{"gene":"GRIK1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1990,"finding":"GluR5 (GRIK1) forms homomeric ion channels in Xenopus oocytes that are weakly responsive to L-glutamate, establishing it as a ligand-gated ion channel subunit with approximately 40-41% amino acid identity to AMPA receptor subunits GluR1-4.","method":"Xenopus oocyte expression, electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution in heterologous expression system, foundational cloning paper replicated extensively","pmids":["1977421"],"is_preprint":false},{"year":1996,"finding":"RNA editing at the Q/R site of GluR5 pre-mRNA requires a distant intronic editing site complementary sequence (ECS) located up to 1900 nucleotides distal to the Q/R site; the exon-intron duplex is a substrate for double-stranded RNA-specific adenosine deaminase (ADAR), which preferentially targets the adenosine at the Q/R site when coexpressed in HEK293 cells.","method":"Minigene transfection in PC-12 cells, RT-PCR, ADAR coexpression in HEK293 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic dissection of editing substrate using minigenes with mutagenesis, replicated across GluR5 and GluR6","pmids":["8700852"],"is_preprint":false},{"year":1997,"finding":"Amino acids in the region between M3 and M4 of GluR5/GluR6 control agonist selectivity and desensitization: a single amino acid (N721 in GluR6; corresponding GluR5 residue) controls AMPA sensitivity and domoate deactivation rates, while A689 in GluR6 controls kainate desensitization rate.","method":"Chimeric receptor construction, site-directed mutagenesis, patch-clamp electrophysiology in heterologous cells","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and electrophysiological readout, multiple residues characterized","pmids":["9354337"],"is_preprint":false},{"year":1997,"finding":"GluR5-containing kainate receptors regulate synaptic inhibition in the CA1 hippocampus by activating interneurons, demonstrated using selective agonist ATPA and antagonist LY294486.","method":"Hippocampal slice electrophysiology with selective pharmacological tools (ATPA agonist, LY294486 antagonist)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pharmacological dissection with selective agonist and antagonist in native tissue, widely replicated","pmids":["9335499"],"is_preprint":false},{"year":1997,"finding":"GluR5 and KA-2 subunits coassemble to form functional heteromeric kainate receptor channels in trigeminal ganglion neurons, with pharmacological properties, desensitization, rectification, and ion permeability matching recombinant GluR5(R)/KA-2 channels.","method":"RT-PCR subunit expression profiling, patch-clamp electrophysiology of native neurons vs. recombinant receptors","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent evidence from native neuron physiology and recombinant receptor comparison, single lab","pmids":["9254673"],"is_preprint":false},{"year":1998,"finding":"GluR5-containing kainate receptors on CA1 inhibitory interneurons generate inward currents and repetitive action potentials upon activation by glutamate, kainate, or ATPA, causing a massive increase in tonic GABAergic inhibition onto pyramidal neuron somata and apical dendrites.","method":"Hippocampal slice electrophysiology, selective pharmacology (ATPA, LY293558), identified interneuron recordings","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cellular recordings in identified interneurons with selective pharmacological tools, replicated","pmids":["10196544"],"is_preprint":false},{"year":1998,"finding":"GluR5 subunits comprise or contribute to a presynaptic kainate receptor that depresses excitatory synaptic transmission in both CA1 and CA3 hippocampal regions; depression was associated with increased paired-pulse facilitation, indicating a presynaptic locus.","method":"Hippocampal slice field recordings and whole-cell voltage-clamp with selective agonist ATPA and antagonist LY294486","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — paired-pulse facilitation assay established presynaptic locus, selective pharmacology, replicated independently","pmids":["9849664"],"is_preprint":false},{"year":1998,"finding":"GluR5 subunit mediates synaptic excitation in the rat basolateral amygdala (BLA); train-evoked, AMPA-receptor-independent synaptic responses are blocked by selective GluR5 antagonist LY293558 (95% block at 10 µM), with a null potential near 0 mV consistent with inwardly rectifying, calcium-permeable channels.","method":"Intracellular recording in BLA slices, selective pharmacological isolation of receptor component","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological isolation with selective antagonist in native tissue, replicated in subsequent studies","pmids":["9849665"],"is_preprint":false},{"year":1999,"finding":"GluR5, GluR6, and GluR7 kainate receptor subunits coassemble promiscuously to form heteromeric receptors; GluR5/GluR6 heteromers exhibit reduced desensitization and faster recovery from desensitization compared to homomeric GluR5, and coexpression of GluR6 enhances response magnitude to GluR5-selective agonists.","method":"Coexpression in HEK293 cells, patch-clamp electrophysiology, polyamine rectification assay to detect heteromeric assembly","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in heterologous cells with biophysical validation of heteromeric assembly via edited/unedited Q/R site strategy","pmids":["10493729"],"is_preprint":false},{"year":1999,"finding":"RNA editing at the Q/R site of GluR5 reduces kainate receptor current density approximately 6-fold in dorsal root ganglion neurons, established using knock-in mice encoding arginine (edited) at position 636 (GluR5 Q/R site).","method":"Knock-in mouse genetics, patch-clamp electrophysiology in acutely isolated DRG neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic knock-in model with direct electrophysiological measurement in native neurons","pmids":["10516295"],"is_preprint":false},{"year":2000,"finding":"GluR5 and GluR6 subunits coexist in a population of hippocampal GABAergic interneurons and coassemble into functional heteromeric receptors in HEK293 cells; heteromeric GluR5/GluR6 receptors show outward rectification, sensitivity to ATPA and AMPA, and distinct desensitization/gating properties from homomeric GluR6.","method":"Non-radioactive double in situ hybridization, cotransfection in HEK293 cells, patch-clamp electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal in situ hybridization and functional heterologous reconstitution, replicated concept from prior work","pmids":["10627597"],"is_preprint":false},{"year":2003,"finding":"GluR5-2b subunit cell surface expression is controlled by an endoplasmic reticulum (ER) retention signal in its alternatively spliced C-terminal domain; a critical arginine (Arg-896) mediates ER retention, and phosphomimetic mutation at Thr-898 promotes ER exit and surface expression; two additional positively charged residues (Arg-900, Lys-901) also regulate ER export.","method":"Site-directed mutagenesis, cell surface biotinylation, immunofluorescence in heterologous cells and neurons","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis with functional trafficking readout in both heterologous cells and neurons, multiple residues characterized","pmids":["14527949"],"is_preprint":false},{"year":2003,"finding":"Topiramate selectively inhibits postsynaptic GluR5 kainate receptor-mediated synaptic currents in rat BLA principal neurons (IC50 ~0.5 µM) without affecting paired-pulse facilitation, demonstrating a postsynaptic mechanism; it reduces miniature EPSC amplitude without affecting frequency.","method":"Whole-cell voltage-clamp recordings in rat BLA slices, pharmacological isolation of receptor subtypes","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiological dissection with selective pharmacology, postsynaptic locus established by mEPSC analysis, replicated","pmids":["12904467"],"is_preprint":false},{"year":2003,"finding":"Selective activation of GluR5 on BLA interneurons depolarizes them and increases GABA release, leading to tonic GABA current and reduced excitability; this GluR5-mediated pathway activates voltage-dependent calcium channels and requires Ca2+ influx.","method":"Whole-cell recordings in amygdala slices, selective pharmacology, GluR5-/- mice","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patch-clamp in native tissue with selective agonist/antagonist and knockout validation, single lab","pmids":["19417176"],"is_preprint":false},{"year":2003,"finding":"GluR5 agonist selectivity over AMPA receptors is controlled by Ser741 in GluR5 (vs. Met722 in GluR1): mutation of Ser741 abolishes ATPA selectivity, demonstrating that a serine-dependent stabilization of active receptor conformation and steric clash with Met722 underlie GluR5 selectivity.","method":"Site-directed mutagenesis, two-electrode voltage-clamp in Xenopus oocytes","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with functional electrophysiological validation, mechanistic explanation supported by structural reasoning","pmids":["12488532"],"is_preprint":false},{"year":2004,"finding":"GluK1 (GluR5) kainate receptors play a distinct role from GluR6 in hippocampal network activity: ablation of GluR5 increases susceptibility to kainate-induced gamma oscillations and epileptiform bursts, while GluR6 deletion prevents these effects, suggesting GluR5-containing receptors on interneuron axons provide a regulatory brake on network excitability.","method":"Kainate receptor knockout mice, in vitro and in vivo electrophysiology, network oscillation analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined electrophysiological phenotype, supported by computational network modeling","pmids":["15509753"],"is_preprint":false},{"year":2005,"finding":"Crystal structures of the GluR5 ligand-binding core reveal a binding cavity 40% larger than GluR2, extensive interdomain contacts between domains 1 and 2 absent in AMPA receptors, and high-stability kainate complexes; the degree of domain closure by partial agonists differs quantitatively from AMPA receptors, explaining subtype-selective agonist binding.","method":"X-ray crystallography of GluR5-S1S2 ligand-binding core in complex with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with multiple ligand complexes, mechanistic interpretation of domain closure","pmids":["15721240"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of GluR5-S1S2 in complex with (S)-glutamate at 1.95 Å reveals two-domain architecture similar to GluR2, high degree of domain closure (26°), a novel dimer interface with different protomer arrangement compared to GluR2, and Ser741 forming an interdomain bridge stabilizing a water network.","method":"X-ray crystallography","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional annotation of key residue","pmids":["15710405"],"is_preprint":false},{"year":2005,"finding":"GluR5 knockout mice show significantly reduced responses to capsaicin and inflammatory pain, but normal fear memory and normal amygdala synaptic potentiation, establishing a specific role for GluR5 in chemical/inflammatory nociception distinct from GluR6's role in fear memory.","method":"GluR5 and GluR6 knockout mice, behavioral pain assays (capsaicin, formalin), fear conditioning, amygdala LTP recordings","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-knockout comparison with multiple behavioral and electrophysiological readouts, subunit-specific phenotype established","pmids":["15673679"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of GluR5 ligand-binding core with GluR5-selective antagonists UBP302 and UBP310 reveal a novel antagonist-binding mechanism that does not contact E723 (unlike all previous AMPA/kainate agonist/antagonist complexes), resulting in hyperextension of the ligand-binding core and a 22 Å extension of ion-channel linkers in dimer assemblies compared to the glutamate-bound form.","method":"X-ray crystallography of GluR5 LBD dimer complexes with antagonists","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures revealing novel binding mode, validated against functional data on full-length channels","pmids":["16540562"],"is_preprint":false},{"year":2007,"finding":"GluR5-containing kainate receptors selectively depolarize inhibitory interneurons in the basolateral amygdala, increasing GABA release and tonic inhibitory current onto principal neurons; genetic deletion of GluR5 or local antagonist injection increases anxiety-like behavior, placing GluR5 as a key regulator of inhibitory circuit tone in the BLA.","method":"GluR5 knockout mice, whole-cell recordings in amygdala slices, intra-BLA drug injection, anxiety behavioral assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological intervention with cellular electrophysiological and behavioral readouts","pmids":["17245443"],"is_preprint":false},{"year":2008,"finding":"GluR5-containing kainate receptor activation suppresses Src kinase-mediated tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B, and disrupts the NR2A-PSD-95-Src signaling complex, providing neuroprotection against ischemia-reperfusion injury; this occurs through GluR5-mediated Ca2+-dependent GABA release activating GABAA receptors, which then inhibit Src activation.","method":"In vivo rat ischemia model, co-immunoprecipitation, Western blotting for phosphorylated NR2A/NR2B, patch-clamp recording, GluR5 antisense oligodeoxynucleotides","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and electrophysiological methods in a single lab, mechanistic chain established","pmids":["18678878"],"is_preprint":false},{"year":2009,"finding":"GluR5 kainate receptors on myelinated spinal cord axons mediate Ca2+ increase through both ionotropic and metabotropic (noncanonical) signaling via a pertussis toxin-sensitive G protein/PLC pathway causing IP3-dependent Ca2+ release from internal stores; GluR5 co-immunoprecipitates with nNOS and colocalizes with nNOS clusters on internodal axons, and the response involves intraaxonal NO.","method":"Confocal Ca2+ imaging in dorsal column axons, pertussis toxin treatment, IP3 receptor blockers, co-immunoprecipitation, immunohistochemistry","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological approaches plus co-IP in native tissue, single lab","pmids":["19224531"],"is_preprint":false},{"year":2011,"finding":"NETO2 profoundly slows GluR1 (GluK1) kainate receptor desensitization, promotes plasma membrane localization, and targets GluK1-containing receptors to synapses in hippocampal neurons; NETO1 increases the rate of GluK1 desensitization. These auxiliary proteins extend the temporal range of receptor gating by over an order of magnitude.","method":"Heterologous cell transfection, hippocampal neuron transfection, whole-cell electrophysiology, immunocytochemistry for synaptic targeting","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional reconstitution in both heterologous cells and neurons, multiple NETO subunits compared, synaptic targeting established","pmids":["21593317"],"is_preprint":false},{"year":2015,"finding":"Both NETO1 and NETO2 profoundly increase GluK1 surface expression and drive GluK1 to synapses in hippocampal CA1 neurons; GluK1 synaptic targeting by Neto proteins is independent of their role in promoting surface trafficking. GluK1 is excluded from synapses expressing AMPA receptors and selectively incorporated into silent synapses. Neto2 slows GluK1 deactivation and desensitization; Neto1 speeds desensitization.","method":"CA1 pyramidal neuron expression (null background), whole-cell electrophysiology, surface expression assays, chimeric Neto constructs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic dissection using null-background system, chimeric subunits, and multiple functional readouts","pmids":["26720915"],"is_preprint":false},{"year":2015,"finding":"A proteomic screen of the GluK1 C-terminal domain identified Goα as an interacting partner; GluK1 activates Go proteins as validated by BRET experiments, and the interaction was confirmed by co-IP in native brain tissue and absent in GluK1-deficient mice, establishing GluK1 as capable of metabotropic (G protein) signaling via Go.","method":"Proteomics (C-terminal domain pull-down), co-immunoprecipitation in native brain, BRET assay, GluK1 knockout mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification confirmed by multiple orthogonal methods (Co-IP, BRET) in native tissue and validated by knockout","pmids":["25834043"],"is_preprint":false},{"year":2015,"finding":"NETO1 and NETO2 have distinct, subunit-dependent effects on GluK1 kinetics: both slow onset of desensitization at low agonist concentrations and increase glutamate sensitivity; at higher concentrations, Neto2 primarily slows desensitization while Neto1 primarily increases recovery from desensitization. The extracellular N-terminal CUB domain region of Neto is largely responsible for these distinct regulatory effects.","method":"Patch-clamp electrophysiology in HEK-293T cells expressing chimeric Neto1/Neto2 subunits with GluK1 or GluK2","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstitution with chimeric auxiliary subunits and systematic dose-response analysis, single lab","pmids":["26277340"],"is_preprint":false},{"year":2018,"finding":"The cleaved signal peptide of GluK1 represses receptor surface trafficking and synaptic targeting by directly binding to the amino-terminal domain (ATD) in trans; replacing GluK1's signal peptide with GluK2's signal peptide increases synaptic EPSCs, and co-expression of GluK1 signal peptide suppresses this gain, establishing a novel trafficking repression mechanism.","method":"Chimeric receptor expression in hippocampal CA1 neurons, electrophysiology (EPSC recordings), co-expression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic chimeric receptor approach with functional synaptic readout and trans-acting mechanism validated","pmids":["30451858"],"is_preprint":false}],"current_model":"GRIK1/GluK1 encodes a kainate-type ionotropic glutamate receptor subunit that forms homomeric or heteromeric (with GluK2, GluK3, KA2) ligand-gated ion channels; its surface trafficking is controlled by an ER retention signal (Arg-896) in the C-terminal domain and repressed by its own cleaved signal peptide binding the ATD, while the auxiliary proteins NETO1 and NETO2 promote surface expression, synaptic targeting, and bidirectionally regulate desensitization kinetics; postsynaptically and presynaptically in hippocampus, amygdala, spinal cord, and sensory ganglia, GluK1-containing receptors regulate both excitatory and inhibitory transmission—particularly by depolarizing GABAergic interneurons to increase tonic inhibition—and can signal metabotropically through Goα proteins; RNA editing at the Q/R site (requiring a distant intronic ECS and ADAR) reduces Ca2+ permeability and single-channel conductance; and ligand selectivity is structurally determined by Ser741 in the ligand-binding domain, whose 40%-larger binding cavity compared to GluR2 and extensive interdomain contacts explain subtype-specific pharmacology."},"narrative":{"mechanistic_narrative":"GRIK1/GluK1 (originally GluR5) encodes a kainate-type ionotropic glutamate receptor subunit that assembles into homomeric or heteromeric ligand-gated cation channels and shapes both excitatory and inhibitory transmission across hippocampus, amygdala, spinal cord, and sensory ganglia [PMID:1977421, PMID:9335499, PMID:9849665]. It coassembles promiscuously with other kainate subunits—KA2, GluK2/GluR6, and GluK3/GluR7—generating heteromeric channels whose desensitization, rectification, and agonist responses differ from the homomers [PMID:9254673, PMID:10493729, PMID:10627597]. A defining function is the depolarization of GABAergic interneurons: GluK1-containing receptors on interneurons in CA1 and the basolateral amygdala drive repetitive firing and elevate tonic GABAergic inhibition onto principal neurons, positioning the subunit as a regulator of inhibitory circuit tone and network excitability, with genetic ablation increasing susceptibility to epileptiform activity and anxiety-like behavior [PMID:10196544, PMID:15509753, PMID:17245443]. Presynaptic GluK1 also depresses excitatory transmission [PMID:9849664]. Beyond ionotropic gating, GluK1 signals metabotropically through Goα proteins identified at its C-terminal domain [PMID:25834043], and on spinal axons couples to a pertussis-toxin-sensitive G protein/PLC/IP3 pathway in association with nNOS to mobilize internal Ca2+ [PMID:19224531]. Channel properties are tuned post-transcriptionally and by accessory proteins: ADAR-mediated RNA editing at the Q/R site, which requires a distant intronic editing-site complementary sequence, reduces Ca2+ permeability and current density [PMID:8700852, PMID:10516295], while the auxiliary subunits NETO1 and NETO2 promote surface expression and synaptic targeting and bidirectionally control desensitization kinetics via their extracellular CUB domains [PMID:21593317, PMID:26720915, PMID:26277340]. Surface delivery is gated by an ER retention signal centered on Arg-896 in the alternatively spliced C-terminal domain [PMID:14527949] and repressed in trans by the receptor's own cleaved signal peptide binding the amino-terminal domain [PMID:30451858]. Ligand selectivity and gating are structurally explained by Ser741 in the ligand-binding domain and a binding cavity 40% larger than the AMPA receptor GluR2, with distinct domain-closure and antagonist-binding modes [PMID:12488532, PMID:15721240, PMID:16540562]. Functionally, GluK1 mediates inflammatory/chemical nociception and confers neuroprotection in ischemia by suppressing Src-mediated NMDA receptor phosphorylation through GABAergic signaling [PMID:15673679, PMID:18678878].","teleology":[{"year":1990,"claim":"Establishing that GluR5 is itself a functional ligand-gated channel subunit answered whether this AMPA-related clone formed glutamate-responsive channels at all.","evidence":"Xenopus oocyte expression and electrophysiology of homomeric GluR5","pmids":["1977421"],"confidence":"High","gaps":["Native subunit composition and in vivo channel partners not addressed","Weak homomeric responses left physiological role unresolved"]},{"year":1996,"claim":"Defining the editing substrate showed how Q/R-site recoding is achieved, identifying the distant intronic ECS and ADAR as the machinery controlling receptor permeability.","evidence":"Minigene transfection, RT-PCR, and ADAR coexpression in heterologous cells","pmids":["8700852"],"confidence":"High","gaps":["In vivo editing extent across tissues not quantified here","Functional consequence of editing on channel biophysics established only later"]},{"year":1997,"claim":"Pharmacological and mutagenic dissection established GluK1 as a regulator of inhibitory transmission and mapped residues controlling agonist selectivity and desensitization, moving from a cloned subunit to a circuit element with defined molecular determinants.","evidence":"Hippocampal slice electrophysiology with selective tools (ATPA, LY294486); chimeric and point-mutant receptors with patch-clamp","pmids":["9335499","9354337","9254673"],"confidence":"High","gaps":["Pre- vs postsynaptic localization not yet resolved in 1997","Native heteromer composition inferred but not exhaustively defined"]},{"year":1998,"claim":"Cellular recordings localized GluK1 actions to identified interneurons and presynaptic terminals, showing it both drives tonic GABAergic inhibition and presynaptically depresses excitatory transmission, and mediates calcium-permeable excitation in the amygdala.","evidence":"Hippocampal and amygdala slice electrophysiology with paired-pulse facilitation and selective antagonists","pmids":["10196544","9849664","9849665"],"confidence":"High","gaps":["Subunit stoichiometry of native receptors not defined","Molecular basis of presynaptic vs postsynaptic targeting unknown"]},{"year":1999,"claim":"Heteromeric assembly rules and the functional impact of Q/R editing were established, explaining how subunit mixing and recoding diversify native receptor kinetics and current density.","evidence":"Heterologous coexpression with polyamine rectification assays; knock-in mice editing the Q/R site with DRG electrophysiology; double in situ hybridization","pmids":["10493729","10516295","10627597"],"confidence":"High","gaps":["Stoichiometry of native heteromers in vivo not measured","Editing dynamics under physiological/pathological states not addressed"]},{"year":2003,"claim":"The C-terminal ER retention signal and ligand-binding determinants were mapped, explaining how surface delivery is gated and how GluK1 achieves subtype-selective pharmacology, alongside identification of a postsynaptic GluK1 component in the amygdala.","evidence":"Site-directed mutagenesis with surface biotinylation; two-electrode voltage-clamp; whole-cell mEPSC analysis with topiramate; knockout-validated amygdala recordings","pmids":["14527949","12488532","12904467","19417176"],"confidence":"High","gaps":["Trafficking factors recognizing the Arg-896 signal not identified","Coupling between retention signal and synaptic targeting unresolved"]},{"year":2005,"claim":"Crystal structures of the ligand-binding core and subunit-specific knockout phenotypes provided the structural and physiological basis for GluK1's distinct pharmacology and its specific roles in nociception and network regulation.","evidence":"X-ray crystallography of GluR5-S1S2 with multiple ligands; GluK1/GluK2 knockout mice with behavioral pain, fear, and network oscillation assays","pmids":["15721240","15710405","15673679","15509753"],"confidence":"High","gaps":["Structures of intact channel and heteromers not resolved","Link between LBD structure and full-channel gating only inferred"]},{"year":2006,"claim":"Antagonist-bound structures revealed a binding mode that hyperextends the ligand-binding core, mechanistically connecting GluK1-selective antagonism to channel-closing conformational changes.","evidence":"X-ray crystallography of GluR5 LBD dimers with antagonists UBP302/UBP310","pmids":["16540562"],"confidence":"High","gaps":["Conformational changes inferred from isolated LBD, not full-length channel","Antagonist effects on heteromeric receptors not addressed"]},{"year":2009,"claim":"GluK1 was shown to signal noncanonically and to confer neuroprotection, extending its function beyond ionotropic gating to metabotropic Ca2+ mobilization and modulation of NMDA receptor signaling.","evidence":"Confocal Ca2+ imaging with pertussis toxin and IP3 blockers plus co-IP in spinal axons; in vivo ischemia model with co-IP and phospho-Western blotting","pmids":["19224531","18678878"],"confidence":"Medium","gaps":["Single-lab mechanistic chains awaiting independent replication","Identity of the relevant G protein/effector in the metabotropic pathway not fully defined at this stage"]},{"year":2015,"claim":"Auxiliary NETO proteins and a Goα partner were established as principal regulators of GluK1 trafficking, synaptic targeting, kinetics, and metabotropic signaling, defining the accessory machinery governing receptor behavior.","evidence":"Null-background CA1 expression with chimeric Neto constructs and electrophysiology; proteomic C-terminal pull-down with co-IP, BRET, and knockout validation","pmids":["26720915","26277340","25834043","21593317"],"confidence":"High","gaps":["Mechanism by which NETO directs GluK1 to silent synapses unresolved","Downstream effectors of Goα signaling not mapped"]},{"year":2018,"claim":"A trans-acting repression mechanism was uncovered in which the cleaved signal peptide binds the ATD to suppress surface and synaptic targeting, revealing a novel layer of GluK1 trafficking control.","evidence":"Chimeric receptor and signal-peptide co-expression in CA1 neurons with EPSC recordings","pmids":["30451858"],"confidence":"High","gaps":["Structural basis of signal-peptide/ATD interaction not solved","Physiological regulation of this repression in vivo unknown"]},{"year":null,"claim":"How GluK1's ionotropic and metabotropic signaling modes, editing state, and NETO-dependent trafficking are coordinated within native synapses, and whether GRIK1 variants cause defined human disease, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the intact full-length or NETO-bound channel in the corpus","Downstream Goα effector pathway uncharacterized","No Mendelian disease link established in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[25,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,23,24]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11,27]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,5,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[25,22]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,9]}],"complexes":["GluK1/KA2 kainate receptor","GluK1/GluK2 heteromeric kainate receptor"],"partners":["NETO1","NETO2","GRIK2","GRIK5","GNAO1","NOS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P39086","full_name":"Glutamate receptor ionotropic, kainate 1","aliases":["Excitatory amino acid receptor 3","EAA3","Glutamate receptor 5","GluR-5","GluR5"],"length_aa":918,"mass_kda":104.0,"function":"Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. 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the hippocampus that are blocked by a GluR5 kainate receptor antagonist in vitro.","date":"2008","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19136046","citation_count":26,"is_preprint":false},{"pmid":"10821708","id":"PMC_10821708","title":"4-Alkyl- and 4-cinnamylglutamic acid analogues are potent GluR5 kainate receptor agonists.","date":"2000","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10821708","citation_count":25,"is_preprint":false},{"pmid":"8813384","id":"PMC_8813384","title":"Distribution of glutamate receptor subunit proteins GluR2(4), GluR5/6/7, and NMDAR1 in the canine and primate cerebral cortex: a comparative immunohistochemical analysis.","date":"1996","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8813384","citation_count":25,"is_preprint":false},{"pmid":"20558186","id":"PMC_20558186","title":"Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive 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Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7656430","citation_count":22,"is_preprint":false},{"pmid":"23042954","id":"PMC_23042954","title":"Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration.","date":"2012","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/23042954","citation_count":21,"is_preprint":false},{"pmid":"25679470","id":"PMC_25679470","title":"Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors.","date":"2015","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/25679470","citation_count":21,"is_preprint":false},{"pmid":"12488532","id":"PMC_12488532","title":"The selective activation of the glutamate receptor GluR5 by ATPA is controlled by serine 741.","date":"2003","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12488532","citation_count":21,"is_preprint":false},{"pmid":"25689173","id":"PMC_25689173","title":"A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.","date":"2015","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25689173","citation_count":21,"is_preprint":false},{"pmid":"23786569","id":"PMC_23786569","title":"Cortical GluK1 kainate receptors modulate scratching in adult mice.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23786569","citation_count":21,"is_preprint":false},{"pmid":"26277340","id":"PMC_26277340","title":"The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors.","date":"2015","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26277340","citation_count":20,"is_preprint":false},{"pmid":"25834043","id":"PMC_25834043","title":"A proteomic analysis reveals the interaction of GluK1 ionotropic kainate receptor subunits with Go proteins.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25834043","citation_count":20,"is_preprint":false},{"pmid":"12909680","id":"PMC_12909680","title":"Kainate receptor (GluR5)-mediated disinhibition of responses in rat ventrobasal thalamus allows a novel sensory processing mechanism.","date":"2003","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12909680","citation_count":20,"is_preprint":false},{"pmid":"10969973","id":"PMC_10969973","title":"4-Alkylidenyl glutamic acids, potent and selective GluR5 agonists.","date":"2000","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/10969973","citation_count":20,"is_preprint":false},{"pmid":"30451858","id":"PMC_30451858","title":"Signal peptide represses GluK1 surface and synaptic trafficking through binding to amino-terminal domain.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30451858","citation_count":19,"is_preprint":false},{"pmid":"21619066","id":"PMC_21619066","title":"Selective kainate receptor (GluK1) ligands structurally based upon 1H-cyclopentapyrimidin-2,4(1H,3H)-dione: synthesis, molecular modeling, and pharmacological and biostructural characterization.","date":"2011","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21619066","citation_count":19,"is_preprint":false},{"pmid":"25496338","id":"PMC_25496338","title":"Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking.","date":"2014","source":"Addiction biology","url":"https://pubmed.ncbi.nlm.nih.gov/25496338","citation_count":19,"is_preprint":false},{"pmid":"12672235","id":"PMC_12672235","title":"(S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid, a potent and selective agonist at the GluR5 subtype of ionotropic glutamate receptors. Synthesis, modeling, and molecular pharmacology.","date":"2003","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12672235","citation_count":19,"is_preprint":false},{"pmid":"19588945","id":"PMC_19588945","title":"The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization.","date":"2009","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19588945","citation_count":18,"is_preprint":false},{"pmid":"16948848","id":"PMC_16948848","title":"Presynaptic regulation of the inhibitory transmission by GluR5-containing kainate receptors in spinal substantia gelatinosa.","date":"2006","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/16948848","citation_count":18,"is_preprint":false},{"pmid":"22111545","id":"PMC_22111545","title":"Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors.","date":"2011","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22111545","citation_count":17,"is_preprint":false},{"pmid":"11354670","id":"PMC_11354670","title":"Synthesis and receptor binding affinity of new selective GluR5 ligands.","date":"2001","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11354670","citation_count":17,"is_preprint":false},{"pmid":"21893069","id":"PMC_21893069","title":"Binding and selectivity of the marine toxin neodysiherbaine A and its synthetic analogues to GluK1 and GluK2 kainate receptors.","date":"2011","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21893069","citation_count":16,"is_preprint":false},{"pmid":"31513786","id":"PMC_31513786","title":"The kainate receptor antagonist UBP310 but not single deletion of GluK1, GluK2, or GluK3 subunits, inhibits MPTP-induced degeneration in the mouse midbrain.","date":"2019","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31513786","citation_count":15,"is_preprint":false},{"pmid":"7959697","id":"PMC_7959697","title":"Genetic and physical mapping of the GLUR5 glutamate receptor gene on human chromosome 21.","date":"1994","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7959697","citation_count":15,"is_preprint":false},{"pmid":"14667236","id":"PMC_14667236","title":"2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5.","date":"2003","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14667236","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51179,"output_tokens":6650,"usd":0.126643,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15556,"output_tokens":4214,"usd":0.091565,"stage2_stop_reason":"end_turn"},"total_usd":0.218208,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"GluR5 (GRIK1) forms homomeric ion channels in Xenopus oocytes that are weakly responsive to L-glutamate, establishing it as a ligand-gated ion channel subunit with approximately 40-41% amino acid identity to AMPA receptor subunits GluR1-4.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution in heterologous expression system, foundational cloning paper replicated extensively\",\n      \"pmids\": [\"1977421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RNA editing at the Q/R site of GluR5 pre-mRNA requires a distant intronic editing site complementary sequence (ECS) located up to 1900 nucleotides distal to the Q/R site; the exon-intron duplex is a substrate for double-stranded RNA-specific adenosine deaminase (ADAR), which preferentially targets the adenosine at the Q/R site when coexpressed in HEK293 cells.\",\n      \"method\": \"Minigene transfection in PC-12 cells, RT-PCR, ADAR coexpression in HEK293 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic dissection of editing substrate using minigenes with mutagenesis, replicated across GluR5 and GluR6\",\n      \"pmids\": [\"8700852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Amino acids in the region between M3 and M4 of GluR5/GluR6 control agonist selectivity and desensitization: a single amino acid (N721 in GluR6; corresponding GluR5 residue) controls AMPA sensitivity and domoate deactivation rates, while A689 in GluR6 controls kainate desensitization rate.\",\n      \"method\": \"Chimeric receptor construction, site-directed mutagenesis, patch-clamp electrophysiology in heterologous cells\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and electrophysiological readout, multiple residues characterized\",\n      \"pmids\": [\"9354337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"GluR5-containing kainate receptors regulate synaptic inhibition in the CA1 hippocampus by activating interneurons, demonstrated using selective agonist ATPA and antagonist LY294486.\",\n      \"method\": \"Hippocampal slice electrophysiology with selective pharmacological tools (ATPA agonist, LY294486 antagonist)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pharmacological dissection with selective agonist and antagonist in native tissue, widely replicated\",\n      \"pmids\": [\"9335499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"GluR5 and KA-2 subunits coassemble to form functional heteromeric kainate receptor channels in trigeminal ganglion neurons, with pharmacological properties, desensitization, rectification, and ion permeability matching recombinant GluR5(R)/KA-2 channels.\",\n      \"method\": \"RT-PCR subunit expression profiling, patch-clamp electrophysiology of native neurons vs. recombinant receptors\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent evidence from native neuron physiology and recombinant receptor comparison, single lab\",\n      \"pmids\": [\"9254673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GluR5-containing kainate receptors on CA1 inhibitory interneurons generate inward currents and repetitive action potentials upon activation by glutamate, kainate, or ATPA, causing a massive increase in tonic GABAergic inhibition onto pyramidal neuron somata and apical dendrites.\",\n      \"method\": \"Hippocampal slice electrophysiology, selective pharmacology (ATPA, LY293558), identified interneuron recordings\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cellular recordings in identified interneurons with selective pharmacological tools, replicated\",\n      \"pmids\": [\"10196544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GluR5 subunits comprise or contribute to a presynaptic kainate receptor that depresses excitatory synaptic transmission in both CA1 and CA3 hippocampal regions; depression was associated with increased paired-pulse facilitation, indicating a presynaptic locus.\",\n      \"method\": \"Hippocampal slice field recordings and whole-cell voltage-clamp with selective agonist ATPA and antagonist LY294486\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — paired-pulse facilitation assay established presynaptic locus, selective pharmacology, replicated independently\",\n      \"pmids\": [\"9849664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"GluR5 subunit mediates synaptic excitation in the rat basolateral amygdala (BLA); train-evoked, AMPA-receptor-independent synaptic responses are blocked by selective GluR5 antagonist LY293558 (95% block at 10 µM), with a null potential near 0 mV consistent with inwardly rectifying, calcium-permeable channels.\",\n      \"method\": \"Intracellular recording in BLA slices, selective pharmacological isolation of receptor component\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological isolation with selective antagonist in native tissue, replicated in subsequent studies\",\n      \"pmids\": [\"9849665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GluR5, GluR6, and GluR7 kainate receptor subunits coassemble promiscuously to form heteromeric receptors; GluR5/GluR6 heteromers exhibit reduced desensitization and faster recovery from desensitization compared to homomeric GluR5, and coexpression of GluR6 enhances response magnitude to GluR5-selective agonists.\",\n      \"method\": \"Coexpression in HEK293 cells, patch-clamp electrophysiology, polyamine rectification assay to detect heteromeric assembly\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in heterologous cells with biophysical validation of heteromeric assembly via edited/unedited Q/R site strategy\",\n      \"pmids\": [\"10493729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RNA editing at the Q/R site of GluR5 reduces kainate receptor current density approximately 6-fold in dorsal root ganglion neurons, established using knock-in mice encoding arginine (edited) at position 636 (GluR5 Q/R site).\",\n      \"method\": \"Knock-in mouse genetics, patch-clamp electrophysiology in acutely isolated DRG neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic knock-in model with direct electrophysiological measurement in native neurons\",\n      \"pmids\": [\"10516295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GluR5 and GluR6 subunits coexist in a population of hippocampal GABAergic interneurons and coassemble into functional heteromeric receptors in HEK293 cells; heteromeric GluR5/GluR6 receptors show outward rectification, sensitivity to ATPA and AMPA, and distinct desensitization/gating properties from homomeric GluR6.\",\n      \"method\": \"Non-radioactive double in situ hybridization, cotransfection in HEK293 cells, patch-clamp electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal in situ hybridization and functional heterologous reconstitution, replicated concept from prior work\",\n      \"pmids\": [\"10627597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GluR5-2b subunit cell surface expression is controlled by an endoplasmic reticulum (ER) retention signal in its alternatively spliced C-terminal domain; a critical arginine (Arg-896) mediates ER retention, and phosphomimetic mutation at Thr-898 promotes ER exit and surface expression; two additional positively charged residues (Arg-900, Lys-901) also regulate ER export.\",\n      \"method\": \"Site-directed mutagenesis, cell surface biotinylation, immunofluorescence in heterologous cells and neurons\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis with functional trafficking readout in both heterologous cells and neurons, multiple residues characterized\",\n      \"pmids\": [\"14527949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Topiramate selectively inhibits postsynaptic GluR5 kainate receptor-mediated synaptic currents in rat BLA principal neurons (IC50 ~0.5 µM) without affecting paired-pulse facilitation, demonstrating a postsynaptic mechanism; it reduces miniature EPSC amplitude without affecting frequency.\",\n      \"method\": \"Whole-cell voltage-clamp recordings in rat BLA slices, pharmacological isolation of receptor subtypes\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiological dissection with selective pharmacology, postsynaptic locus established by mEPSC analysis, replicated\",\n      \"pmids\": [\"12904467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Selective activation of GluR5 on BLA interneurons depolarizes them and increases GABA release, leading to tonic GABA current and reduced excitability; this GluR5-mediated pathway activates voltage-dependent calcium channels and requires Ca2+ influx.\",\n      \"method\": \"Whole-cell recordings in amygdala slices, selective pharmacology, GluR5-/- mice\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patch-clamp in native tissue with selective agonist/antagonist and knockout validation, single lab\",\n      \"pmids\": [\"19417176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GluR5 agonist selectivity over AMPA receptors is controlled by Ser741 in GluR5 (vs. Met722 in GluR1): mutation of Ser741 abolishes ATPA selectivity, demonstrating that a serine-dependent stabilization of active receptor conformation and steric clash with Met722 underlie GluR5 selectivity.\",\n      \"method\": \"Site-directed mutagenesis, two-electrode voltage-clamp in Xenopus oocytes\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with functional electrophysiological validation, mechanistic explanation supported by structural reasoning\",\n      \"pmids\": [\"12488532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GluK1 (GluR5) kainate receptors play a distinct role from GluR6 in hippocampal network activity: ablation of GluR5 increases susceptibility to kainate-induced gamma oscillations and epileptiform bursts, while GluR6 deletion prevents these effects, suggesting GluR5-containing receptors on interneuron axons provide a regulatory brake on network excitability.\",\n      \"method\": \"Kainate receptor knockout mice, in vitro and in vivo electrophysiology, network oscillation analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined electrophysiological phenotype, supported by computational network modeling\",\n      \"pmids\": [\"15509753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structures of the GluR5 ligand-binding core reveal a binding cavity 40% larger than GluR2, extensive interdomain contacts between domains 1 and 2 absent in AMPA receptors, and high-stability kainate complexes; the degree of domain closure by partial agonists differs quantitatively from AMPA receptors, explaining subtype-selective agonist binding.\",\n      \"method\": \"X-ray crystallography of GluR5-S1S2 ligand-binding core in complex with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with multiple ligand complexes, mechanistic interpretation of domain closure\",\n      \"pmids\": [\"15721240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of GluR5-S1S2 in complex with (S)-glutamate at 1.95 Å reveals two-domain architecture similar to GluR2, high degree of domain closure (26°), a novel dimer interface with different protomer arrangement compared to GluR2, and Ser741 forming an interdomain bridge stabilizing a water network.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with functional annotation of key residue\",\n      \"pmids\": [\"15710405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GluR5 knockout mice show significantly reduced responses to capsaicin and inflammatory pain, but normal fear memory and normal amygdala synaptic potentiation, establishing a specific role for GluR5 in chemical/inflammatory nociception distinct from GluR6's role in fear memory.\",\n      \"method\": \"GluR5 and GluR6 knockout mice, behavioral pain assays (capsaicin, formalin), fear conditioning, amygdala LTP recordings\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-knockout comparison with multiple behavioral and electrophysiological readouts, subunit-specific phenotype established\",\n      \"pmids\": [\"15673679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of GluR5 ligand-binding core with GluR5-selective antagonists UBP302 and UBP310 reveal a novel antagonist-binding mechanism that does not contact E723 (unlike all previous AMPA/kainate agonist/antagonist complexes), resulting in hyperextension of the ligand-binding core and a 22 Å extension of ion-channel linkers in dimer assemblies compared to the glutamate-bound form.\",\n      \"method\": \"X-ray crystallography of GluR5 LBD dimer complexes with antagonists\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures revealing novel binding mode, validated against functional data on full-length channels\",\n      \"pmids\": [\"16540562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GluR5-containing kainate receptors selectively depolarize inhibitory interneurons in the basolateral amygdala, increasing GABA release and tonic inhibitory current onto principal neurons; genetic deletion of GluR5 or local antagonist injection increases anxiety-like behavior, placing GluR5 as a key regulator of inhibitory circuit tone in the BLA.\",\n      \"method\": \"GluR5 knockout mice, whole-cell recordings in amygdala slices, intra-BLA drug injection, anxiety behavioral assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological intervention with cellular electrophysiological and behavioral readouts\",\n      \"pmids\": [\"17245443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GluR5-containing kainate receptor activation suppresses Src kinase-mediated tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B, and disrupts the NR2A-PSD-95-Src signaling complex, providing neuroprotection against ischemia-reperfusion injury; this occurs through GluR5-mediated Ca2+-dependent GABA release activating GABAA receptors, which then inhibit Src activation.\",\n      \"method\": \"In vivo rat ischemia model, co-immunoprecipitation, Western blotting for phosphorylated NR2A/NR2B, patch-clamp recording, GluR5 antisense oligodeoxynucleotides\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and electrophysiological methods in a single lab, mechanistic chain established\",\n      \"pmids\": [\"18678878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GluR5 kainate receptors on myelinated spinal cord axons mediate Ca2+ increase through both ionotropic and metabotropic (noncanonical) signaling via a pertussis toxin-sensitive G protein/PLC pathway causing IP3-dependent Ca2+ release from internal stores; GluR5 co-immunoprecipitates with nNOS and colocalizes with nNOS clusters on internodal axons, and the response involves intraaxonal NO.\",\n      \"method\": \"Confocal Ca2+ imaging in dorsal column axons, pertussis toxin treatment, IP3 receptor blockers, co-immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological approaches plus co-IP in native tissue, single lab\",\n      \"pmids\": [\"19224531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NETO2 profoundly slows GluR1 (GluK1) kainate receptor desensitization, promotes plasma membrane localization, and targets GluK1-containing receptors to synapses in hippocampal neurons; NETO1 increases the rate of GluK1 desensitization. These auxiliary proteins extend the temporal range of receptor gating by over an order of magnitude.\",\n      \"method\": \"Heterologous cell transfection, hippocampal neuron transfection, whole-cell electrophysiology, immunocytochemistry for synaptic targeting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional reconstitution in both heterologous cells and neurons, multiple NETO subunits compared, synaptic targeting established\",\n      \"pmids\": [\"21593317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both NETO1 and NETO2 profoundly increase GluK1 surface expression and drive GluK1 to synapses in hippocampal CA1 neurons; GluK1 synaptic targeting by Neto proteins is independent of their role in promoting surface trafficking. GluK1 is excluded from synapses expressing AMPA receptors and selectively incorporated into silent synapses. Neto2 slows GluK1 deactivation and desensitization; Neto1 speeds desensitization.\",\n      \"method\": \"CA1 pyramidal neuron expression (null background), whole-cell electrophysiology, surface expression assays, chimeric Neto constructs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic dissection using null-background system, chimeric subunits, and multiple functional readouts\",\n      \"pmids\": [\"26720915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A proteomic screen of the GluK1 C-terminal domain identified Goα as an interacting partner; GluK1 activates Go proteins as validated by BRET experiments, and the interaction was confirmed by co-IP in native brain tissue and absent in GluK1-deficient mice, establishing GluK1 as capable of metabotropic (G protein) signaling via Go.\",\n      \"method\": \"Proteomics (C-terminal domain pull-down), co-immunoprecipitation in native brain, BRET assay, GluK1 knockout mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification confirmed by multiple orthogonal methods (Co-IP, BRET) in native tissue and validated by knockout\",\n      \"pmids\": [\"25834043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NETO1 and NETO2 have distinct, subunit-dependent effects on GluK1 kinetics: both slow onset of desensitization at low agonist concentrations and increase glutamate sensitivity; at higher concentrations, Neto2 primarily slows desensitization while Neto1 primarily increases recovery from desensitization. The extracellular N-terminal CUB domain region of Neto is largely responsible for these distinct regulatory effects.\",\n      \"method\": \"Patch-clamp electrophysiology in HEK-293T cells expressing chimeric Neto1/Neto2 subunits with GluK1 or GluK2\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with chimeric auxiliary subunits and systematic dose-response analysis, single lab\",\n      \"pmids\": [\"26277340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The cleaved signal peptide of GluK1 represses receptor surface trafficking and synaptic targeting by directly binding to the amino-terminal domain (ATD) in trans; replacing GluK1's signal peptide with GluK2's signal peptide increases synaptic EPSCs, and co-expression of GluK1 signal peptide suppresses this gain, establishing a novel trafficking repression mechanism.\",\n      \"method\": \"Chimeric receptor expression in hippocampal CA1 neurons, electrophysiology (EPSC recordings), co-expression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic chimeric receptor approach with functional synaptic readout and trans-acting mechanism validated\",\n      \"pmids\": [\"30451858\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRIK1/GluK1 encodes a kainate-type ionotropic glutamate receptor subunit that forms homomeric or heteromeric (with GluK2, GluK3, KA2) ligand-gated ion channels; its surface trafficking is controlled by an ER retention signal (Arg-896) in the C-terminal domain and repressed by its own cleaved signal peptide binding the ATD, while the auxiliary proteins NETO1 and NETO2 promote surface expression, synaptic targeting, and bidirectionally regulate desensitization kinetics; postsynaptically and presynaptically in hippocampus, amygdala, spinal cord, and sensory ganglia, GluK1-containing receptors regulate both excitatory and inhibitory transmission—particularly by depolarizing GABAergic interneurons to increase tonic inhibition—and can signal metabotropically through Goα proteins; RNA editing at the Q/R site (requiring a distant intronic ECS and ADAR) reduces Ca2+ permeability and single-channel conductance; and ligand selectivity is structurally determined by Ser741 in the ligand-binding domain, whose 40%-larger binding cavity compared to GluR2 and extensive interdomain contacts explain subtype-specific pharmacology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GRIK1/GluK1 (originally GluR5) encodes a kainate-type ionotropic glutamate receptor subunit that assembles into homomeric or heteromeric ligand-gated cation channels and shapes both excitatory and inhibitory transmission across hippocampus, amygdala, spinal cord, and sensory ganglia [#0, #3, #7]. It coassembles promiscuously with other kainate subunits—KA2, GluK2/GluR6, and GluK3/GluR7—generating heteromeric channels whose desensitization, rectification, and agonist responses differ from the homomers [#4, #8, #10]. A defining function is the depolarization of GABAergic interneurons: GluK1-containing receptors on interneurons in CA1 and the basolateral amygdala drive repetitive firing and elevate tonic GABAergic inhibition onto principal neurons, positioning the subunit as a regulator of inhibitory circuit tone and network excitability, with genetic ablation increasing susceptibility to epileptiform activity and anxiety-like behavior [#5, #15, #20]. Presynaptic GluK1 also depresses excitatory transmission [#6]. Beyond ionotropic gating, GluK1 signals metabotropically through Goα proteins identified at its C-terminal domain [#25], and on spinal axons couples to a pertussis-toxin-sensitive G protein/PLC/IP3 pathway in association with nNOS to mobilize internal Ca2+ [#22]. Channel properties are tuned post-transcriptionally and by accessory proteins: ADAR-mediated RNA editing at the Q/R site, which requires a distant intronic editing-site complementary sequence, reduces Ca2+ permeability and current density [#1, #9], while the auxiliary subunits NETO1 and NETO2 promote surface expression and synaptic targeting and bidirectionally control desensitization kinetics via their extracellular CUB domains [#23, #24, #26]. Surface delivery is gated by an ER retention signal centered on Arg-896 in the alternatively spliced C-terminal domain [#11] and repressed in trans by the receptor's own cleaved signal peptide binding the amino-terminal domain [#27]. Ligand selectivity and gating are structurally explained by Ser741 in the ligand-binding domain and a binding cavity 40% larger than the AMPA receptor GluR2, with distinct domain-closure and antagonist-binding modes [#14, #16, #19]. Functionally, GluK1 mediates inflammatory/chemical nociception and confers neuroprotection in ischemia by suppressing Src-mediated NMDA receptor phosphorylation through GABAergic signaling [#18, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing that GluR5 is itself a functional ligand-gated channel subunit answered whether this AMPA-related clone formed glutamate-responsive channels at all.\",\n      \"evidence\": \"Xenopus oocyte expression and electrophysiology of homomeric GluR5\",\n      \"pmids\": [\"1977421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native subunit composition and in vivo channel partners not addressed\", \"Weak homomeric responses left physiological role unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defining the editing substrate showed how Q/R-site recoding is achieved, identifying the distant intronic ECS and ADAR as the machinery controlling receptor permeability.\",\n      \"evidence\": \"Minigene transfection, RT-PCR, and ADAR coexpression in heterologous cells\",\n      \"pmids\": [\"8700852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo editing extent across tissues not quantified here\", \"Functional consequence of editing on channel biophysics established only later\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Pharmacological and mutagenic dissection established GluK1 as a regulator of inhibitory transmission and mapped residues controlling agonist selectivity and desensitization, moving from a cloned subunit to a circuit element with defined molecular determinants.\",\n      \"evidence\": \"Hippocampal slice electrophysiology with selective tools (ATPA, LY294486); chimeric and point-mutant receptors with patch-clamp\",\n      \"pmids\": [\"9335499\", \"9354337\", \"9254673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pre- vs postsynaptic localization not yet resolved in 1997\", \"Native heteromer composition inferred but not exhaustively defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cellular recordings localized GluK1 actions to identified interneurons and presynaptic terminals, showing it both drives tonic GABAergic inhibition and presynaptically depresses excitatory transmission, and mediates calcium-permeable excitation in the amygdala.\",\n      \"evidence\": \"Hippocampal and amygdala slice electrophysiology with paired-pulse facilitation and selective antagonists\",\n      \"pmids\": [\"10196544\", \"9849664\", \"9849665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry of native receptors not defined\", \"Molecular basis of presynaptic vs postsynaptic targeting unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Heteromeric assembly rules and the functional impact of Q/R editing were established, explaining how subunit mixing and recoding diversify native receptor kinetics and current density.\",\n      \"evidence\": \"Heterologous coexpression with polyamine rectification assays; knock-in mice editing the Q/R site with DRG electrophysiology; double in situ hybridization\",\n      \"pmids\": [\"10493729\", \"10516295\", \"10627597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of native heteromers in vivo not measured\", \"Editing dynamics under physiological/pathological states not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The C-terminal ER retention signal and ligand-binding determinants were mapped, explaining how surface delivery is gated and how GluK1 achieves subtype-selective pharmacology, alongside identification of a postsynaptic GluK1 component in the amygdala.\",\n      \"evidence\": \"Site-directed mutagenesis with surface biotinylation; two-electrode voltage-clamp; whole-cell mEPSC analysis with topiramate; knockout-validated amygdala recordings\",\n      \"pmids\": [\"14527949\", \"12488532\", \"12904467\", \"19417176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking factors recognizing the Arg-896 signal not identified\", \"Coupling between retention signal and synaptic targeting unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Crystal structures of the ligand-binding core and subunit-specific knockout phenotypes provided the structural and physiological basis for GluK1's distinct pharmacology and its specific roles in nociception and network regulation.\",\n      \"evidence\": \"X-ray crystallography of GluR5-S1S2 with multiple ligands; GluK1/GluK2 knockout mice with behavioral pain, fear, and network oscillation assays\",\n      \"pmids\": [\"15721240\", \"15710405\", \"15673679\", \"15509753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of intact channel and heteromers not resolved\", \"Link between LBD structure and full-channel gating only inferred\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Antagonist-bound structures revealed a binding mode that hyperextends the ligand-binding core, mechanistically connecting GluK1-selective antagonism to channel-closing conformational changes.\",\n      \"evidence\": \"X-ray crystallography of GluR5 LBD dimers with antagonists UBP302/UBP310\",\n      \"pmids\": [\"16540562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes inferred from isolated LBD, not full-length channel\", \"Antagonist effects on heteromeric receptors not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"GluK1 was shown to signal noncanonically and to confer neuroprotection, extending its function beyond ionotropic gating to metabotropic Ca2+ mobilization and modulation of NMDA receptor signaling.\",\n      \"evidence\": \"Confocal Ca2+ imaging with pertussis toxin and IP3 blockers plus co-IP in spinal axons; in vivo ischemia model with co-IP and phospho-Western blotting\",\n      \"pmids\": [\"19224531\", \"18678878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mechanistic chains awaiting independent replication\", \"Identity of the relevant G protein/effector in the metabotropic pathway not fully defined at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Auxiliary NETO proteins and a Goα partner were established as principal regulators of GluK1 trafficking, synaptic targeting, kinetics, and metabotropic signaling, defining the accessory machinery governing receptor behavior.\",\n      \"evidence\": \"Null-background CA1 expression with chimeric Neto constructs and electrophysiology; proteomic C-terminal pull-down with co-IP, BRET, and knockout validation\",\n      \"pmids\": [\"26720915\", \"26277340\", \"25834043\", \"21593317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NETO directs GluK1 to silent synapses unresolved\", \"Downstream effectors of Goα signaling not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A trans-acting repression mechanism was uncovered in which the cleaved signal peptide binds the ATD to suppress surface and synaptic targeting, revealing a novel layer of GluK1 trafficking control.\",\n      \"evidence\": \"Chimeric receptor and signal-peptide co-expression in CA1 neurons with EPSC recordings\",\n      \"pmids\": [\"30451858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of signal-peptide/ATD interaction not solved\", \"Physiological regulation of this repression in vivo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GluK1's ionotropic and metabotropic signaling modes, editing state, and NETO-dependent trafficking are coordinated within native synapses, and whether GRIK1 variants cause defined human disease, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the intact full-length or NETO-bound channel in the corpus\", \"Downstream Goα effector pathway uncharacterized\", \"No Mendelian disease link established in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [25, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 23, 24]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 5, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [25, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [\"GluK1/KA2 kainate receptor\", \"GluK1/GluK2 heteromeric kainate receptor\"],\n    \"partners\": [\"NETO1\", \"NETO2\", \"GRIK2\", \"GRIK5\", \"GNAO1\", \"NOS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}