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Showing GRIK2 — GLUK2 is a alias.

GRIK2

Glutamate receptor ionotropic, kainate 2 · UniProt Q13002

Length
908 aa
Mass
102.6 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    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

    PMID:9494120

    Open questions at the time
    • Did not resolve the atomic structure of the bound site
    • Did not address subunit stoichiometry or gating coupling
  2. 2007 High

    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

    PMID:17847003

    Open questions at the time
    • Did not define the cellular circuit mechanism underlying cognitive impairment
    • Single family
  3. 2010 High

    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

    PMID:20404149 PMID:20805577

    Open questions at the time
    • Did not provide a full-length structural model
    • Mechanism of desensitization-coupled conformational change not yet resolved
  4. 2011 High

    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

    PMID:21893069

    Open questions at the time
    • Isolated LBD does not report full-receptor gating
    • Did not address auxiliary-subunit effects on the binding pocket
  5. 2012 High

    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

    PMID:22089239 PMID:22509486 PMID:22522402

    Open questions at the time
    • SUMO ligase machinery acting on GluK2 not identified
    • How the phospho/SUMO switch is set in vivo unresolved
  6. 2012 Medium

    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

    PMID:22483987

    Open questions at the time
    • Single lab, co-IP based
    • Stoichiometry and direct nature of GluK2-MLK3 contact not defined
  7. 2013 High

    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

    PMID:23720540 PMID:23940260

    Open questions at the time
    • Did not capture full-length desensitized intermediate
    • In vivo relevance of fatty-acid modulation unaddressed
  8. 2013 Medium

    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

    PMID:23975096

    Open questions at the time
    • Trafficking checkpoint sensing agonist occupancy not identified
    • Single heterologous system
  9. 2014 High

    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

    PMID:25201974 PMID:25316086

    Open questions at the time
    • Whether parkin ubiquitinates GluK2 directly not established
    • Interplay between Y590 and S868/SUMO pathways unresolved
  10. 2015 Medium

    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

    PMID:26277340

    Open questions at the time
    • Did not localize the binding interface to a specific GluK2 region
    • Single heterologous system
  11. 2018 High

    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

    PMID:30498132

    Open questions at the time
    • Physiological trigger of subunit-asymmetric gating in native receptors unknown
  12. 2018 High

    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

    PMID:30559217

    Open questions at the time
    • Mechanism targeting ADAR2 for degradation not detailed
    • Timescale relative to other scaling pathways unresolved
  13. 2019 High

    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

    PMID:31628192

    Open questions at the time
    • Did not provide a structural model of the NTD-CUB1 contact
  14. 2020 Medium

    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

    PMID:27607061 PMID:32567721 PMID:33005130

    Open questions at the time
    • KCC2 and TTBK2 findings rest on single labs
    • Whether spine and trafficking roles are channel-independent not fully resolved
  15. 2021 High

    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

    PMID:33724189 PMID:36121930 PMID:36857176

    Open questions at the time
    • Spine morphogenesis study is overexpression-based
    • Native-state allosteric modulation in vivo not addressed
  16. 2021 High

    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

    PMID:28180184 PMID:33949707 PMID:34375587

    Open questions at the time
    • Mechanism linking gating defects to hypomyelination unresolved
    • Autoantibody epitope not mapped
  17. 2023 Medium

    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

    PMID:37656490 PMID:37720087

    Open questions at the time
    • Molecular coupling of GluK2 to PLD not defined
    • Both rest on single labs
  18. 2024 Medium

    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

    PMID:38467901 PMID:39661706

    Open questions at the time
    • Cold-transduction signaling mechanism in DRG not defined
    • Mast cell pathway mechanism single lab
  19. 2025 High

    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

    PMID:39592599 PMID:40442317 PMID:40846810 PMID:41197725 PMID:41391686

    Open questions at the time
    • In vivo Neto subunit-specific contributions to circuit function not fully resolved
    • Therapeutic targeting of pore block unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the integrated phospho/SUMO/editing/auxiliary regulatory network coordinates GluK2 surface dynamics across distinct physiological contexts (synaptic plasticity, peripheral sensation, excitotoxicity) remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0005215 transporter activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9709957 Sensory Perception 1
Partners
GRIK5GRIP1KCC2NETO1NETO2PRKNSEZ6TTBK2
Complex memberships
GluK2 homotetrameric kainate receptorGluK2-Neto1/Neto2 receptor complexGluK2/GluK5 heterotetrameric kainate receptor

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 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. Phosphomimetic and non-phosphorylatable mutagenesis, SUMO-1 infusion, patch-clamp electrophysiology, surface biotinylation in neurons Nature neuroscience High 22089239 22522402
2011 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. Phosphomimetic mutagenesis (S846A, S868A), SUMO-1 intracellular infusion, whole-cell patch-clamp in HEK293 cells and neurons, surface biotinylation Proceedings of the National Academy of Sciences of the United States of America High 22089239
2012 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. Overexpression of WT vs. SUMOylation-deficient GluK2 mutant, co-immunoprecipitation, kinase activity assay in cultured cortical neurons and rat brain ischemia model FEBS letters Medium 22483987
2014 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. Site-directed mutagenesis (Y590), whole-cell patch-clamp, calcium imaging, co-immunoprecipitation of GluK2 with Src, rat ischemia/reperfusion model with biochemical assays Proceedings of the National Academy of Sciences of the United States of America High 25201974
2014 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. Co-immunoprecipitation, surface biotinylation, whole-cell patch-clamp, parkin knockout/loss-of-function in primary cultured neurons and in vivo mouse brain expression Nature communications High 25316086
2012 GluK2 and GluK5 assemble as heterotetramers with 2:2 stoichiometry in the plasma membrane of live cells, as directly counted by single-molecule imaging. Single-molecule imaging (fluorescence subunit counting) in live cell plasma membranes Cell reports High 22509486
2021 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. Cryo-electron microscopy structural determination in multiple states eLife High 33724189
2023 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. Cryo-electron microscopy structural determination of GluK2 complexes with BPAM344, DNQX, and perampanel Cell reports High 36857176
2025 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. Time-resolved cryo-electron microscopy, electrophysiology Nature structural & molecular biology High 40846810
2025 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. Cryo-electron microscopy, electrophysiology (functional validation of N-glycan mutants) Nature structural & molecular biology High 40442317
2019 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. Electrophysiology in HEK293T cells with deletion mutants, chimeric constructs, and charge-neutralization mutagenesis The Journal of biological chemistry High 31628192
2010 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. Cysteine mutant cross-linking in full-length GluK2, non-reducing SDS-PAGE, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 20404149
1998 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. Expression of recombinant GluR-6 fragments in insect cells, deletion analysis, S1-S2 chimeras between GluR-6 and GluR-D, [3H]kainate binding assays The Biochemical journal High 9494120
2018 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. Proteasome inhibition, ADAR2 knockdown (siRNA), surface biotinylation, activity suppression (TTX treatment) in hippocampal neurons Journal of cell science High 30559217
2010 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. Scanning mutagenesis of GluK2, whole-cell patch-clamp electrophysiology, fatty acid application, polyamine block assays The Journal of general physiology High 20805577
2020 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. Co-immunoprecipitation, surface biotinylation in neurons, electrophysiology in hippocampal slices, in vitro and in vivo glycan analysis (HNK-1), SEZ6 knockout The EMBO journal High 32567721
2020 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. In vivo lentiviral knockdown of GluK2, co-immunoprecipitation, FRAP of β-actin, mEPSC recordings, KCC2 rescue overexpression Frontiers in cellular neuroscience Medium 33005130
2016 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. Xenopus oocyte expression, dual-electrode voltage clamp, confocal microscopy of EGFP-tagged GluK2, overexpression of dominant-negative RAB5(N133I) Cellular physiology and biochemistry Medium 27607061
2013 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. Double mutant cycle analysis, whole-cell patch-clamp electrophysiology, scanning mutagenesis in GluK2 The Journal of general physiology High 23940260
2011 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. X-ray crystallography of ligand-binding domains with multiple bound ligands Journal of molecular biology High 21893069
2018 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. Cysteine mutagenesis, Cd2+ application, whole-cell patch-clamp, MTSEA modification, heteromeric and chimeric receptor analysis The Journal of general physiology High 30498132
2024 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. GluK2 knockout mouse behavioral analysis (cold/heat/mechanical sensitivity tests), DRG neuron analysis Nature neuroscience High 38467901
2023 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. Immunofluorescence, western blotting, far-western blotting, electrophysiology in spindle mechanosensory terminals, ionotropic function-ablated mouse model Experimental physiology Medium 37656490
2021 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. Cell-based assay, immunoprecipitation, confocal microscopy in neurons, electrophysiology in GluK2-expressing HEK293 cells Annals of neurology High 33949707
2023 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. GluK2 editing-deficient knock-in mice, electrophysiology (postsynaptic KAR currents, ISAHP, LTP), western blotting for AMPAR subunits iScience Medium 37720087
2015 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. Patch-clamp electrophysiology in HEK-293T cells, Neto1/Neto2 chimeric subunit analysis Neuropharmacology Medium 26277340
2013 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. Point mutations reducing agonist affinity in GluK2 or GluK5 subunits, surface expression assays in heterologous cells, rescue with competitive antagonist or WT partner subunit Cellular and molecular neurobiology Medium 23975096
2013 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. Site-directed mutagenesis, X-ray crystallography of LBD, patch-clamp electrophysiology Open biology High 23720540
2017 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. Whole-exome sequencing to identify de novo variant, whole-cell voltage-clamp recordings of mutant KARs in heterologous expression system Neurology. Genetics Medium 28180184
2021 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. Whole-exome sequencing, whole-cell voltage-clamp electrophysiology in heterologous expression system, membrane localization assays American journal of human genetics High 34375587
2025 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. Cryo-electron microscopy structural determination, molecular dynamics simulations Nature communications High 39592599
2010 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. Laser-pulse photolysis with whole-cell patch-clamp recording, detailed kinetic mechanism analysis of WT and M867I mutant GluK2 Biochemistry Medium 20863077
2021 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. Overexpression of GluK2(Q) vs. GluK2(R) in primary cultured hippocampal neurons, GluK1-GluK2 domain-swap chimeras, confocal imaging of spine morphology Synapse Medium 36121930
2017 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. Co-immunoprecipitation, overexpression of SUMO-modified PKC, western blotting for GluK2 phosphorylation levels Channels Low 28837400
2021 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. Co-immunoprecipitation, synaptic fractionation, intrathecal GRIP siRNA, behavioral pain assays in rats Neurochemical research Medium 33847855
2025 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. Laser-pulse photolysis combined with whole-cell patch-clamp recording in HEK293 cells expressing GluK2 with NETO1 or NETO2 The Journal of biological chemistry Medium 41197725
2020 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. Surface biotinylation, co-immunoprecipitation, inhibitors of clathrin-independent endocytosis, Ca2+ chelators, calcineurin inhibitors in cultured neurons Journal of integrative neuroscience Medium 33070524
2025 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. CRISPR/Cas9 knock-in mouse generation, behavioral analysis battery, EEG recording Neurobiology of disease Medium 41391686
2024 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. In vitro mast cell degranulation assays, in vivo intradermal and topical administration, transcriptomic analysis, Ki-67 and BrdU incorporation assays, mouse inflammatory models Science translational medicine Medium 39661706
2007 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. Genetic linkage analysis, mutation identification, electrophysiological characterization of mutant protein (loss of function) American journal of human genetics High 17847003

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Molecular psychiatry 137 18332879
2007 A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. American journal of human genetics 127 17847003
2012 SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity. Nature neuroscience 91 22522402
2011 Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosis. Proceedings of the National Academy of Sciences of the United States of America 70 22089239
2014 Contribution of aberrant GluK2-containing kainate receptors to chronic seizures in temporal lobe epilepsy. Cell reports 62 25043179
2013 Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms. Psychopharmacology 54 23660601
2011 Convergent genomic studies identify association of GRIK2 and NPAS2 with chronic fatigue syndrome. Neuropsychobiology 54 21912186
1994 Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment. Genomics 49 8034316
2011 Fluoxetine affects GluK2 editing, glutamate-evoked Ca(2+) influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes. Journal of psychiatry & neuroscience : JPN 48 21320410
2012 Assembly stoichiometry of the GluK2/GluK5 kainate receptor complex. Cell reports 45 22509486
1994 Functional expression and pharmacological characterization of the human EAA4 (GluR6) glutamate receptor: a kainate selective channel subunit. Receptors & channels 43 7536611
2014 Parkin regulates kainate receptors by interacting with the GluK2 subunit. Nature communications 42 25316086
2017 A gain-of-function mutation in the GRIK2 gene causes neurodevelopmental deficits. Neurology. Genetics 41 28180184
2010 Domain organization and function in GluK2 subtype kainate receptors. Proceedings of the National Academy of Sciences of the United States of America 40 20404149
2021 Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2. Annals of neurology 38 33949707
2010 Association between polymorphisms in GRIK2 gene and obsessive-compulsive disorder: a family-based study. CNS neuroscience & therapeutics 36 20370803
2021 Architecture and structural dynamics of the heteromeric GluK2/K5 kainate receptor. eLife 34 33724189
2021 Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders. American journal of human genetics 34 34375587
1998 Characterization of the kainate-binding domain of the glutamate receptor GluR-6 subunit. The Biochemical journal 34 9494120
2014 Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice. Hippocampus 30 24753134
2009 Down-regulation of GluK2 kainate receptor expression by chronic treatment with mood-stabilizing anti-convulsants or lithium in cultured astrocytes and brain, but not in neurons. Neuropharmacology 29 19596362
2020 Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3. The EMBO journal 28 32567721
2004 Maternal transmission disequilibrium of the glutamate receptor GRIK2 in schizophrenia. Neuroreport 28 15305151
2001 Genomic organization of the human GRIK2 gene and evidence for multiple splicing variants. Gene 28 11675011
2007 Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder. Cellular and molecular neurobiology 27 17712621
2023 Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel. Cell reports 23 36857176
2019 Neto proteins regulate gating of the kainate-type glutamate receptor GluK2 through two binding sites. The Journal of biological chemistry 22 31628192
2015 The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors. Neuropharmacology 20 26277340
2014 Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia. Proceedings of the National Academy of Sciences of the United States of America 20 25201974
1995 Refinement of map position of the human GluR6 kainate receptor gene (GRIK2) and lack of association and linkage with idiopathic generalized epilepsies. Neurology 20 7675232
2024 The kainate receptor GluK2 mediates cold sensing in mice. Nature neuroscience 19 38467901
2023 GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy. Annals of neurology 19 37341588
2018 ADAR2-mediated Q/R editing of GluK2 regulates kainate receptor upscaling in response to suppression of synaptic activity. Journal of cell science 19 30559217
2012 Association of genes on chromosome 6, GRIK2 , TMEM217 and TMEM63B (linked to MRPL14 ) with diabetic retinopathy. Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde 19 23037145
2010 Fatty acid modulation and polyamine block of GluK2 kainate receptors analyzed by scanning mutagenesis. The Journal of general physiology 19 20805577
2009 Functional characterization and in silico docking of full and partial GluK2 kainate receptor agonists. Molecular pharmacology 19 19225180
2020 Connexin 36 Mediates Orofacial Pain Hypersensitivity Through GluK2 and TRPA1. Neuroscience bulletin 18 33067780
2002 Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia. Psychiatry research 18 12467946
2017 Sevoflurane activates hippocampal CA3 kainate receptors (Gluk2) to induce hyperactivity during induction and recovery in a mouse model. British journal of anaesthesia 16 28981700
2011 Does conventional anti-bipolar and antidepressant drug therapy reduce NMDA-mediated neuronal excitation by downregulating astrocytic GluK2 function? Pharmacology, biochemistry, and behavior 16 21463649
2011 Binding and selectivity of the marine toxin neodysiherbaine A and its synthetic analogues to GluK1 and GluK2 kainate receptors. Journal of molecular biology 16 21893069
2021 A comparative analysis of kainate receptor GluK2 and GluK5 knockout mice in a pure genetic background. Behavioural brain research 15 33631192
2019 The structural arrangement and dynamics of the heteromeric GluK2/GluK5 kainate receptor as determined by smFRET. Biochimica et biophysica acta. Biomembranes 15 31194959
2019 The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain. Experimental neurology 15 31513786
2012 SUMOylation of the kainate receptor subunit GluK2 contributes to the activation of the MLK3-JNK3 pathway following kainate stimulation. FEBS letters 15 22483987
2012 TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease. Biochemical and biophysical research communications 15 22771793
2012 Modification and movement: Phosphorylation and SUMOylation regulate endocytosis of GluK2-containing kainate receptors. Communicative & integrative biology 15 22808340
2021 GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy. Cancer immunology, immunotherapy : CII 14 34405274
2020 The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines. Frontiers in cellular neuroscience 13 33005130
2019 The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging. Molecular metabolism 13 31767166
2013 Q/R site interactions with the M3 helix in GluK2 kainate receptor channels revealed by thermodynamic mutant cycles. The Journal of general physiology 13 23940260
2024 A novel AAV9-dual microRNA-vector targeting GRIK2 in the hippocampus as a treatment for mesial temporal lobe epilepsy. Molecular therapy. Methods & clinical development 12 39429724
2023 The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2. Experimental physiology 12 37656490
2024 Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels. Nature communications 11 39592599
2024 Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation. Science translational medicine 11 39661706
2013 Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors. Bioorganic & medicinal chemistry 11 24368028
2010 Channel-opening kinetic mechanism for human wild-type GluK2 and the M867I mutant kainate receptor. Biochemistry 11 20863077
2006 Genetic analysis of the GRIK2 modifier effect in Huntington's disease. BMC neuroscience 11 16959037
2012 Neuroprotection of GluK1 kainate receptor agonist ATPA against ischemic neuronal injury through inhibiting GluK2 kainate receptor-JNK3 pathway via GABA(A) receptors. Brain research 10 22516108
2009 GluK2-mediated excitability within the superficial layers of the entorhinal cortex. PloS one 10 19440371
2018 Cadmium opens GluK2 kainate receptors with cysteine substitutions at the M3 helix bundle crossing. The Journal of general physiology 9 30498132
2016 PDZ1 inhibitor peptide protects neurons against ischemia via inhibiting GluK2-PSD-95-module-mediated Fas signaling pathway. Brain research 9 26892027
2025 Structural basis of GluK2 kainate receptor activation by a partial agonist. Nature structural & molecular biology 8 40442317
2024 The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. FEBS letters 8 38369668
2018 High Conformational Variability in the GluK2 Kainate Receptor Ligand-Binding Domain. Structure (London, England : 1993) 8 30482727
2016 Pharmacological Modulation of GluK1 and GluK2 by NETO1, NETO2, and PSD95. Assay and drug development technologies 8 26991362
2019 Correlation between GRIK2 rs6922753, rs2227283 polymorphism and aggressive behaviors with Bipolar Mania in the Chinese Han population. Brain and behavior 7 31631587
2015 Molecular Dynamics Investigation of gluazo, a Photo-Switchable Ligand for the Glutamate Receptor GluK2. PloS one 7 26308344
2013 Correlating efficacy and desensitization with GluK2 ligand-binding domain movements. Open biology 7 23720540
2025 Activation of kainate receptor GluK2-Neto2 complex. Nature structural & molecular biology 6 40846810
2021 Intrathecal Injection of GRIP-siRNA Reduces Postoperative Synaptic Abundance of Kainate Receptor GluK2 Subunits in Rat Dorsal Horns and Pain Hypersensitivity. Neurochemical research 6 33847855
2019 Isoforms of Ionotropic Glutamate Receptor GRIK2 Induce Senescence of Carcinoma Cells. Cancer genomics & proteomics 6 30587499
2016 Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 27607061
2013 Agonist binding to the GluK5 subunit is sufficient for functional surface expression of heteromeric GluK2/GluK5 kainate receptors. Cellular and molecular neurobiology 6 23975096
2024 Anti-GluK2 Encephalitis in an Asian Child: A Case Report and Literature Review. ImmunoTargets and therapy 5 39717712
2023 GluK2 Q/R editing regulates kainate receptor signaling and long-term potentiation of AMPA receptors. iScience 5 37720087
2020 Truncated RUNX1 Generated by the Fusion of RUNX1 to Antisense GRIK2 via a Cryptic Chromosome Translocation Enhances Sensitivity to Granulocyte Colony-Stimulating Factor. Cytogenetic and genome research 5 32544910
2022 Experimental and Computational Structural Studies of 2,3,5-Trisubstituted and 1,2,3,5-Tetrasubstituted Indoles as Non-Competitive Antagonists of GluK1/GluK2 Receptors. Molecules (Basel, Switzerland) 4 35458681
2022 Transcriptomic and Phenotypic Analysis of CRISPR/Cas9-Mediated gluk2 Knockout in Zebrafish. Genes 4 36011351
2020 Clathrin-independent but dynamin-dependent mechanisms mediate Ca2+-triggered endocytosis of the glutamate GluK2 receptor upon excitotoxicity. Journal of integrative neuroscience 4 33070524
2025 Anti-GluK2 antibody-positive autoimmune encephalitis concurrent with multiple myeloma: a case report. BMC neurology 3 39833741
2023 Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor. Proteins 3 37526035
2020 A Novel Susceptibility Locus Near GRIK2 Associated With Erosive Esophagitis in a Korean Cohort. Clinical and translational gastroenterology 3 32132452
2019 Interaction among GRIK2 gene on epilepsy susceptibility in Chinese children. Acta neurologica Scandinavica 3 30908586
2023 Structural dynamics of GluK2 kainate receptors in apo and partial agonist bound states. Research square 2 38076992
2021 Structural Arrangement Produced by Concanavalin A Binding to Homomeric GluK2 Receptors. Membranes 2 34436376
2020 Senescence of Normal Human Fibroblasts Relates to the Expression of Ionotropic Glutamate Receptor GluR6/Grik2. Cancer genomics & proteomics 2 33099472
2012 Molecular and pharmacological evidence for a facilitatory functional role of pre-synaptic GLUK2/3 kainate receptors on GABA release in rat trigeminal caudal nucleus. European journal of pain (London, England) 2 22392917
2011 Non-syndromic autosomal recessive mental retardation in Tunisian families : exclusion of GRIK2 and TUSC3 genes. La Tunisie medicale 2 21557188
2025 Pathological gain-of-function human variants in the GRIK2 kainate receptor gene cause wide-ranging behavioral dysfunction and seizures in mouse models. Neurobiology of disease 1 41391686
2023 NETO2-GluK2 interaction contributes to postoperative pain hypersensitivity through inducing PKCγ activation and synaptic incorporation of AMPA receptor GluR1 subunits in rat dorsal horn. Neuroscience letters 1 37544581
2023 Epigenetic signature discriminates lymphatic metastasis in BRAF wild-type thyroid carcinoma: methylation role of GRIK2. Epigenomics 1 37990886
2022 Alternative Promoters of GRIK2 (GluR6) Gene in Human Carcinoma Cell Lines Are Regulated by Differential Methylation of CpG Dinucleotides. Genes 1 35328043
2022 Kainate receptors GluK1 and GluK2 differentially regulate synapse morphology. Synapse (New York, N.Y.) 1 36121930
2017 PKC SUMOylation inhibits the binding of 14-3-3τ to GluK2. Channels (Austin, Tex.) 1 28837400
2015 Discovery of novel small-molecule antagonists for GluK2. Bioorganic & medicinal chemistry letters 1 25913117
2014 Synthesis and molecular docking of novel non-competitive antagonists of GluK2 receptor. Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents 1 25620864
2026 GRIK2 drives LUAD progression via the cAMP/PKA/CREB pathway. Tissue & cell 0 42184490
2025 GluK2 kainate receptor subunit-selective, potentiating RNA aptamer. Scientific reports 0 40935837
2025 A comparative study of NETO1 and NETO2 on channel-opening kinetics of GluK2 kainate receptors. The Journal of biological chemistry 0 41197725

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