurons, surface biotinylation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and electrophysiology, multiple orthogonal methods within single rigorous study\",\n      \"pmids\": [\"22089239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Brain ischemia evokes sustained GluK2 SUMOylation in hippocampal CA1; SUMOylated GluK2 promotes its interaction with MLK3, thereby activating the MLK3-JNK3 apoptotic signaling pathway. Inhibiting GluK2 endocytosis decreases MLK3-JNK3 activation and GluK2-MLK3 binding.\",\n      \"method\": \"Overexpression of WT vs. SUMOylation-deficient GluK2 mutant, co-immunoprecipitation, kinase activity assay in cultured cortical neurons and rat brain ischemia model\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with mutant overexpression and functional kinase assay, single lab\",\n      \"pmids\": [\"22483987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Src family kinases phosphorylate GluK2 at tyrosine 590 (Y590) in response to brain ischemia/reperfusion. GluK2-Y590 phosphorylation increases whole-cell currents and calcium influx in response to kainate, facilitates GluK2 endocytosis, and activates JNK3 and c-Jun downstream proapoptotic signaling.\",\n      \"method\": \"Site-directed mutagenesis (Y590), whole-cell patch-clamp, calcium imaging, co-immunoprecipitation of GluK2 with Src, rat ischemia/reperfusion model with biochemical assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with electrophysiology, calcium imaging, and co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25201974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Parkin interacts with the GluK2 subunit of kainate receptors; loss of parkin function causes GluK2 protein accumulation in the plasma membrane, potentiates KAR currents, and increases KAR-dependent excitotoxicity in neurons and in mouse brain.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, whole-cell patch-clamp, parkin knockout/loss-of-function in primary cultured neurons and in vivo mouse brain expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, surface biotinylation, electrophysiology, and in vivo model all in one study\",\n      \"pmids\": [\"25316086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GluK2 and GluK5 assemble as heterotetramers with 2:2 stoichiometry in the plasma membrane of live cells, as directly counted by single-molecule imaging.\",\n      \"method\": \"Single-molecule imaging (fluorescence subunit counting) in live cell plasma membranes\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct single-molecule counting in live cells, rigorous quantitative method, single lab\",\n      \"pmids\": [\"22509486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of the GluK2/GluK5 heteromeric kainate receptor in apo, antagonist-bound, and desensitized states show the receptor assembles with two copies of each subunit, GluK5 subunits proximal to the channel, and that during desensitization GluK2 (but not GluK5) subunits undergo major structural rearrangements facilitating channel closure.\",\n      \"method\": \"Cryo-electron microscopy structural determination in multiple states\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures in multiple states, direct structural determination, single study\",\n      \"pmids\": [\"33724189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures show BPAM344 (positive allosteric modulator) binds at the ligand-binding domain dimer interface (two molecules per dimer) and stabilizes GluK2 in the closed state in the absence of agonist; perampanel (negative allosteric modulator) binds to extracellular collar sites of the ion channel in two out of four GluK2 subunits and also stabilizes the closed state.\",\n      \"method\": \"Cryo-electron microscopy structural determination of GluK2 complexes with BPAM344, DNQX, and perampanel\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with bound ligands, direct visualization of binding sites, single rigorous study\",\n      \"pmids\": [\"36857176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GluK2 in complex with Neto2 in apo closed and open (agonist kainate + BPAM344) states show that Neto2 binding prevents tightening of the LBD dimer-dimer interface during activation and slows deactivation kinetics, while not changing individual LBD or ion channel behavior.\",\n      \"method\": \"Time-resolved cryo-electron microscopy, electrophysiology\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures in multiple states combined with electrophysiology, single rigorous study\",\n      \"pmids\": [\"40846810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of homomeric GluK2 in apo and partial agonist (domoate)-bound states reveal that the apo state is captured in a desensitized conformation, confirming KAR desensitization prior to activation; domoate-bound GluK2 populates intermediate and desensitized states. N-glycans at the ATD-LBD interface modulate receptor gating by interfering with cation binding at the LBD dimer interface.\",\n      \"method\": \"Cryo-electron microscopy, electrophysiology (functional validation of N-glycan mutants)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures in multiple states with electrophysiological functional validation, single rigorous study\",\n      \"pmids\": [\"40442317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The N-terminal domain (NTD) of GluK2 binds the first CUB domain of Neto1/Neto2 (NTD-CUB1 interaction), and the GluK2 core binds Neto proteins through domains other than CUB1. The NTD-CUB1 interaction mediates Neto1/Neto2 differential regulation of GluK2 gating kinetics and recovery from desensitization; the NTD itself stabilizes the GluK2 desensitized state.\",\n      \"method\": \"Electrophysiology in HEK293T cells with deletion mutants, chimeric constructs, and charge-neutralization mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic mutagenesis and chimeric receptor analysis with functional electrophysiology, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"31628192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cysteine mutant cross-linking experiments in full-length GluK2 established that the ATD and LBD extracellular domains assemble as a dimer of dimers with subunit partner-swapping between ATD and LBD layers, and that cross-linking either the ATD or LBD inhibits GluK2 activation.\",\n      \"method\": \"Cysteine mutant cross-linking in full-length GluK2, non-reducing SDS-PAGE, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-type biochemical cross-linking combined with functional electrophysiology in single study\",\n      \"pmids\": [\"20404149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The kainate-binding site of GluR-6 (GluK2) is formed exclusively by two discontinuous extracellular segments S1 and S2 homologous to bacterial amino-acid-binding proteins; both S1 and S2 contribute to agonist selectivity.\",\n      \"method\": \"Expression of recombinant GluR-6 fragments in insect cells, deletion analysis, S1-S2 chimeras between GluR-6 and GluR-D, [3H]kainate binding assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic deletion and chimera analysis with direct ligand-binding assays, single rigorous study\",\n      \"pmids\": [\"9494120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAR2-dependent Q/R editing of GluK2 mRNA (converting glutamine to arginine) regulates KAR surface expression. Suppression of synaptic activity induces proteasomal degradation of ADAR2, which reduces GluK2 Q/R editing; because GluK2(Q)-containing KARs assemble and exit the ER more efficiently, this leads to KAR upscaling. Partial ADAR2 knockdown phenocopies and occludes KAR upscaling.\",\n      \"method\": \"Proteasome inhibition, ADAR2 knockdown (siRNA), surface biotinylation, activity suppression (TTX treatment) in hippocampal neurons\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (KD, inhibitor, surface biotinylation, occlusion experiment) in single study\",\n      \"pmids\": [\"30559217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Scanning mutagenesis of the pore-loop, M1, and M3 helices identified three abutting surfaces along M1-M2-M3 where substitutions render GluK2(Q) channels susceptible to fatty acid inhibition. Arginine substitutions at M3 positions F611, L614, S618, and T621 increase chloride permeability and eliminate polyamine block, demonstrating the importance of the central cavity in ionic selectivity.\",\n      \"method\": \"Scanning mutagenesis of GluK2, whole-cell patch-clamp electrophysiology, fatty acid application, polyamine block assays\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional electrophysiology across multiple residues, single rigorous study\",\n      \"pmids\": [\"20805577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Seizure protein 6 (SEZ6) interacts with GluK2 through its ectodomain and promotes post-ER transport of GluK2 in the secretory pathway; loss of SEZ6 reduces GluK2/3 surface levels, reduces kainate-evoked currents, and prevents HNK-1 glycosylation modification of GluK2/3.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation in neurons, electrophysiology in hippocampal slices, in vitro and in vivo glycan analysis (HNK-1), SEZ6 knockout\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, electrophysiology, surface biotinylation, and in vivo KO, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32567721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GluK2 interacts with the K-Cl cotransporter KCC2 to regulate structural maturation of dendritic spines. GluK2 silencing in CA3 hippocampal neurons alters dendritic spine morphology and reduces mEPSC frequency; this is associated with redistribution of KCC2, reduction of 4.1N and cofilin expression, and increased F-actin stability (measured by FRAP). Overexpression of KCC2 rescues the aberrant spine morphology caused by GluK2 deficiency.\",\n      \"method\": \"In vivo lentiviral knockdown of GluK2, co-immunoprecipitation, FRAP of β-actin, mEPSC recordings, KCC2 rescue overexpression\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, FRAP, electrophysiology, and rescue experiment in single study from one lab\",\n      \"pmids\": [\"33005130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TTBK2 (tau tubulin kinase 2) downregulates GluK2 activity by decreasing receptor protein abundance at the cell membrane via RAB5-dependent endocytosis; this effect requires TTBK2 kinase activity and is absent with truncated TTBK2(450), which lacks the C-terminal region mutated in SCA11 patients.\",\n      \"method\": \"Xenopus oocyte expression, dual-electrode voltage clamp, confocal microscopy of EGFP-tagged GluK2, overexpression of dominant-negative RAB5(N133I)\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional electrophysiology with localization imaging and RAB5 epistasis in heterologous system, single lab\",\n      \"pmids\": [\"27607061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Double mutant cycle analysis of GluK2 demonstrated strong energetic coupling between the Q/R site residue in the pore loop (M2) and L614 in the M3 helix at the central cavity; replacement of L614 with smaller side chains reverses fatty acid effects on edited GluK2(R) channels from inhibition to potentiation.\",\n      \"method\": \"Double mutant cycle analysis, whole-cell patch-clamp electrophysiology, scanning mutagenesis in GluK2\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — thermodynamic double mutant cycle analysis with functional electrophysiology, rigorous quantitative approach\",\n      \"pmids\": [\"23940260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of GluK1 and GluK2 ligand-binding domains bound to dysiherbaine analogues identified three amino acids (Thr503, Ser706, Ser726 in GluK1 vs. Ala487, Asn690, Thr710 in GluK2) generating differences in binding mode and receptor selectivity. All ligands induced full domain closure regardless of agonist efficacy.\",\n      \"method\": \"X-ray crystallography of ligand-binding domains with multiple bound ligands\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with multiple ligands defining binding pocket residues, single rigorous study\",\n      \"pmids\": [\"21893069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cysteine substitutions at A657C (within SYTANLAAF motif) and adjacent L659C in the GluK2 M3 bundle-crossing gate allow direct channel activation by Cd2+; activation by Cd2+ requires substitution at only two of four subunits in the tetramer, and occurs similarly for either the A/C or B/D conformations. This demonstrates rapid and reversible channel activation independent of agonist-site occupancy.\",\n      \"method\": \"Cysteine mutagenesis, Cd2+ application, whole-cell patch-clamp, MTSEA modification, heteromeric and chimeric receptor analysis\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis combined with chemical gating and functional electrophysiology, rigorous mechanistic study\",\n      \"pmids\": [\"30498132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GluK2 is expressed in dorsal root ganglion somatosensory neurons and functions as a cold-temperature sensor in the periphery; GluK2 knockout mice exhibit a specific deficit in sensing cold (but not cool, hot, or mechanical) temperatures in behavioral assays. This identifies a role for GluK2 as a thermoreceptor co-opted from its function as a glutamate chemoreceptor.\",\n      \"method\": \"GluK2 knockout mouse behavioral analysis (cold/heat/mechanical sensitivity tests), DRG neuron analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific behavioral phenotype and cellular localization analysis, published in high-tier journal\",\n      \"pmids\": [\"38467901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GluK2 functions as a metabotropic receptor coupled to phospholipase D (PLD) in primary mechanosensory spindle terminals, independent of its ionotropic function. Immunofluorescence and western blotting showed GluK2 is the only glutamate receptor subunit present in these terminals; in a mouse model with ionotropic function ablated in GluK2, spindle glutamatergic responses were still present, confirming purely metabotropic signaling.\",\n      \"method\": \"Immunofluorescence, western blotting, far-western blotting, electrophysiology in spindle mechanosensory terminals, ionotropic function-ablated mouse model\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple protein detection methods plus functional assay with ablation model, single lab\",\n      \"pmids\": [\"37656490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Autoantibodies against GluK2 in patients with autoimmune encephalitis internalize GluK2 in HEK293 cells and neurons, causing a significant reduction of GluK2-mediated currents; this antibody-mediated internalization is reversible in neurons.\",\n      \"method\": \"Cell-based assay, immunoprecipitation, confocal microscopy in neurons, electrophysiology in GluK2-expressing HEK293 cells\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CBA, co-IP, confocal, electrophysiology) in single study\",\n      \"pmids\": [\"33949707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GluK2 Q/R editing status (edited GluK2(R) vs. unedited GluK2(Q)) controls the balance between ionotropic and metabotropic KAR signaling at mossy fiber-CA3 synapses. GluK2(Q) editing-deficient mice show increased postsynaptic KAR ionotropic function and presynaptic facilitation but reduced metabotropic KAR function; they also display fewer GluA1/GluA3-containing AMPARs and reduced LTP at CA1-Schaffer collateral synapses.\",\n      \"method\": \"GluK2 editing-deficient knock-in mice, electrophysiology (postsynaptic KAR currents, ISAHP, LTP), western blotting for AMPAR subunits\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with electrophysiology and biochemistry, single lab\",\n      \"pmids\": [\"37720087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Neto1 and Neto2 have distinct subunit-dependent effects on GluK2 gating: co-expression of Neto2 with GluK2 homomers increases recovery from desensitization and slows desensitization onset at all glutamate concentrations; chimeric analysis showed the extracellular N-terminal CUB domain region is largely responsible for the distinct regulatory effects.\",\n      \"method\": \"Patch-clamp electrophysiology in HEK-293T cells, Neto1/Neto2 chimeric subunit analysis\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic chimeric analysis with functional electrophysiology, single lab\",\n      \"pmids\": [\"26277340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Agonist binding to the GluK5 subunit, but not GluK2, is both necessary and sufficient for surface expression of heteromeric GluK2/GluK5 receptors; occupancy of the GluK2 agonist site alone is not sufficient for surface trafficking of the heteromer.\",\n      \"method\": \"Point mutations reducing agonist affinity in GluK2 or GluK5 subunits, surface expression assays in heterologous cells, rescue with competitive antagonist or WT partner subunit\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mutagenesis with surface expression assays, systematic rescue experiments, single lab\",\n      \"pmids\": [\"23975096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mutations K531A and R775A in the GluK2 LBD dimer interface attenuate desensitization; K531A also switches relative efficacies of glutamate and kainate. Crystal structures reveal new dimer contacts with K531 truncation and show that absence of chloride at the dimer-interface anion binding site (R775A) is sufficient to attenuate desensitization, suggesting charge balance at the dimer interface maintains instability required for rapid desensitization.\",\n      \"method\": \"Site-directed mutagenesis, X-ray crystallography of LBD, patch-clamp electrophysiology\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures combined with mutagenesis and electrophysiology, single study with orthogonal methods\",\n      \"pmids\": [\"23720540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A de novo gain-of-function point mutation A657T in GluK2 causes constitutive channel activity in nominally glutamate-free media, profoundly altered channel gating, and neurodevelopmental deficits (ataxia, motor and speech delay, intellectual disability) in a human patient.\",\n      \"method\": \"Whole-exome sequencing to identify de novo variant, whole-cell voltage-clamp recordings of mutant KARs in heterologous expression system\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional characterization in heterologous system single study; replicated in context of broader cohort study (PMID 34375587)\",\n      \"pmids\": [\"28180184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutations in the M3 transmembrane domain of GluK2 (p.Ala657Thr, p.Thr660Lys, p.Thr660Arg) and the M3-S2 linker (p.Ile668Thr) cause complex alterations in channel gating kinetics of homomeric and heteromeric KARs. p.Thr660Lys and p.Thr660Arg mutations produce markedly slowed gating kinetics similar to p.Ala657Thr, and p.Thr660Lys is associated with severe epilepsy while both p.Thr660Lys and p.Thr660Arg cause hypomyelination.\",\n      \"method\": \"Whole-exome sequencing, whole-cell voltage-clamp electrophysiology in heterologous expression system, membrane localization assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic electrophysiological characterization of multiple independent mutants, replicated in multiple patients, correlation with clinical phenotype\",\n      \"pmids\": [\"34375587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GluK2 ion channel pore in complex with polyamine channel blockers (spermine, Kukoamine A, NpTx-8, PhTx-74) reveal that blockers reside inside the pore intracellular to the closed M3 helix bundle-crossing gate, with hydrophobic heads in the central cavity and positively charged polyamine tails spanning the selectivity filter, establishing the trapping mechanism of KAR channel block.\",\n      \"method\": \"Cryo-electron microscopy structural determination, molecular dynamics simulations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with four different blockers plus MD simulations, single rigorous study\",\n      \"pmids\": [\"39592599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The M867I mutation in the C-terminus of human GluK2 (associated with autism) slows the channel desensitization rate by ~1.6-fold at saturating glutamate but does not affect channel-opening or channel-closing rate constants. Wild-type human GluK2 has a ~3-fold smaller channel-opening rate constant than rat GluK2 but an identical channel-closing rate and ~2-fold lower EC50.\",\n      \"method\": \"Laser-pulse photolysis with whole-cell patch-clamp recording, detailed kinetic mechanism analysis of WT and M867I mutant GluK2\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous kinetic analysis in heterologous system, single lab, single method type\",\n      \"pmids\": [\"20863077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GluK2 Q/R editing of the calcium permeability gate regulates synapse morphology: overexpression of calcium-permeable GluK2(Q) increases spine length and head area in hippocampal neurons compared to calcium-impermeable GluK2(R); the N-terminal domain (NTD) is responsible for this morphogenic effect, as shown by NTD-swap chimeras between GluK2 and GluK1.\",\n      \"method\": \"Overexpression of GluK2(Q) vs. GluK2(R) in primary cultured hippocampal neurons, GluK1-GluK2 domain-swap chimeras, confocal imaging of spine morphology\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression with chimeric domain analysis in primary neurons, single lab\",\n      \"pmids\": [\"36121930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUMOylation of PKC (not of GluK2 itself) inhibits the binding of 14-3-3τ to GluK2a by decreasing PKC-mediated phosphorylation of GluK2a, establishing a pathway by which PKC SUMOylation regulates the 14-3-3τ–GluK2a complex and may contribute to KAR-EPSC decay kinetics.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of SUMO-modified PKC, western blotting for GluK2 phosphorylation levels\",\n      \"journal\": \"Channels\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP study from single lab, no direct electrophysiological validation in this paper\",\n      \"pmids\": [\"28837400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Postoperative pain (plantar incision) induces synaptic delivery of GluK2 in ipsilateral spinal dorsal horns and increases GluK2-GRIP interaction; knockdown of GRIP with intrathecal siRNA reduces synaptic GluK2 abundance and attenuates postoperative pain hypersensitivity.\",\n      \"method\": \"Co-immunoprecipitation, synaptic fractionation, intrathecal GRIP siRNA, behavioral pain assays in rats\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with functional siRNA knockdown and behavioral readout, single lab\",\n      \"pmids\": [\"33847855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NETO2 slows GluK2 channel-opening rate (~7-fold) and channel-closing rate (~3-fold), while NETO1 slows both rates by ~2-fold; this establishes differential kinetic regulation of GluK2 channel gating by the two Neto auxiliary subunits.\",\n      \"method\": \"Laser-pulse photolysis combined with whole-cell patch-clamp recording in HEK293 cells expressing GluK2 with NETO1 or NETO2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous kinetic analysis in heterologous system, single lab, single method\",\n      \"pmids\": [\"41197725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GluK2 internalization during kainate excitotoxicity occurs through a clathrin-independent but dynamin-dependent mechanism regulated by intracellular Ca2+/calcineurin signaling; PICK1-GluK2 interaction is regulated by Ca2+/calcineurin, and calcineurin activation is linked to dynamin function.\",\n      \"method\": \"Surface biotinylation, co-immunoprecipitation, inhibitors of clathrin-independent endocytosis, Ca2+ chelators, calcineurin inhibitors in cultured neurons\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple inhibitor approaches with co-IP and surface biotinylation, single lab\",\n      \"pmids\": [\"33070524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"De novo gain-of-function Grik2 knock-in mouse models (orthologous to human p.Ala657Thr and p.Thr660Lys) exhibit developmental, motor, cognitive, and behavioral impairments; GluK2(T660K) mice additionally show interictal EEG abnormalities and handling-induced seizures, establishing in vivo pathogenicity of these gain-of-function mutations.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse generation, behavioral analysis battery, EEG recording\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in models with behavioral and electrophysiological characterization, single study\",\n      \"pmids\": [\"41391686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GluK2 is selectively expressed on dermal mast cells; GluK2 agonism (SYM2081) inhibits mast cell degranulation in response to MrgprB2 agonism, suppresses expression of Mrgprb2 and mast cell proliferation genes, and reduces skin inflammation in murine dermatitis and rosacea models.\",\n      \"method\": \"In vitro mast cell degranulation assays, in vivo intradermal and topical administration, transcriptomic analysis, Ki-67 and BrdU incorporation assays, mouse inflammatory models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo assays, single lab, novel peripheral function\",\n      \"pmids\": [\"39661706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A homozygous complex mutation in GRIK2 causing loss of the first ligand-binding domain, adjacent transmembrane domain, and pore loop results in complete loss of GLuK6 (GluK2) function and segregates with moderate-to-severe autosomal recessive intellectual disability in a consanguineous Iranian family, establishing that GluK2 is indispensable for higher brain function.\",\n      \"method\": \"Genetic linkage analysis, mutation identification, electrophysiological characterization of mutant protein (loss of function)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic co-segregation with electrophysiological functional validation, first proof of concept\",\n      \"pmids\": [\"17847003\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GluK2 (GRIK2) is a kainate-type ionotropic glutamate receptor subunit that assembles as a homotetrameric or 2:2 heteromeric (with GluK5) ligand-gated ion channel; its activity, surface expression, and synaptic plasticity are tightly regulated by PKC-mediated phosphorylation at S868 (which promotes SUMO modification at K886 to drive endocytosis or, without SUMOylation, promotes recycling), by Src-mediated phosphorylation at Y590 (increasing currents and downstream JNK3 apoptotic signaling), by ADAR2-dependent Q/R mRNA editing (controlling calcium permeability, ER exit, and the balance between ionotropic and metabotropic signaling), and by auxiliary subunits Neto1/Neto2 (which bind via CUB domain interactions with the GluK2 NTD to slow gating kinetics and modulate desensitization). GluK2 also acts as a cold thermoreceptor in peripheral somatosensory DRG neurons and as a metabotropic PLD-coupled receptor in mechanosensory spindle terminals, and it plays roles in dendritic spine maturation through interaction with KCC2 and in excitotoxic signaling through SUMOylation-mediated interaction with MLK3-JNK3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRIK2 encodes GluK2, a kainate-type ionotropic glutamate receptor subunit that assembles as homotetramers or, with GluK5, as 2:2 heterotetramers with GluK5 subunits positioned proximal to the channel [#5, #6]. The extracellular domains assemble as a dimer of dimers with subunit partner-swapping between the amino-terminal and ligand-binding domain (LBD) layers, and the kainate-binding site is built from two discontinuous segments, S1 and S2, that together set agonist selectivity [#11, #12]. Gating is governed by charge balance at the LBD dimer interface, where chloride occupancy and key interface residues maintain the instability required for rapid desensitization; structural studies capture the receptor in apo desensitized, agonist-bound, and antagonist-bound states, with GluK2 subunits undergoing the major rearrangements that close the channel [#27, #6, #9]. The M1–M2–M3 pore region determines ionic selectivity and polyamine block, with the M3 bundle-crossing gate (SYTANLAAF motif) coupling to the central cavity and selectivity filter [#14, #20, #30]. Receptor function is extensively tuned post-transcriptionally and post-translationally: ADAR2-dependent Q/R editing controls calcium permeability, ER exit, surface expression, and the balance between ionotropic and metabotropic signaling [#13, #24]; PKC phosphorylation at S868 promotes SUMOylation at K886 to drive endocytosis during long-term depression, whereas S868 phosphorylation without SUMOylation favors recycling and surface retention [#0, #1]; and Src phosphorylation at Y590 augments currents and calcium influx during ischemia [#3]. Auxiliary Neto1/Neto2 subunits bind the GluK2 N-terminal domain via their CUB1 domain to slow gating and modulate desensitization [#10, #8, #35], while trafficking partners including parkin, SEZ6, and TTBK2 control surface abundance [#4, #15, #17]. Beyond synaptic transmission, GluK2 acts as a peripheral cold thermoreceptor in dorsal root ganglion neurons, signals metabotropically through phospholipase D in muscle spindle terminals, and regulates dendritic spine maturation via interaction with KCC2 [#21, #22, #16]. Excitotoxic and apoptotic signaling proceeds through SUMOylated GluK2 recruitment of the MLK3–JNK3 cascade [#2, #3]. Loss-of-function GRIK2 mutation causes autosomal recessive intellectual disability, and de novo gain-of-function mutations in the M3 region cause neurodevelopmental disorders with epilepsy and hypomyelination [#39, #28, #29, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing where agonist binds was prerequisite to understanding receptor activation; this work localized the kainate-binding pocket to two discontinuous extracellular segments.\",\n      \"evidence\": \"Recombinant GluR-6 fragment expression, deletion analysis, S1-S2 chimeras, and [3H]kainate binding\",\n      \"pmids\": [\"9494120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the atomic structure of the bound site\", \"Did not address subunit stoichiometry or gating coupling\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether GluK2 is essential for human brain function was unknown; a loss-of-function mutation segregating with intellectual disability established its indispensable role.\",\n      \"evidence\": \"Genetic linkage in a consanguineous family plus electrophysiological characterization of the mutant\",\n      \"pmids\": [\"17847003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the cellular circuit mechanism underlying cognitive impairment\", \"Single family\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolving how the extracellular domains and pore are organized clarified the gating machinery; cross-linking established a dimer-of-dimers architecture with partner swapping, and pore mutagenesis defined the ionic selectivity determinants.\",\n      \"evidence\": \"Cysteine cross-linking in full-length GluK2 and scanning mutagenesis of M1-M2-M3 with electrophysiology\",\n      \"pmids\": [\"20404149\", \"20805577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide a full-length structural model\", \"Mechanism of desensitization-coupled conformational change not yet resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How agonist selectivity differs among kainate subunits was unclear; LBD crystal structures with dysiherbaine analogues identified the specific residues governing binding mode.\",\n      \"evidence\": \"X-ray crystallography of GluK1 and GluK2 LBDs with multiple ligands\",\n      \"pmids\": [\"21893069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isolated LBD does not report full-receptor gating\", \"Did not address auxiliary-subunit effects on the binding pocket\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The molecular code controlling receptor surface fate was undefined; PKC phosphorylation at S868 was shown to gate a bifurcation between SUMO-driven endocytosis (LTD) and recycling-driven surface retention, and heteromer stoichiometry was directly counted.\",\n      \"evidence\": \"Phosphomimetic/non-phosphorylatable mutagenesis, SUMO-1 infusion, surface biotinylation, electrophysiology, and single-molecule subunit counting\",\n      \"pmids\": [\"22522402\", \"22089239\", \"22509486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase machinery acting on GluK2 not identified\", \"How the phospho/SUMO switch is set in vivo unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether GluK2 modification links to cell death was unknown; ischemia-induced SUMOylation was shown to recruit MLK3 and activate the JNK3 apoptotic cascade.\",\n      \"evidence\": \"Mutant overexpression, co-IP, and kinase assays in cortical neurons and a rat ischemia model\",\n      \"pmids\": [\"22483987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, co-IP based\", \"Stoichiometry and direct nature of GluK2-MLK3 contact not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The structural basis of rapid desensitization and Q/R-site pore coupling was unclear; interface mutagenesis with crystallography and double-mutant cycle analysis linked dimer-interface charge balance and the Q/R–L614 axis to gating and lipid modulation.\",\n      \"evidence\": \"Site-directed mutagenesis, LBD crystallography, double mutant cycle analysis, and patch-clamp\",\n      \"pmids\": [\"23720540\", \"23940260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture full-length desensitized intermediate\", \"In vivo relevance of fatty-acid modulation unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Which subunit controls heteromer surface delivery was unknown; agonist occupancy of GluK5, not GluK2, was found necessary and sufficient for GluK2/GluK5 surface expression.\",\n      \"evidence\": \"Affinity-reducing point mutations and surface expression rescue assays in heterologous cells\",\n      \"pmids\": [\"23975096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking checkpoint sensing agonist occupancy not identified\", \"Single heterologous system\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Additional regulatory inputs to GluK2 function were sought; Src-mediated Y590 phosphorylation was shown to boost currents and feed proapoptotic signaling, and parkin was identified as a trafficking regulator restraining surface GluK2 and excitotoxicity.\",\n      \"evidence\": \"Site-directed mutagenesis, electrophysiology, calcium imaging, co-IP, surface biotinylation, and ischemia / parkin-loss models\",\n      \"pmids\": [\"25201974\", \"25316086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether parkin ubiquitinates GluK2 directly not established\", \"Interplay between Y590 and S868/SUMO pathways unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"How auxiliary subunits differentially shape gating was unclear; Neto1 and Neto2 were shown to have distinct, CUB-domain-dependent effects on desensitization and recovery.\",\n      \"evidence\": \"Patch-clamp with Neto1/Neto2 chimeric subunit analysis in HEK-293T cells\",\n      \"pmids\": [\"26277340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not localize the binding interface to a specific GluK2 region\", \"Single heterologous system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether the gate can be activated independently of agonist occupancy was untested; engineered cysteines in the M3 bundle crossing allowed direct Cd2+ activation requiring only two of four subunits, demonstrating agonist-site-independent gating.\",\n      \"evidence\": \"Cysteine mutagenesis, Cd2+ application, MTSEA modification, and chimeric receptor electrophysiology\",\n      \"pmids\": [\"30498132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of subunit-asymmetric gating in native receptors unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How activity scales KAR abundance was unknown; activity-dependent ADAR2 degradation reduces Q/R editing, and the more efficiently ER-exiting GluK2(Q) isoform drives KAR upscaling.\",\n      \"evidence\": \"Proteasome inhibition, ADAR2 siRNA, TTX activity suppression, surface biotinylation, and occlusion experiments in neurons\",\n      \"pmids\": [\"30559217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism targeting ADAR2 for degradation not detailed\", \"Timescale relative to other scaling pathways unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The molecular interface for Neto regulation was undefined; the GluK2 NTD was shown to bind Neto CUB1, mediating differential gating control while stabilizing the desensitized state.\",\n      \"evidence\": \"Deletion mutants, chimeric constructs, charge-neutralization mutagenesis, and electrophysiology in HEK293T cells\",\n      \"pmids\": [\"31628192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide a structural model of the NTD-CUB1 contact\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Trafficking and morphogenic roles were broadened; SEZ6 promotes post-ER GluK2 transport and HNK-1 glycosylation, GluK2-KCC2 interaction regulates spine maturation, and TTBK2 downregulates GluK2 via RAB5-dependent endocytosis.\",\n      \"evidence\": \"Co-IP, surface biotinylation, slice/oocyte electrophysiology, FRAP, glycan analysis, and SEZ6 knockout / RAB5 epistasis\",\n      \"pmids\": [\"32567721\", \"33005130\", \"27607061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KCC2 and TTBK2 findings rest on single labs\", \"Whether spine and trafficking roles are channel-independent not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Atomic-resolution mechanism of the intact heteromer and allosteric drug action was lacking; cryo-EM resolved GluK2/GluK5 across functional states and defined positive and negative allosteric modulator binding sites, while Q/R editing was linked to NTD-dependent spine morphogenesis.\",\n      \"evidence\": \"Cryo-EM in apo/antagonist/desensitized states, cryo-EM with BPAM344/perampanel, and GluK2(Q)/(R) overexpression with chimeras\",\n      \"pmids\": [\"33724189\", \"36857176\", \"36121930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spine morphogenesis study is overexpression-based\", \"Native-state allosteric modulation in vivo not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The genetic-physiologic basis of GRIK2 disease was extended beyond loss-of-function; M3-region de novo gain-of-function mutations were shown to slow gating and correlate with epilepsy and hypomyelination, and GluK2 autoantibodies were shown to internalize the receptor in encephalitis.\",\n      \"evidence\": \"Whole-exome sequencing, voltage-clamp characterization of multiple mutants, and antibody cell-based / neuronal internalization assays\",\n      \"pmids\": [\"34375587\", \"28180184\", \"33949707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking gating defects to hypomyelination unresolved\", \"Autoantibody epitope not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether GluK2 signals non-canonically and how editing tunes signaling mode were addressed; Q/R editing was shown to set the ionotropic/metabotropic balance at mossy fiber synapses, and GluK2 was found to act as a PLD-coupled metabotropic receptor in spindle terminals.\",\n      \"evidence\": \"Editing-deficient knock-in mice with electrophysiology and biochemistry, plus protein detection and an ionotropic-ablated mouse in spindle terminals\",\n      \"pmids\": [\"37720087\", \"37656490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular coupling of GluK2 to PLD not defined\", \"Both rest on single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Peripheral, non-synaptic functions were established; GluK2 acts as a cold thermoreceptor in DRG neurons and an inhibitory regulator of dermal mast cell degranulation.\",\n      \"evidence\": \"GluK2 knockout mouse behavioral thermosensation assays, and mast cell degranulation/transcriptomic assays in dermatitis and rosacea models\",\n      \"pmids\": [\"38467901\", \"39661706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cold-transduction signaling mechanism in DRG not defined\", \"Mast cell pathway mechanism single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural mechanisms of auxiliary regulation, homomeric gating, channel block, and in vivo disease pathogenicity were resolved; cryo-EM defined how Neto2 and N-glycans shape gating, how polyamine blockers are trapped in the pore, kinetic Neto1/Neto2 effects, and knock-in mice confirmed gain-of-function pathogenicity.\",\n      \"evidence\": \"Time-resolved cryo-EM with electrophysiology, cryo-EM/MD of pore blockers, laser-pulse photolysis kinetics, and CRISPR knock-in behavioral/EEG analysis\",\n      \"pmids\": [\"40846810\", \"40442317\", \"39592599\", \"41197725\", \"41391686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo Neto subunit-specific contributions to circuit function not fully resolved\", \"Therapeutic targeting of pore block unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the integrated phospho/SUMO/editing/auxiliary regulatory network coordinates GluK2 surface dynamics across distinct physiological contexts (synaptic plasticity, peripheral sensation, excitotoxicity) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking trafficking regulators (parkin, SEZ6, TTBK2, GRIP, PICK1) to specific physiological states\", \"Mechanism of metabotropic GluK2-PLD coupling unknown\", \"Structural basis of disease mutations in native heteromers not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [5, 6, 11, 14, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 6, 21, 22]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [14, 20, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 25, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 5, 13, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 17, 36]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13, 15, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 24, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [22, 2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 15, 17, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\n      \"GluK2/GluK5 heterotetrameric kainate receptor\",\n      \"GluK2 homotetrameric kainate receptor\",\n      \"GluK2-Neto1/Neto2 receptor complex\"\n    ],\n    \"partners\": [\n      \"GRIK5\",\n      \"NETO1\",\n      \"NETO2\",\n      \"PRKN\",\n      \"SEZ6\",\n      \"TTBK2\",\n      \"KCC2\",\n      \"GRIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}