Affinage

GRIK2

Glutamate receptor ionotropic, kainate 2 · UniProt Q13002

Length
908 aa
Mass
102.6 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRIK2 encodes GluK2, a kainate-type ionotropic glutamate receptor subunit that assembles into homomeric or heteromeric (2:2 with GluK5) tetrameric ligand-gated cation channels mediating fast excitatory neurotransmission, synaptic plasticity, and—beyond the CNS—cold thermosensation and metabotropic signaling coupled to phospholipase D (PMID:7536611, PMID:22509486, PMID:38467901, PMID:37656490). Channel gating is governed by a dimer-of-dimers architecture in which the M3 helix bundle-crossing gate opens upon agonist binding, LBD dimer-interface stability controls desensitization, and N-glycans at the ATD–LBD interface modulate cation binding to tune gating; auxiliary subunits Neto1/2 slow channel kinetics by preventing LBD dimer tightening during activation, while SEZ6 promotes glycosylation and forward trafficking (PMID:20404149, PMID:23720540, PMID:40442317, PMID:40846810, PMID:32567721). Surface expression is dynamically regulated by ADAR2-mediated Q/R editing—which controls Ca²⁺ permeability, ER exit efficiency, and the balance between ionotropic and metabotropic signaling—and by a PKC phosphorylation (S868)–SUMOylation (K886) cascade that drives agonist-evoked endocytosis required for hippocampal mossy-fiber LTD (PMID:30559217, PMID:37720087, PMID:22089239, PMID:22522402). Gain-of-function de novo variants in the M3 domain (A657T, T660K/R) cause constitutive channel activity associated with severe epilepsy and neurodevelopmental disorder (PMID:28180184, PMID:34375587).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1994 High

    Establishing that GRIK2 encodes a functional kainate-selective ionotropic glutamate receptor resolved the molecular identity of kainate-type currents and showed homomeric GluK2 channels are permeable to both Na⁺ and Ca²⁺.

    Evidence Heterologous expression in HEK-293 cells with radioligand binding, whole-cell electrophysiology, and ion permeability assays

    PMID:7536611

    Open questions at the time
    • Heteromeric assembly rules unknown
    • Native auxiliary subunit composition not addressed
    • In vivo synaptic role not tested
  2. 1998 High

    Mapping the agonist-binding site to two discontinuous extracellular segments (S1 and S2) established that the ligand-binding domain is structurally homologous to bacterial periplasmic binding proteins, explaining kainate vs. AMPA selectivity.

    Evidence Recombinant S1-S2 chimeras between GluR-6 and GluR-D expressed in insect cells with [³H]kainate binding

    PMID:9494120

    Open questions at the time
    • No atomic-resolution structure of the binding site
    • Mechanism coupling agonist binding to channel opening unknown
  3. 2010 High

    Demonstrating the dimer-of-dimers extracellular architecture with domain-swapped ATD and LBD layers, and showing that cross-linking either domain inhibits activation, established the structural framework for understanding how extracellular conformational changes gate the pore.

    Evidence Cysteine cross-linking mutagenesis in full-length GluK2 with electrophysiological readout

    PMID:20404149

    Open questions at the time
    • Full-length high-resolution structure not yet available
    • Mechanism of desensitization at atomic level unresolved
  4. 2010 High

    Systematic scanning mutagenesis of the transmembrane domain revealed that Q/R editing controls susceptibility to fatty acid inhibition and polyamine block through physical coupling between the pore helix and M3, later confirmed by thermodynamic double-mutant cycle analysis.

    Evidence Scanning mutagenesis and electrophysiology (2010); double-mutant cycle analysis (2013)

    PMID:20805577 PMID:23940260

    Open questions at the time
    • Structural basis of fatty acid binding site not determined
    • Physiological relevance of fatty acid modulation in vivo unclear
  5. 2012 High

    Discovering that PKC phosphorylation at S868 promotes SUMOylation at K886, and that both modifications are sequentially required for KAR internalization during hippocampal LTD, defined the post-translational cascade governing activity-dependent GluK2 endocytosis.

    Evidence Phospho/SUMO-site mutagenesis with SUMOylation assays, surface expression assays, and mossy-fiber LTD recordings in hippocampal slices

    PMID:22089239 PMID:22522402

    Open questions at the time
    • E3 SUMO ligase identity for GluK2 not established
    • Whether this pathway operates at all KAR-expressing synapses unknown
  6. 2012 High

    Single-molecule subunit counting established the 2:2 GluK2/GluK5 stoichiometry, resolving debate about heteromeric KAR composition and providing a framework for interpreting heteromeric gating.

    Evidence Single-molecule fluorescence imaging in live cells expressing tagged subunits

    PMID:22509486

    Open questions at the time
    • Arrangement of subunits around the pore axis not determined
    • Whether other heteromeric combinations share 2:2 stoichiometry unknown
  7. 2012 Medium

    Linking ischemia-induced GluK2 SUMOylation to MLK3–JNK3 pro-apoptotic signaling revealed a non-ionotropic pathological signaling role for internalized GluK2.

    Evidence Co-IP, kinase assays, and SUMOylation-deficient mutant in rat global brain ischemia model

    PMID:22483987

    Open questions at the time
    • Single-lab finding; independent replication lacking
    • Whether MLK3 binding is direct or scaffold-mediated not resolved
  8. 2013 High

    Crystal structures of LBD dimer-interface mutants (K531A, R775A) revealed that charge balance at the dimer interface governs rapid desensitization, providing a structural mechanism for desensitization distinct from channel block.

    Evidence LBD crystal structures combined with mutagenesis and electrophysiology

    PMID:23720540

    Open questions at the time
    • How LBD dimer rupture propagates to the transmembrane gate not structurally resolved
    • Full-length desensitized-state structure not available at this time
  9. 2014 High

    Identifying parkin as a direct GluK2 interactor that limits surface expression via ubiquitination connected KAR regulation to Parkinson's disease biology and excitotoxicity.

    Evidence Co-IP, surface biotinylation, electrophysiology in parkin-mutant neurons and mouse brain

    PMID:25316086

    Open questions at the time
    • Specific ubiquitination sites on GluK2 not mapped
    • Whether parkin-GluK2 interaction is relevant in dopaminergic neurons unknown
  10. 2014 High

    Demonstrating that Src phosphorylates GluK2 at Y590 to potentiate currents and calcium influx during ischemia identified a second kinase pathway (distinct from PKC–SUMO) controlling GluK2 activity and linked it to excitotoxic JNK3 signaling.

    Evidence GluK2-Src Co-IP, Y590 mutagenesis, electrophysiology, Ca²⁺ imaging in rat ischemia model

    PMID:25201974

    Open questions at the time
    • Whether Src phosphorylation at Y590 occurs under physiological (non-ischemic) conditions unknown
    • Interplay between Src and PKC pathways on GluK2 not addressed
  11. 2017 High

    Functional characterization of the de novo A657T variant as constitutively active established the first gain-of-function channelopathy mechanism for GRIK2 in neurodevelopmental disease.

    Evidence Whole-exome sequencing with whole-cell electrophysiology of mutant GluK2 in heterologous cells

    PMID:28180184

    Open questions at the time
    • Whether compensatory mechanisms exist in vivo not tested
    • Therapeutic strategy for gain-of-function variants not explored
  12. 2018 High

    Showing that ADAR2 degradation reduces Q/R editing and increases ER exit efficiency of unedited GluK2(Q) revealed that RNA editing acts as a homeostatic mechanism controlling KAR surface expression during activity suppression.

    Evidence ADAR2 knockdown, proteasome inhibition, and surface expression assays in neurons

    PMID:30559217

    Open questions at the time
    • Whether editing-dependent trafficking regulation operates bidirectionally in vivo not shown
    • Structural basis for differential ER exit of edited vs. unedited GluK2 unknown
  13. 2018 High

    Cadmium activation of Cys-substituted M3 residues A657C and L659C, independent of agonist binding, directly demonstrated that the M3 helix bundle crossing is the activation gate and that gate opening requires movement at only two of four subunits.

    Evidence Cysteine-substitution mutagenesis with Cd²⁺ activation electrophysiology and kinetic modeling

    PMID:30498132

    Open questions at the time
    • Gate geometry at atomic resolution not yet available
    • Whether asymmetric gating applies to heteromeric channels not tested
  14. 2019 High

    Mapping the Neto auxiliary subunit interaction to the GluK2 NTD–CUB1 interface via electrostatic contacts explained how Neto proteins modulate deactivation, desensitization, and recovery kinetics.

    Evidence Domain-deletion and charge-reversal mutagenesis with electrophysiology in HEK293T cells

    PMID:31628192

    Open questions at the time
    • Structural model of GluK2–Neto complex not yet determined
    • In vivo stoichiometry of Neto at synapses unknown
  15. 2020 High

    Identifying SEZ6 as a trafficking chaperone that promotes GluK2 post-ER transport and HNK-1 glycosylation revealed a new layer of secretory pathway regulation specific to KARs.

    Evidence Co-IP, surface biotinylation, SEZ6 KO mouse hippocampal slice electrophysiology, glycosylation analysis

    PMID:32567721

    Open questions at the time
    • Whether SEZ6 is a stoichiometric complex partner or transient chaperone unclear
    • SEZ6-binding site on GluK2 ectodomain not mapped
  16. 2020 High

    Demonstrating that GluK2 forms a complex with KCC2 and that GluK2 loss destabilizes dendritic spines via reduced 4.1N and active cofilin revealed a structural, non-ionotropic role for GluK2 in spine maturation.

    Evidence In vivo AAV-mediated GluK2 knockdown in CA3, Co-IP, FRAP of β-actin, KCC2 rescue

    PMID:33005130

    Open questions at the time
    • Whether GluK2-KCC2 interaction is direct or scaffold-mediated not resolved
    • Relevant phosphorylation or trafficking signals not identified
  17. 2021 High

    Cryo-EM structures of GluK2/GluK5 heteromers in apo, antagonist-bound, and desensitized states revealed that GluK5 occupies pore-proximal positions and GluK2 undergoes the major rearrangements during desensitization, explaining asymmetric subunit roles.

    Evidence Cryo-EM of GluK2/GluK5 in multiple functional states

    PMID:33724189

    Open questions at the time
    • Open-state structure of the heteromer not captured
    • How GluK5 proximity to the pore influences conductance unknown
  18. 2021 High

    Functional characterization of additional M3 variants (T660K, T660R) as constitutively active, alongside replication of A657T, expanded the gain-of-function GRIK2 channelopathy spectrum to include severe epilepsy with hypomyelination.

    Evidence Whole-exome sequencing of patients, electrophysiology of recombinant homomeric and heteromeric mutant KARs

    PMID:34375587

    Open questions at the time
    • Genotype–phenotype correlation across full variant spectrum incomplete
    • Whether heteromeric context rescues or worsens gain-of-function unclear in vivo
  19. 2023 High

    Knock-in editing-deficient mice demonstrated that Q/R editing controls the balance between ionotropic and metabotropic KAR signaling in vivo, with unedited GluK2(Q) enhancing ionotropic function but reducing metabotropic signaling and downstream AMPAR expression.

    Evidence GluK2 Q/R editing-deficient knock-in mice, hippocampal slice electrophysiology, AMPAR subunit immunoblotting

    PMID:37720087

    Open questions at the time
    • Molecular mechanism linking editing state to metabotropic coupling not defined
    • Behavioral consequences of editing imbalance not fully characterized
  20. 2023 Medium

    Identifying homomeric GluK2 as the PLD-coupled metabotropic receptor in muscle spindle afferents demonstrated that GluK2 can function as a purely metabotropic receptor independent of its ionotropic activity.

    Evidence Immunofluorescence, western/far-western blotting, pharmacology, and electrophysiology in ionotropic-function-ablated mouse model

    PMID:37656490

    Open questions at the time
    • Single-lab finding awaiting independent replication
    • How GluK2 couples to PLD without canonical G-protein domains unknown
  21. 2023 High

    Cryo-EM structures with PAM (BPAM344), antagonist (DNQX), and NAM (perampanel) mapped allosteric modulator binding sites to the LBD dimer interface and extracellular collar, establishing the structural pharmacology framework for KAR drug design.

    Evidence Cryo-EM structures with bound modulators

    PMID:36857176

    Open questions at the time
    • Open-state PAM-bound structure not captured
    • Selectivity determinants versus AMPA receptors for perampanel binding not fully explained
  22. 2024 High

    GluK2 knockout mice showing a selective cold-sensing deficit established that GluK2 functions as a cold thermoreceptor in peripheral DRG neurons, representing a co-opted function distinct from its central chemoreceptor role.

    Evidence GluK2 KO mice with behavioral thermal/mechanical assays and DRG neuron analysis

    PMID:38467901

    Open questions at the time
    • Biophysical mechanism of cold sensing by GluK2 unknown
    • Whether cold sensitivity requires channel opening or metabotropic signaling not determined
  23. 2024 High

    Cryo-EM structures of GluK2 with trapped polyamine blockers revealed the structural basis of use-dependent channel block: blockers reside intracellular to the closed M3 gate with polyamine tails spanning the selectivity filter.

    Evidence Cryo-EM with spermine, Kukoamine A, NpTx-8, PhTx-74; molecular dynamics simulations

    PMID:39592599

    Open questions at the time
    • Dynamics of blocker entry and exit during channel gating not captured
    • Whether trapping mechanism differs in heteromeric channels unknown
  24. 2025 High

    Cryo-EM structures of GluK2–Neto2 in apo and open states revealed that Neto2 slows gating by preventing tightening of the LBD dimer-of-dimers interface during activation, without altering individual LBD or pore conformations, providing the first structural explanation for auxiliary subunit modulation of KAR kinetics.

    Evidence Time-resolved cryo-EM ± Neto2, electrophysiology

    PMID:40846810

    Open questions at the time
    • Neto1 structural mechanism not yet determined for comparison
    • Whether Neto2 occupancy is variable at native synapses unknown
  25. 2025 High

    Apo GluK2 cryo-EM structures captured a pre-activation desensitized conformation, and N-glycan mutagenesis at the ATD–LBD interface altered gating, demonstrating that glycosylation tunes channel function by modulating cation binding at the LBD dimer interface.

    Evidence Cryo-EM of apo and domoate-bound GluK2, electrophysiology of N-glycosylation mutants

    PMID:40442317

    Open questions at the time
    • Physiological regulation of glycan occupancy not addressed
    • Whether pre-activation desensitization occurs in native neuronal KARs unknown
  26. 2025 High

    Quantitative kinetic analysis showed NETO2 slows GluK2 channel-opening ~7-fold and closing ~3-fold versus ~2-fold for NETO1, establishing distinct kinetic signatures for each auxiliary subunit.

    Evidence Laser-pulse photolysis with whole-cell patch-clamp in HEK-293 cells

    PMID:41197725

    Open questions at the time
    • Whether Neto1 and Neto2 can co-occupy a single GluK2 tetramer not tested
    • How kinetic differences translate to synaptic waveform shaping in vivo not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the biophysical mechanism of cold thermosensation by GluK2, how GluK2 couples to PLD-dependent metabotropic signaling without canonical G-protein domains, the identity of the E3 SUMO ligase mediating GluK2 SUMOylation, and the full structural basis of heteromeric KAR gating in the open state.
  • Cold-sensing mechanism unknown
  • Metabotropic coupling mechanism undefined
  • Open-state heteromeric KAR structure lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 1 R-HSA-9709957 Sensory Perception 1
Partners
ADAR2GRIK5KCC2NETO1NETO2PRKNSEZ6SRC
Complex memberships
GluK2 homotetramerGluK2-KCC2 complexGluK2-Neto2 complexGluK2/GluK5 heterotetramer

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Human GluK2 (GluR6/GRIK2) encodes a kainate-selective ionotropic glutamate receptor that forms functional homomeric channels when expressed in HEK-293 cells, showing high-affinity kainate binding, rapidly desensitizing currents activated by kainate, glutamate, and domoate (but not AMPA), and permeability to both Na+ and Ca2+ ions; desensitization was attenuated by concanavalin A. Heterologous expression in COS/HEK-293 cells, radioligand binding, whole-cell electrophysiology, ion permeability assays Receptors & channels High 7536611
1998 The kainate-binding site of 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, demonstrated using soluble S1-S2 chimeras between GluR-6 and GluR-D expressed in insect cells. Recombinant fragment expression in insect cells, [3H]kainate binding assay, S1-S2 chimera analysis The Biochemical journal High 9494120
2010 The extracellular domains of GluK2 assemble as a dimer-of-dimers in which the amino-terminal domain (ATD) and ligand-binding domain (LBD) swap dimer partners between layers; cross-linking either the ATD or LBD inhibits channel activation, and cross-links within vs. between LBD dimers have distinct functional effects, establishing a conserved extracellular architecture shared with AMPA receptors. Cysteine mutant cross-linking in full-length GluK2, functional electrophysiology, guided by crystal structures Proceedings of the National Academy of Sciences of the United States of America High 20404149
2010 RNA editing at the Q/R site of GluK2 determines susceptibility to inhibition by cis-unsaturated fatty acids (arachidonic acid, DHA) and block by cytoplasmic polyamines; scanning mutagenesis identified three surfaces along M1/M2/M3 helices where substitutions confer fatty acid sensitivity to GluK2(Q), and four M3 positions (F611, L614, S618, T621) where Arg substitution increases chloride permeability and eliminates polyamine block. Scanning mutagenesis, whole-cell electrophysiology, fatty acid and polyamine pharmacology The Journal of general physiology High 20805577
2011 Kainate stimulation causes rapid PKC-mediated phosphorylation of GluK2 at two C-terminal sites (S846 and S868); phosphorylation at S868 specifically enhances GluK2 SUMOylation and promotes agonist-dependent endocytosis in neurons, while S846A mutation does not prevent SUMOylation or endocytosis. Phosphomimetic/alanine mutagenesis, SUMOylation assays in vitro and in neurons, endocytosis assays, whole-cell electrophysiology in HEK293 cells Proceedings of the National Academy of Sciences of the United States of America High 22089239
2012 PKC-mediated phosphorylation of GluK2 at S868 promotes GluK2 SUMOylation at K886; both modifications are required for internalization of GluK2-containing KARs during LTD at rat hippocampal mossy fiber synapses. Phosphorylation of S868 in the absence of SUMOylation instead increases KAR surface expression by facilitating receptor recycling. Mutagenesis of phosphorylation and SUMOylation sites, hippocampal slice electrophysiology (LTD recordings), surface expression assays Nature neuroscience High 22522402
2012 GluK2 and GluK5 subunits assemble into heteromeric kainate receptors with a defined 2:2 stoichiometry, as determined by direct single-molecule subunit counting in the plasma membranes of live cells. Single-molecule imaging (subunit counting) in live cells expressing fluorescently tagged GluK2 and GluK5 Cell reports High 22509486
2012 Global brain ischemia induces sustained elevation of GluK2 SUMOylation; SUMOylated GluK2 undergoes endocytosis and the internalized GluK2 binds MLK3, activating the MLK3-JNK3 pathway, contributing to ischemic neuronal death. SUMOylation-deficient GluK2 mutant does not activate MLK3-JNK3 signaling. Overexpression of WT and SUMOylation-deficient GluK2 mutants, immunoprecipitation, kinase activity assays, ischemia model in rats FEBS letters Medium 22483987
2013 Double mutant cycle analysis revealed strong energetic coupling between the Q/R site residue and L614 in the M3 helix of GluK2; substitution at L614 selectively reverses the inhibitory effect of fatty acids on edited GluK2(R) channels, converting inhibition to potentiation, demonstrating physical interaction between the pore helix and M3 that underlies Q/R-site-dependent channel properties. Double mutant cycle analysis, whole-cell electrophysiology, mutagenesis The Journal of general physiology High 23940260
2013 Mutation of K531 and R775 at the GluK2 ligand-binding domain (LBD) dimer interface attenuates desensitization and can switch relative agonist efficacies; crystal structures of these mutants reveal conformational changes including new dimer contacts (K531A) and loss of chloride binding at the dimer interface, demonstrating that charge balance at the LBD dimer interface is necessary for rapid and complete desensitization. Site-directed mutagenesis, LBD crystal structures, electrophysiology Open biology High 23720540
2014 Parkin interacts directly with the GluK2 KAR subunit; loss of parkin function causes GluK2 protein accumulation at the plasma membrane, potentiates KAR currents, and increases KAR-dependent excitotoxicity in primary neurons and in mouse brain. Co-immunoprecipitation, surface biotinylation, whole-cell electrophysiology in primary neurons, in vivo parkin mutant mouse model Nature communications High 25316086
2014 Brain ischemia induces rapid Src family kinase-mediated phosphorylation of GluK2 at Y590 in rat hippocampus; GluK2 binds Src, and Y590 phosphorylation increases whole-cell kainate currents, calcium influx, and facilitates GluK2 endocytosis, as well as activation of the JNK3-c-Jun pro-apoptotic pathway. Co-immunoprecipitation (GluK2-Src), mutagenesis (Y590), whole-cell electrophysiology, Ca2+ imaging, ischemia model in rats Proceedings of the National Academy of Sciences of the United States of America High 25201974
2017 A de novo A657T point mutation in the GluK2 M3 transmembrane domain causes constitutive channel activity (channels active in nominally glutamate-free solution) and profoundly altered gating, establishing a gain-of-function mechanism for this neurodevelopmental disorder variant. Whole-exome sequencing to identify variant, whole-cell voltage-clamp in heterologous expression system Neurology. Genetics High 28180184
2018 ADAR2-mediated Q/R editing of GluK2 is reduced by activity suppression via proteasomal degradation of ADAR2; unedited GluK2(Q) assembles and exits the ER more efficiently, leading to upscaling of KAR surface expression; this mechanism is selective for KARs and does not apply to AMPA receptor GluA2 Q/R editing. ADAR2 knockdown (siRNA), proteasome inhibition, surface expression assays, neuron KAR upscaling model Journal of cell science High 30559217
2018 Cadmium (Cd2+) directly activates GluK2 channels bearing cysteine substitutions at A657C or L659C in the M3 helix bundle-crossing gate, independent of agonist binding; Cd activation requires Cys substitution at only two of four subunits and is similar whether in A/C or B/D subunit conformations, revealing the mechanism of the M3 bundle-crossing gate. Cys-substitution mutagenesis, Cd2+ exposure electrophysiology, MTSEA modification, heteromeric and chimeric channel analysis, kinetic modeling The Journal of general physiology High 30498132
2019 Neto proteins regulate GluK2 gating through two binding sites: the GluK2 N-terminal domain (NTD) binds the first CUB domain of Neto proteins (NTD-CUB1), and the GluK2 core binds Netos through other domains. NTD-CUB1 interaction regulates deactivation/desensitization kinetics and recovery from desensitization; the NTD stabilizes GluK2 desensitization state. Electrostatic interactions between positively charged GluK2 NTD residues and negatively charged Neto CUB1 residues mediate this interaction. Domain deletion mutagenesis, charge-reversal mutagenesis, electrophysiology in HEK293T cells The Journal of biological chemistry High 31628192
2020 Seizure protein 6 (SEZ6) interacts with GluK2 through its ectodomain and promotes post-ER transport in the secretory pathway; loss of SEZ6 reduces surface levels of GluK2/3 in neurons, reduces kainate-evoked currents in hippocampal CA1 neurons, and prevents HNK-1 glycosylation of GluK2/3. Co-immunoprecipitation, surface biotinylation, hippocampal slice electrophysiology, SEZ6 knockout mouse, glycosylation analysis The EMBO journal High 32567721
2020 GluK2 interacts with KCC2 in hippocampal CA3 neurons; GluK2 deficiency alters KCC2 subcellular distribution, reduces dendritic spine maturation, decreases mEPSC frequency, and reduces expression of 4.1N and active cofilin, stabilizing F-actin in spines. These phenotypes are rescued by KCC2 overexpression, demonstrating a GluK2-KCC2 complex required for structural spine maturation. In vivo GluK2 knockdown (local AAV), FRAP of β-actin, immunostaining for KCC2, co-immunoprecipitation, mEPSC recordings, KCC2 rescue overexpression Frontiers in cellular neuroscience High 33005130
2021 Patient-derived GluK2 antibodies internalize GluK2 in HEK293 cells and neurons (reversibly), and reduce GluK2-mediated currents following the time course of antibody-mediated internalization, establishing that anti-GluK2 autoantibodies cause encephalitis primarily through receptor internalization. Cell-based assay with GluK2-expressing HEK293 cells, immunoprecipitation, confocal microscopy in neurons, electrophysiology in HEK293 cells Annals of neurology High 33949707
2021 De novo variants encoding GluK2 p.Thr660Lys, p.Thr660Arg, and p.Ala657Thr (all in the M3 transmembrane domain) cause markedly slowed gating kinetics in recombinant homomeric and heteromeric KARs and alter membrane localization; p.Thr660Lys and p.Thr660Arg exhibit constitutive-like activity, associating with severe epilepsy and hypomyelination in affected individuals. Whole-exome sequencing, whole-cell electrophysiology of recombinant mutant KARs, surface expression assays American journal of human genetics High 34375587
2021 The GluK2/GluK5 heteromeric kainate receptor assembles with GluK5 subunits proximal to the channel; during desensitization GluK2, but not GluK5, subunits undergo major structural rearrangements to facilitate channel closure, mediated by linkers connecting pore helices to ligand-binding domains. Cryo-EM structure determination of GluK2/GluK5 heteromer in apo, antagonist-bound, and desensitized states eLife High 33724189
2023 Cryo-EM structures of GluK2 with positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator perampanel reveal that two BPAM344 molecules bind per LBD dimer interface to stabilize a closed state, while perampanel binds extracellular collar sites in two of four subunits to also stabilize the closed state. Cryo-EM structure determination, pharmacological characterization Cell reports High 36857176
2023 GluK2 Q/R editing controls the balance between ionotropic and metabotropic KAR signaling at mossy fiber-CA3 synapses; editing-deficient GluK2(Q) mice display increased postsynaptic KAR function and presynaptic facilitation (ionotropic), but reduced metabotropic KAR function (ISAHP inhibition), and fewer GluA1/GluA3-containing AMPARs with reduced LTP at CA1 synapses. Knock-in editing-deficient mice, hippocampal slice electrophysiology, AMPAR subunit immunoblotting iScience High 37720087
2023 Homomeric GluK2 is identified as the PLD-coupled metabotropic glutamate receptor (PLD-mGluR) in primary mechanosensory spindle terminals; evidence from immunofluorescence, western and far-western blotting shows GluK2 is the only glutamate receptor subunit present, and in a mouse model with ionotropic function ablated in GluK2, spindle glutamatergic responses are preserved, confirming purely metabotropic signaling. Immunofluorescence, western blotting, far-western blotting, pharmacological profiling, ionotropic-function ablated mouse model electrophysiology Experimental physiology Medium 37656490
2024 GluK2 knockout mice exhibit a specific deficit in sensing cold (but not cool, heat, or mechanical stimuli), identifying GluK2 as a cold-sensing thermoreceptor in dorsal root ganglion somatosensory neurons in the periphery, co-opted from its role as a central glutamate-sensing chemoreceptor. GluK2 knockout mice, behavioral thermal and mechanical sensitivity assays, DRG neuron functional analysis Nature neuroscience High 38467901
2024 Closed-state cryo-EM structures of GluK2 in complex with polyamine channel blockers (spermine, Kukoamine A, NpTx-8, PhTx-74) reveal that blockers reside inside the ion channel pore intracellular to the closed M3 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-EM structure determination, molecular dynamics simulations Nature communications High 39592599
2025 Cryo-EM structures of GluK2 KAR with auxiliary subunit Neto2 in apo closed and agonist/PAM-activated open states reveal that Neto2 binding prevents tightening of the interface between two LBD dimers during activation and slows deactivation kinetics, without affecting individual/dimeric LBD behavior or the ion channel itself. Time-resolved cryo-EM in presence and absence of Neto2, electrophysiology Nature structural & molecular biology High 40846810
2025 Cryo-EM structures of homomeric rat GluK2 in unliganded apo and partial agonist (domoate)-bound states reveal that apo GluK2 is captured in a desensitized conformation (pre-activation desensitization), and partial agonist-bound GluK2 populates intermediate and desensitized states; N-glycans at the ATD-LBD interface modulate gating by interfering with cation binding at the LBD dimer interface. Cryo-EM, electrophysiology of N-glycosylation mutants Nature structural & molecular biology High 40442317
2016 TTBK2 (tau tubulin kinase 2) down-regulates GluK2 activity by decreasing receptor protein abundance at the plasma membrane via RAB5-dependent endocytosis; expression of kinase-dead TTBK2 or truncated TTBK2(450) does not reduce GluK2 membrane levels, and the effect is blocked by dominant-negative RAB5. Xenopus oocyte expression, two-electrode voltage clamp, confocal microscopy of EGFP-tagged GluK2, dominant-negative RAB5 co-expression Cellular physiology and biochemistry Medium 27607061
2017 SUMOylation of PKC (not GluK2) represses the interaction between 14-3-3τ and GluK2a-containing receptors by reducing PKC-mediated phosphorylation of GluK2a; this regulatory mechanism may contribute to control of KAR-EPSC decay kinetics. Co-immunoprecipitation, phosphorylation analysis, SUMOylation assays Channels Low 28837400
2025 NETO1 slows GluK2 channel-opening and channel-closing rates ~2-fold, while NETO2 slows channel-opening ~7-fold and channel-closing ~3-fold, and also reduces EC50 and slows desensitization more than NETO1, establishing NETO2 as the more impactful auxiliary subunit on GluK2 homomeric channel kinetics. Laser-pulse photolysis + whole-cell patch-clamp in HEK-293 cells, kinetic mechanism analysis The Journal of biological chemistry High 41197725

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Arabidopsis protein kinases GRIK1 and GRIK2 specifically activate SnRK1 by phosphorylating its activation loop. Plant physiology 143 19339507
2008 Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Molecular psychiatry 136 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 61 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 52 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 47 21320410
2012 Assembly stoichiometry of the GluK2/GluK5 kainate receptor complex. Cell reports 45 22509486
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