Affinage

GRIK4

Glutamate receptor ionotropic, kainate 4 · UniProt Q16099

Length
956 aa
Mass
107.2 kDa
Annotated
2026-06-10
47 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRIK4 encodes GluK4 (KA1), a high-affinity kainate-type ionotropic glutamate receptor subunit that shapes excitatory transmission in the hippocampal trisynaptic circuit and sets the threshold for glutamate-driven excitotoxicity (PMID:22203159, PMID:23357115). Structurally, its ligand-binding domain combines AMPA-receptor-like binding-site residues with GluK1-like domain closure and D1-D2 interlobe contacts, accounting for its high kainate affinity (PMID:27524200). In the adult forebrain GluK4 expression is restricted largely to CA3 pyramidal cells and dentate gyrus granule cells, where the subunit modulates presynaptic mossy fiber excitability and is required for mossy fiber long-term potentiation (PMID:10973593, PMID:22203159). GluK4 dosage bidirectionally controls circuit function: loss of the gene produces anxiolytic, antidepressant-like, and neuroprotective phenotypes along with impaired spatial memory and pre-pulse inhibition (PMID:22203159, PMID:23357115), whereas forebrain overexpression enhances synaptic information transfer through the trisynaptic circuit, produces a reversible excitatory/inhibitory imbalance that disrupts amygdala output, and generates autism- and depression-related behaviors (PMID:26446216, PMID:29949767). GluK4 also transduces injury signals: its protein levels are up-regulated in hippocampus through tPA/plasmin-dependent proteolysis of laminin, an event required for kainate-induced excitotoxic neurodegeneration and blocked by anti-KA1 antibody, with downstream signaling through the JNK pathway (PMID:19114596, PMID:23357115).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 Medium

    Establishing where the KA1/GluK4 subunit resides was the first step toward assigning it a circuit role; immunolocalization showed a broader CNS distribution than expected and a postsynaptic position in CA3.

    Evidence Anti-peptide antibody immunohistochemistry and electron microscopy across hippocampus, cortex, cerebellum and glia

    PMID:11000488

    Open questions at the time
    • Localization alone does not establish a functional or synaptic role
    • Subunit composition of native receptors at these sites not defined
  2. 2000 Medium

    Defining the developmental expression program clarified that GluK4 becomes restricted to the CA3/dentate region in the adult, focusing later functional studies on the trisynaptic circuit.

    Evidence YAC transgenic Cre-reporter mice with Cre immunohistochemistry and X-gal staining

    PMID:10973593

    Open questions at the time
    • Reporter expression may not capture all sites of endogenous protein
    • Functional consequence of restriction not addressed
  3. 2008 High

    Connecting GluK4 to injury signaling, this work showed that tPA/plasmin-generated laminin fragments up-regulate KA1 and that this up-regulation is causally required for excitotoxic neurodegeneration.

    Evidence Conditional laminin gamma1 KO and tPA KO mice, laminin fragment infusion rescue, and anti-KA1 antibody neutralization in vitro and in vivo

    PMID:19114596

    Open questions at the time
    • Molecular mechanism linking laminin fragments to KA1 transcription/translation not defined
    • Downstream death pathway not resolved here
  4. 2008 Low

    A human genetic association linked GRIK4 expression level to bipolar disorder risk, raising the possibility that receptor dosage influences mood.

    Evidence Case-control genetic study with replication plus mRNA expression analysis of 3' UTR deletion carriers

    PMID:18824690

    Open questions at the time
    • RNA secondary structure mechanism is postulated, not demonstrated
    • No causal link between the variant and circuit phenotype shown
  5. 2011 High

    Loss-of-function genetics tested GluK4's behavioral and synaptic role, showing it is needed for mossy fiber LTP and that its absence is anxiolytic and antidepressant-like.

    Evidence Grik4 knockout mice with a battery of behavioral assays and mossy fiber LTP electrophysiology

    PMID:22203159

    Open questions at the time
    • Mechanism of presynaptic excitability modulation inferred, not directly measured
    • Cell-type-specific contributions not separated
  6. 2013 High

    Extending the KO phenotype, this work tied GluK4 to spatial memory, sensorimotor gating, and—critically—excitotoxic vulnerability via the JNK pathway.

    Evidence Grik4 KO mice in Morris water maze, pre-pulse inhibition, intrahippocampal kainate and hypoxia-ischemia models, with Western analysis of JNK signaling

    PMID:23357115

    Open questions at the time
    • Direct biochemical coupling of GluK4 to JNK not demonstrated
    • Whether neuroprotection is cell-autonomous unresolved
  7. 2015 High

    Gain-of-function genetics established that increased GluK4 dosage is itself pathogenic, enhancing trisynaptic transmission and producing autism- and mood-related behaviors.

    Evidence Grik4 forebrain-overexpressing transgenic mice with behavioral assays and hippocampal slice electrophysiology

    PMID:26446216

    Open questions at the time
    • Molecular basis of enhanced transmission not dissected
    • Relationship to human dosage variation not established
  8. 2016 High

    The crystal structure answered why GluK4 binds kainate with high affinity, revealing AMPA-like binding residues paired with GluK1-like domain closure.

    Evidence X-ray crystallography of the GluK4 LBD bound to kainate at 2.05 Å with thermofluor and radioligand binding

    PMID:27524200

    Open questions at the time
    • Full-length receptor and gating not addressed
    • Heteromeric assembly behavior not structurally defined
  9. 2018 High

    Refining the dosage model, mild Grik4 overexpression was shown to cause a reversible excitatory/inhibitory imbalance disrupting amygdala output, demonstrating circuit-level reversibility.

    Evidence Grik4 forebrain-overexpressing transgenic mice with in vivo electrophysiology, amygdala circuit analysis, and normalization of gene dosage

    PMID:29949767

    Open questions at the time
    • Synaptic locus of the imbalance not pinpointed
    • Translation to therapeutic dosage modulation untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GluK4 dosage and laminin/tPA-driven up-regulation are coupled mechanistically to JNK- and ER-stress-dependent death versus circuit-level behavioral outcomes remains unresolved.
  • No direct molecular link between GluK4 and JNK or ER-stress effectors established
  • Subunit composition of native GluK4-containing receptors in each circuit undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0005215 transporter activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-5357801 Programmed Cell Death 2
Complex memberships
kainate receptor

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 KA1/GluK4 subunit immunoreactivity was localized by immunohistochemistry and electron microscopy to dendritic structures in the CA3 area of the hippocampus (postsynaptic to commissural-associational fibers rather than mossy fiber terminals), CA1 pyramidal cell apical dendrites, cortical layer V pyramidal neurons, GABAergic interneurons, Purkinje cells, and glial cells (oligodendrocytes and astrocytes), indicating a broader CNS distribution than previously appreciated. Immunohistochemistry with anti-peptide antibody to C-terminus of KA1, electron microscopy, cell fractionation Brain research. Molecular brain research Medium 11000488
2000 The KA1 (GluK4) gene promoter drives expression broadly throughout the developing brain during early postnatal development, becoming restricted mainly to hippocampal CA3 pyramidal cells and dentate gyrus granule cells in the adult brain, as established by YAC transgenic Cre-reporter mice. YAC transgenic mice expressing Cre from KA1 gene locus, Cre immunohistochemistry, X-gal staining in double transgenic KA1-Cre/lacZ reporter mice Brain research Medium 10973593
2008 Proteolytic fragments of laminin, generated via tPA-dependent plasmin activity, up-regulate the KA1 subunit of the kainate receptor in hippocampus following kainate injection. This KA1 up-regulation is required for excitotoxic neurodegeneration: laminin gamma1 KO and tPA KO mice both lack KA1 up-regulation and are resistant to kainate-induced neuronal death. Infusion of plasmin-digested laminin-1 restores KA1 up-regulation and neurodegeneration. Anti-KA1 antibody protects against kainate-induced neuronal death both in vitro and in vivo. Conditional hippocampal laminin gamma1 KO mice, tPA KO mice, intrahippocampal laminin fragment infusion, anti-KA1 antibody neutralization, in vitro and in vivo neurodegeneration assays The Journal of cell biology High 19114596
2011 Genetic ablation of GluK4 (Grik4 knockout mice) produces anxiolytic and antidepressant-like phenotypes (elevated zero maze, marble burying, novelty-induced suppression of feeding, forced swim test, sucrose preference). GluK4 expression is restricted to CA3 hippocampus and dentate gyrus in forebrain. Grik4 KO impairs mossy fiber long-term potentiation, likely through loss of kainate receptor modulation of presynaptic mossy fiber axon excitability. Grik4 knockout mice, behavioral assays (elevated zero maze, marble burying, novelty-induced suppression of feeding, forced swim test, sucrose preference test), mossy fiber LTP electrophysiology Behavioural brain research High 22203159
2013 GluK4 knockout mice show impaired spatial memory acquisition and recall in Morris water maze, marked hyperactivity, and impaired pre-pulse inhibition. GluK4 KO mice are robustly neuroprotected in CA3 following intrahippocampal kainate injection and throughout the hippocampus following hypoxia-ischemia. Biochemical analysis suggests GluK4 mediates excitotoxicity through the JNK signaling pathway. GluK4 knockout mice, Morris water maze, pre-pulse inhibition, intrahippocampal kainate injection, hypoxia-ischemia model, Western blot analysis of JNK pathway Neuroscience High 23357115
2015 Forebrain overexpression of grik4 in mice causes social impairment, enhanced anxiety, and depressive states, accompanied by more efficient synaptic information transfer through the hippocampal trisynaptic circuit, demonstrating that increased GluK4 dosage alters synaptic transmission and produces autism spectrum disorder-related behavioral features. Grik4 forebrain-overexpressing transgenic mice, behavioral assays, hippocampal slice electrophysiology of trisynaptic circuit The Journal of neuroscience High 26446216
2016 The X-ray crystal structure of the GluK4 ligand-binding domain (LBD) bound to kainate was solved at 2.05 Å resolution. Binding-site residues in GluK4 are most similar to AMPA receptor subfamily, but domain closure and D1-D2 interlobe contacts induced by kainate are similar to low-affinity kainate receptor GluK1, providing a structural explanation for the high kainate binding affinity of GluK4-LBD. X-ray crystallography at 2.05 Å, thermofluor assay, radiolabel binding affinity assays Structure High 27524200
2018 Mild gain of Grik4 dosage in mouse forebrain enhances synaptic transmission and causes a persistent imbalance of inhibitory and excitatory activity, disturbing circuits responsible for main amygdala outputs. These changes in glutamatergic activity are reversible when Grik4 levels are normalized. Grik4 forebrain-overexpressing transgenic mice, in vivo electrophysiology, circuit analysis of amygdala outputs, normalization of Grik4 expression Cell reports High 29949767
2008 A deletion variant in the 3' UTR of GRIK4 is associated with protection against bipolar disorder. Expression studies showed that deletion-carrying mRNA transcripts were relatively more abundant, suggesting the protective effect is mediated through increased kainate receptor expression, possibly due to differences in RNA secondary structure between insertion and deletion alleles. Case-control genetic study with replication, mRNA expression analysis of variant carriers Proceedings of the National Academy of Sciences of the United States of America Low 18824690
2010 KA1 subunit mRNA and protein are expressed in the substantia gelatinosa of the trigeminal subnucleus caudalis, with expression levels significantly higher in juvenile than adult mice, suggesting an age-dependent role in nociceptive processing. RT-PCR, Western blot, immunohistochemistry in juvenile, prepubescent, and adult mice Journal of veterinary science Low 21113098
2015 Up-regulation of KA1 receptor following intrahippocampal kainate or tunicamycin (ER stress inducer) injection correlates with neuronal death and elevated ER stress marker P-eIF2α, suggesting KA1 participates in transmitting apoptotic signals leading to ER dysfunction and neurodegeneration. Intrahippocampal microinjection of kainate or tunicamycin in mice, FJB staining for cell death, immunofluorescence for KA1 and P-eIF2α Nan fang yi ke da xue xue bao Low 25736111
2012 KA1 and KA2 kainate receptor subunits are present on the dendritic arbors of direction-selective retinal ganglion cells (DS-RGCs) in both developing and adult mouse retina, but no asymmetric distribution was found that would predict direction selectivity. Immunocytochemistry, Lucifer yellow injection for DS-RGC morphology, confocal microscopy Acta histochemica et cytochemica Low 22489103

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. The American journal of psychiatry 156 17671280
1998 Expression of NMDAR1, GluR1, GluR7, and KA1 glutamate receptor mRNAs is decreased in frontal cortex of "neuroleptic-free" schizophrenics: evidence on reversible up-regulation by typical neuroleptics. Journal of neurochemistry 145 9832144
2006 Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Molecular psychiatry 91 16819533
2007 Are some genetic risk factors common to schizophrenia, bipolar disorder and depression? Evidence from DISC1, GRIK4 and NRG1. Neurotoxicity research 54 17449450
2008 A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder. Proceedings of the National Academy of Sciences of the United States of America 53 18824690
2011 Genetic ablation of the GluK4 kainate receptor subunit causes anxiolytic and antidepressant-like behavior in mice. Behavioural brain research 48 22203159
2002 Sphingomonas sp. strain KA1, carrying a carbazole dioxygenase gene homologue, degrades chlorinated dibenzo-p-dioxins in soil. FEMS microbiology letters 46 12052549
1996 The effect of chronic haloperidol treatment on glutamate receptor subunit (GluR1, GluR2, KA1, KA2, NR1) mRNAs and glutamate binding protein mRNA in rat forebrain. Neuroscience letters 45 8843098
2015 Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 26446216
2005 Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia. Psychiatry research 40 16325263
2013 The GluK4 kainate receptor subunit regulates memory, mood, and excitotoxic neurodegeneration. Neuroscience 39 23357115
2013 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay. American journal of medical genetics. Part A 31 24449200
2018 Increased Grik4 Gene Dosage Causes Imbalanced Circuit Output and Human Disease-Related Behaviors. Cell reports 30 29949767
2016 Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase. The Biochemical journal 25 27879374
2017 AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women. Journal of neuroimmunology 24 28284346
2014 GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. Pharmacogenomics 24 25303296
2000 KA1-like kainate receptor subunit immunoreactivity in neurons and glia using a novel anti-peptide antibody. Brain research. Molecular brain research 23 11000488
2012 AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 22 22980146
2015 The role of GRIK4 gene in treatment-resistant depression. Genetics research 21 26139080
2018 Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain. Structure (London, England : 1993) 20 30099988
2008 Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor. The Journal of cell biology 19 19114596
1994 The genes encoding the glutamate receptor subunits KA1 and KA2 (GRIK4 and GRIK5) are located on separate chromosomes in human, mouse, and rat. Proceedings of the National Academy of Sciences of the United States of America 19 7527545
2012 Failure to replicate influence of GRIK4 and GNB3 polymorphisms on treatment outcome in major depression. Neuropsychobiology 18 22222462
2000 Developmental profile of kainate receptor subunit KA1 revealed by Cre expression in YAC transgenic mice. Brain research 17 10973593
2016 Influence of GRIK4 genetic variants on the electroconvulsive therapy response. Neuroscience letters 13 27222927
2015 KA1-targeted regulatory domain mutations activate Chk1 in the absence of DNA damage. Scientific reports 12 26039276
1996 Contrasting effects of electroconvulsive shock on mRNAs encoding the high affinity kainate receptor subunits (KA1 and KA2) and cyclophilin in the rat. Brain research 12 8963683
2016 The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate. Structure (London, England : 1993) 10 27524200
2015 Optimization of crude oil degradation by Dietzia cinnamea KA1, capable of biosurfactant production. Journal of basic microbiology 10 26615815
2018 Chk1 KA1 domain auto-phosphorylation stimulates biological activity and is linked to rapid proteasomal degradation. Scientific reports 9 30510197
2008 No genetic association between polymorphisms in the kainate-type glutamate receptor gene, GRIK4, and schizophrenia in the Chinese population. Progress in neuro-psychopharmacology & biological psychiatry 8 18289755
2024 GRIK phosphorylates and activates KIN10 which also promotes its degradation. Frontiers in plant science 7 38590740
2018 A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 7 29243543
2012 Synaptic Pattern of KA1 and KA2 upon the Direction-Selective Ganglion Cells in Developing and Adult Mouse Retina. Acta histochemica et cytochemica 7 22489103
2019 GRIK4 and GRM7 gene may be potential indicator of venlafaxine treatment reponses in Chinese of Han ethnicity. Medicine 6 31083176
2020 Impact of GRIK4 gene polymorphisms on cognitive dysfunction in patients with major depression. Revue neurologique 5 32245654
2008 Crystallization and preliminary X-ray diffraction studies of a novel ferredoxin involved in the dioxygenation of carbazole by Novosphingobium sp. KA1. Acta crystallographica. Section F, Structural biology and crystallization communications 5 18607094
2017 Common variants in GRIK4 and major depressive disorder: An association study in the Chinese Han population. Neuroscience letters 4 28583584
2010 Crystallization and preliminary X-ray diffraction studies of a ferredoxin reductase component of carbazole 1,9a-dioxygenase from Novosphingobium sp. KA1. Acta crystallographica. Section F, Structural biology and crystallization communications 4 20516607
2018 KA1 Domains: Unity in Mechanistic Diversity. Structure (London, England : 1993) 3 30089246
2010 Crystallization and preliminary X-ray diffraction studies of a terminal oxygenase of carbazole 1,9a-dioxygenase from Novosphingobium sp. KA1. Acta crystallographica. Section F, Structural biology and crystallization communications 3 21045300
2024 SARS-CoV-2-derived protein Orf9b enhances MARK2 activity via interaction with the autoinhibitory KA1 domain. FEBS letters 1 38969617
2025 Mitosis Localization Signal (MLS) extends KA1 and regulates MELK kinase localization to plasma membrane and activity in Xenopus embryo. Developmental biology 0 40816457
2015 [Role of KA1 receptor in excitotoxic neurodegeneration in mouse hippocampus triggered by kainic acid- or tunicamycin-induced endoplasmic reticulum stress]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 25736111
2010 Expression of KA1 kainate receptor subunit in the substantia gelatinosa of the trigeminal subnucleus caudalis in mice. Journal of veterinary science 0 21113098
1998 Linkage mapping of the interleukin 1beta converting enzyme (Il1bc) and the glutamate receptor subunit KA1 (Grik4) genes to rat chromosome 8. Folia biologica 0 10730851
1993 Epithelial cell membrane specific, novel monoclonal antibody KA-1. Journal of dermatological science 0 8395199

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