{"gene":"GABBR2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1998,"finding":"GABBR2 (GABA(B)R2) forms a functional heterodimer with GABBR1 (GABA(B)R1); neither subunit alone activates GIRK-type potassium channels, but co-expression of both confers robust channel stimulation. Immunoprecipitation demonstrated physical association of the two polypeptides, likely as heterodimers.","method":"Heterologous co-expression in cells, GIRK channel electrophysiology, immunoprecipitation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional reconstitution in heterologous system with electrophysiology plus reciprocal immunoprecipitation, replicated across multiple subsequent studies","pmids":["9872315"],"is_preprint":false},{"year":1999,"finding":"Human GABBR2, when expressed alone (without GABBR1) in CHO cells, localizes to the cell surface and negatively couples to adenylyl cyclase in response to GABA, baclofen, and 3-aminopropyl(methyl)phosphinic acid; this coupling is blocked by the antagonist 2-hydroxysaclofen.","method":"Heterologous expression in COS and CHO cells, adenylyl cyclase activity assay, pharmacological antagonism","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with pharmacological validation in a single lab; contradicts later consensus that homomeric GABBR2 is non-functional, so confidence is tempered","pmids":["10328880"],"is_preprint":false},{"year":2000,"finding":"Heteromeric assembly of GABBR1 and GABBR2 is required for baclofen-mediated inhibition of Ca2+ channel currents in sympathetic neurons; knockdown of endogenous GABBR1 via antisense markedly reduced the inhibitory effect of baclofen, and the effect was pertussis toxin-sensitive and voltage-dependent.","method":"Nuclear microinjection of sense/antisense constructs into superior cervical ganglion neurons, patch-clamp recording, pertussis toxin treatment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct loss-of-function (antisense) in neurons combined with electrophysiology and pharmacological controls in a rigorous study","pmids":["10751439"],"is_preprint":false},{"year":2017,"finding":"De novo GABBR2 variants found in Rett-like and epileptic encephalopathy patients reduce receptor function; EE-associated variants cause a more profound reduction in receptor activity than RTT-like variants and show greater responsiveness to agonist rescue in a Xenopus tropicalis animal model.","method":"Whole-exome sequencing, cell culture functional assays, Xenopus tropicalis in vivo model, agonist rescue experiments","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assessment in cell culture and animal model by single lab, two orthogonal systems","pmids":["28856709"],"is_preprint":false},{"year":2020,"finding":"GABBR2 mediates central sensitization in chronic migraine through a GABBR2/PKA/SynCAM1 signaling pathway in the periaqueductal gray; baclofen (GABABR agonist) and PKA inhibitor H89 alleviated hyperalgesia and reduced VGLUT2, glutamate, CGRP, and c-Fos, while antagonist CGP35348 and PKA agonist had opposing effects.","method":"Rat chronic migraine model, intraventricular injection of pharmacological agents, Western blot, ELISA, immunohistochemistry","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in vivo with multiple molecular readouts, single lab","pmids":["32931071"],"is_preprint":false},{"year":2021,"finding":"GABBR2 regulates post-ischemic angiogenesis through the glycolysis pathway; GABBR2 knockdown in HUVECs suppressed hypoxia-induced proliferation, migration, and tube formation, and reduced expression of glycolytic enzymes HKII, PFKFB3, and PKM1; GABBR2 downregulation in mice reduced blood flow recovery after hindlimb ischemia.","method":"Lentiviral knockdown in HUVECs, tube formation/migration/proliferation assays, XF analyzer metabolic assay, hindlimb ischemia mouse model, adenoviral overexpression, Western blot","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with metabolic mechanistic readout, single lab","pmids":["34422926"],"is_preprint":false},{"year":2023,"finding":"Androgen receptor (AR) directly binds the GABBR2 promoter and drives its transcription; AR knockdown reduces GABBR2 expression, dihydrotestosterone treatment induces it, and antiandrogen hydroxyflutamide partially reverses induction. GABBR2 upregulation in cisplatin-resistant bladder cancer cells contributes to resistance, and GABBR2 knockdown or pharmacological antagonism (CGP46381) sensitizes AR-positive cells to cisplatin.","method":"Chromatin immunoprecipitation (ChIP), AR knockdown/DHT treatment, GABBR2 knockdown, GABABR antagonist treatment, cisplatin cytotoxicity assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional pharmacological and genetic validation, single lab","pmids":["37762034"],"is_preprint":false},{"year":2003,"finding":"GABBR2 protein is expressed in rat testis and sperm with a shorter transcript than in brain (3.0 kb vs. 5.6 kb due to truncated 3'UTR); in sperm, GABBR2 protein is localized to the acrosome region of the sperm head.","method":"RT-PCR, Northern blot, Western blot, RACE-PCR, indirect immunofluorescence","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal detection methods establishing localization, single lab","pmids":["14967916"],"is_preprint":false},{"year":2026,"finding":"Disease-associated GABBR2 missense variants (p.A567T, p.S695I, p.I705N) associated with epileptic encephalopathy display strong constitutive activity (50-100% of maximal GABA-induced wild-type activity) as individual subunits or heterodimers. In Gabbr2I704N/+ knock-in mice, constitutive activity increases at both pre- and postsynaptic GBRs, but receptor responsiveness to agonists is reduced; adaptive downregulation of both GB1 and GB2 subunits and G protein signaling components occurs. Positive allosteric modulator treatment normalized network activity in these mice.","method":"Luciferase reporter assay in heterologous cells, CRISPR knock-in mouse, in vitro and in vivo electrophysiology (EEG, brain slice), proteomics, positive allosteric modulator pharmacology","journal":"Brain","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reconstitution in cells, knock-in mouse, electrophysiology, proteomics) in a single rigorous study","pmids":["40994051"],"is_preprint":false},{"year":2026,"finding":"De novo missense variants in GABBR2 produce a range of gain- and loss-of-function alterations: (i) increased constitutive activity with decreased GABA efficacy, (ii) reduced GABA potency, or (iii) reduced surface expression with decreased GABA efficacy, as characterized by in vitro functional assays.","method":"In vitro functional characterization of variants in heterologous cells (luciferase reporter assay, surface expression assay)","journal":"NPJ genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in heterologous cells with multiple variants, single lab","pmids":["41803176"],"is_preprint":false},{"year":2025,"finding":"TAp73α binds directly to HDAC2 and disassembles the HDAC2/REST repressor complex, thereby derepressing neuronal GABBR2 expression in melanoma cells; TAp73α-induced GABBR2 upregulation promotes EMT marker upregulation, cancer cell invasiveness and proliferation.","method":"Multi-omics (transcriptomics, proteomics, cistromics), 3D protein modeling, protein-protein interaction assays, functional invasion/proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with PPI and functional assays, single lab, mechanism partially inferred from binding studies","pmids":["40505831"],"is_preprint":false},{"year":2025,"finding":"Global knockout of GABBR2 (via Cre-mediated conditional disruption of a floxed Gabbr2 allele) recapitulates the germline GABBR2 knockout phenotype, including spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory, abnormal neuronal architecture, increased neuronal cell death, and premature death.","method":"CRISPR loxP insertion, Cre-mediated conditional knockout (Actin-Cre), EEG, behavioral assays, histology, immunohistochemistry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with multiple phenotypic readouts, single lab","pmids":["41397015"],"is_preprint":false},{"year":2026,"finding":"Carbamazepine upregulates GABBR2 protein expression and activates it to suppress the AC/cAMP/PKA signaling pathway, triggering apoptosis of hypothalamic GnRH neurons; GABBR2 knockdown in GT1-7 cells attenuates CBZ-induced AC/cAMP/PKA inhibition, reduces apoptosis, and partially restores GnRH secretion.","method":"In vivo rat model (long-term CBZ dosing), GT1-7 cell line GABBR2 knockdown, Western blot, ELISA, cAMP/PKA pathway assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in cell model plus in vivo correlate, single lab","pmids":["41571204"],"is_preprint":false},{"year":2024,"finding":"GABBR2 overexpression in human neuroblastoma cells (SH-SY5Y, BE(2)-M17) increases intracellular Ca2+ concentration, reactive oxygen species production, mitochondrial permeability transition pore opening, and apoptosis.","method":"Expression plasmid transfection, intracellular Ca2+ measurement, ROS assay, mitochondrial permeability assay, apoptosis assay","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment in cell lines, single lab, no mechanistic dissection of how GABBR2 causes these effects","pmids":["39724481"],"is_preprint":false},{"year":2025,"finding":"GABBR2 overexpression in N2a/APP cells increased ADAM10 expression and decreased BACE1 expression, leading to upregulation of sAPPα and downregulation of sAPPβ, suggesting GABBR2 modulates APP processing toward the non-amyloidogenic pathway.","method":"Expression plasmid transfection in N2a/APP cells, Western blot for ADAM10, BACE1, sAPPα, sAPPβ","journal":"Biochemistry and biophysics reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment in one cell line, single lab, no mechanistic dissection","pmids":["40927314"],"is_preprint":false}],"current_model":"GABBR2 encodes the GB2 subunit of the GABAB receptor, which heterodimerizes with GABBR1/GB1 to form a functional G protein-coupled receptor: GB1 binds GABA while GB2 couples to Gi/o proteins to inhibit adenylyl cyclase, suppress Ca2+ channels, and activate GIRK potassium channels; disease-associated GABBR2 missense variants confer constitutive receptor activity or loss-of-function that drives neurodevelopmental phenotypes through adaptive downregulation of receptor and G protein signaling components, and beyond the nervous system GABBR2 participates in endothelial glycolysis-dependent angiogenesis, AR-driven cisplatin resistance in bladder cancer, and APP processing modulation."},"narrative":{"mechanistic_narrative":"GABBR2 encodes the GB2 subunit of the GABA-B receptor, a Gi/o-coupled GPCR that mediates inhibitory neurotransmission: it heterodimerizes with GABBR1/GB1 to form the functional receptor, and only co-expression of both subunits confers robust activation of GIRK-type potassium channels [PMID:9872315]. Within the heterodimer GB2 provides the G protein coupling and effector functions—heteromeric assembly is required for baclofen-mediated, pertussis toxin-sensitive inhibition of voltage-gated Ca2+ channel currents in neurons [PMID:10751439], and the receptor negatively couples to adenylyl cyclase in response to GABA, baclofen and 3-aminopropyl(methyl)phosphinic acid, an effect blocked by GABA-B antagonists [PMID:10328880]. Loss of GABBR2 in mice produces spontaneous epileptiform activity, hyperalgesia, impaired memory, abnormal neuronal architecture and premature death, establishing its essential role in CNS function [PMID:41397015]. De novo GABBR2 missense variants cause neurodevelopmental disease spanning Rett-like syndrome and epileptic encephalopathy through a spectrum of functional consequences: loss of receptor activity, reduced agonist potency or surface expression, and gain-of-function constitutive activity [PMID:28856709, PMID:41803176]; epileptic encephalopathy variants confer strong constitutive activity that, in a Gabbr2 knock-in mouse, drives adaptive downregulation of both receptor subunits and G protein signaling components, with positive allosteric modulators normalizing network activity [PMID:40994051]. Beyond the nervous system, GABBR2 acts through PKA- and cAMP-dependent signaling in diverse contexts—central sensitization in chronic migraine via a GABBR2/PKA/SynCAM1 pathway [PMID:32931071], glycolysis-dependent post-ischemic angiogenesis [PMID:34422926], androgen receptor-driven cisplatin resistance in bladder cancer [PMID:37762034], and GnRH neuron apoptosis [PMID:41571204].","teleology":[{"year":1998,"claim":"Established that GB2 is not an independent receptor but an obligate heterodimerization partner of GB1, resolving how the functional GABA-B receptor is assembled.","evidence":"Heterologous co-expression with GIRK channel electrophysiology and reciprocal immunoprecipitation","pmids":["9872315"],"confidence":"High","gaps":["Stoichiometry and structural basis of the heterodimer not resolved","Did not assign which subunit performs G protein coupling versus ligand binding"]},{"year":1999,"claim":"Tested whether GB2 alone can signal, finding it could reach the surface and negatively couple to adenylyl cyclase—an observation that conflicts with the later consensus of obligate heterodimerization.","evidence":"Homomeric expression in COS/CHO cells with adenylyl cyclase assay and pharmacological antagonism","pmids":["10328880"],"confidence":"Medium","gaps":["Contradicts later consensus that homomeric GABBR2 is non-functional","Possible endogenous GB1 contribution not excluded"]},{"year":2000,"claim":"Demonstrated in native neurons that heteromeric assembly is required for the receptor's inhibition of Ca2+ channel currents, linking the heterodimer to a physiological effector through Gi/o.","evidence":"Antisense knockdown of GABBR1 in sympathetic neurons with patch-clamp and pertussis toxin controls","pmids":["10751439"],"confidence":"High","gaps":["Did not isolate the specific role of GB2 versus GB1 in the coupling","Specific Gi/o subtype not identified"]},{"year":2003,"claim":"Extended GABBR2 expression beyond brain, identifying a testis/sperm isoform with a truncated 3'UTR localized to the sperm acrosome, raising a non-neuronal role.","evidence":"RT-PCR, Northern/Western blot, RACE-PCR and immunofluorescence in rat testis and sperm","pmids":["14967916"],"confidence":"Medium","gaps":["Functional role of acrosomal GABBR2 not established","No heterodimerization partner identified in sperm"]},{"year":2017,"claim":"Connected de novo GABBR2 variants to neurodevelopmental disease, showing EE-associated variants reduce receptor function more severely than RTT-like variants and respond to agonist rescue.","evidence":"Whole-exome sequencing with cell culture functional assays and Xenopus tropicalis in vivo agonist rescue","pmids":["28856709"],"confidence":"Medium","gaps":["Did not capture gain-of-function/constitutive variants identified later","Mechanism linking reduced activity to phenotype severity not dissected"]},{"year":2026,"claim":"Resolved that disease variants act through gain-of-function constitutive activity, not only loss of function, and showed the network response involves compensatory receptor downregulation correctable by positive allosteric modulators.","evidence":"Luciferase reporter assays, CRISPR knock-in mouse, EEG and slice electrophysiology, proteomics and PAM pharmacology","pmids":["40994051","41803176"],"confidence":"High","gaps":["Structural basis of constitutive activity not defined","Whether PAM correction translates to behavioral/clinical benefit not shown"]},{"year":2025,"claim":"Defined the consequences of total GABBR2 loss in vivo, confirming its essential role in neuronal survival, network excitability, nociception and memory.","evidence":"Conditional Cre-mediated knockout with EEG, behavioral, histological and immunohistochemical readouts","pmids":["41397015"],"confidence":"Medium","gaps":["Cell-type-specific contributions to phenotypes not parsed","Molecular cause of neuronal death not identified"]},{"year":2026,"claim":"Implicated GABBR2 in non-neuronal disease contexts acting through canonical cAMP/PKA and metabolic effectors, broadening its functional scope beyond synaptic inhibition.","evidence":"In vivo and cell-model loss/gain-of-function across migraine PAG, ischemic angiogenesis, bladder cancer cisplatin resistance and GnRH neuron apoptosis","pmids":["32931071","34422926","37762034","41571204"],"confidence":"Medium","gaps":["Whether GB1 heterodimerization is required in these peripheral contexts is unclear","Direct receptor-level mechanism not established in several systems"]},{"year":null,"claim":"How GABBR2 transcriptional regulation (AR, TAp73alpha/HDAC2/REST) and its reported modulation of APP processing integrate with its canonical heterodimeric signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["APP processing and Ca2+/ROS/apoptosis effects rest on single overexpression experiments without mechanistic dissection","Whether transcriptional control by AR or TAp73alpha operates in neurons is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,11]}],"complexes":["GABA-B receptor heterodimer (GB1/GB2)"],"partners":["GABBR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75899","full_name":"Gamma-aminobutyric acid type B receptor subunit 2","aliases":["G-protein coupled receptor 51","HG20"],"length_aa":941,"mass_kda":105.8,"function":"Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054, PubMed:9872316, PubMed:9872744). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:24305054). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644, PubMed:10773016, PubMed:10906333, PubMed:9872744). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:22660477, PubMed:9872744). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:10075644, PubMed:22660477, PubMed:9872316, PubMed:9872744). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable)","subcellular_location":"Cell membrane; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/O75899/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GABBR2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GABBR2","total_profiled":1310},"omim":[{"mim_id":"617904","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 59; DEE59","url":"https://www.omim.org/entry/617904"},{"mim_id":"617903","title":"NEURODEVELOPMENTAL DISORDER WITH POOR LANGUAGE AND LOSS OF HAND SKILLS; NDPLHS","url":"https://www.omim.org/entry/617903"},{"mim_id":"611195","title":"JANUS KINASE AND MICROTUBULE-INTERACTING PROTEIN 1; JAKMIP1","url":"https://www.omim.org/entry/611195"},{"mim_id":"610464","title":"G PROTEIN-COUPLED RECEPTOR 156; GPR156","url":"https://www.omim.org/entry/610464"},{"mim_id":"607340","title":"GAMMA-AMINOBUTYRIC ACID B RECEPTOR 2; GABBR2","url":"https://www.omim.org/entry/607340"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":62.4}],"url":"https://www.proteinatlas.org/search/GABBR2"},"hgnc":{"alias_symbol":["HG20","GABABR2","GPRC3B"],"prev_symbol":["GPR51"]},"alphafold":{"accession":"O75899","domains":[{"cath_id":"3.40.50.2300","chopping":"54-177_334-421","consensus_level":"medium","plddt":93.2192,"start":54,"end":421},{"cath_id":"1.20.1070","chopping":"479-677","consensus_level":"high","plddt":87.221,"start":479,"end":677}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75899","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75899-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75899-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GABBR2","jax_strain_url":"https://www.jax.org/strain/search?query=GABBR2"},"sequence":{"accession":"O75899","fasta_url":"https://rest.uniprot.org/uniprotkb/O75899.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75899/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75899"}},"corpus_meta":[{"pmid":"9872315","id":"PMC_9872315","title":"GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9872315","citation_count":856,"is_preprint":false},{"pmid":"12081656","id":"PMC_12081656","title":"Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development.","date":"2002","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12081656","citation_count":96,"is_preprint":false},{"pmid":"10328880","id":"PMC_10328880","title":"Molecular identification of the human GABABR2: cell surface expression and coupling to adenylyl cyclase in the absence of GABABR1.","date":"1999","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/10328880","citation_count":94,"is_preprint":false},{"pmid":"10751439","id":"PMC_10751439","title":"Heteromeric assembly of GABA(B)R1 and GABA(B)R2 receptor subunits inhibits Ca(2+) current in sympathetic neurons.","date":"2000","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10751439","citation_count":90,"is_preprint":false},{"pmid":"28856709","id":"PMC_28856709","title":"GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.","date":"2017","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28856709","citation_count":71,"is_preprint":false},{"pmid":"14961561","id":"PMC_14961561","title":"Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits.","date":"2004","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14961561","citation_count":69,"is_preprint":false},{"pmid":"11304711","id":"PMC_11304711","title":"Differential expression of GABA(B)R1 and GABA(B)R2 receptor immunoreactivity in neurochemically identified neurons of the rat neostriatum.","date":"2001","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11304711","citation_count":38,"is_preprint":false},{"pmid":"11707323","id":"PMC_11707323","title":"Human GABA(B)R genomic structure: evidence for splice variants in GABA(B)R1 but not GABA(B)R2.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11707323","citation_count":38,"is_preprint":false},{"pmid":"19763258","id":"PMC_19763258","title":"Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European- and African-American populations.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19763258","citation_count":34,"is_preprint":false},{"pmid":"14967916","id":"PMC_14967916","title":"Identification of GABABR2 in rat testis and sperm.","date":"2003","source":"The Journal of reproduction and 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glutamate-associated central sensitization through GABABR2-SynCAM1 signaling in chronic migraine rats.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32931071","citation_count":15,"is_preprint":false},{"pmid":"21371537","id":"PMC_21371537","title":"The level and distribution of the GABA(B)R2 receptor subunit in the rat's central auditory system.","date":"2011","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21371537","citation_count":15,"is_preprint":false},{"pmid":"16538684","id":"PMC_16538684","title":"GABA(B) receptors in the centromedian/parafascicular thalamic nuclear complex: an ultrastructural analysis of GABA(B)R1 and GABA(B)R2 in the monkey thalamus.","date":"2006","source":"The Journal of comparative 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labeling","date":"2025-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.684016","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23863,"output_tokens":3771,"usd":0.064077,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11469,"output_tokens":3041,"usd":0.066685,"stage2_stop_reason":"end_turn"},"total_usd":0.130762,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"GABBR2 (GABA(B)R2) forms a functional heterodimer with GABBR1 (GABA(B)R1); neither subunit alone activates GIRK-type potassium channels, but co-expression of both confers robust channel stimulation. Immunoprecipitation demonstrated physical association of the two polypeptides, likely as heterodimers.\",\n      \"method\": \"Heterologous co-expression in cells, GIRK channel electrophysiology, immunoprecipitation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional reconstitution in heterologous system with electrophysiology plus reciprocal immunoprecipitation, replicated across multiple subsequent studies\",\n      \"pmids\": [\"9872315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human GABBR2, when expressed alone (without GABBR1) in CHO cells, localizes to the cell surface and negatively couples to adenylyl cyclase in response to GABA, baclofen, and 3-aminopropyl(methyl)phosphinic acid; this coupling is blocked by the antagonist 2-hydroxysaclofen.\",\n      \"method\": \"Heterologous expression in COS and CHO cells, adenylyl cyclase activity assay, pharmacological antagonism\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with pharmacological validation in a single lab; contradicts later consensus that homomeric GABBR2 is non-functional, so confidence is tempered\",\n      \"pmids\": [\"10328880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Heteromeric assembly of GABBR1 and GABBR2 is required for baclofen-mediated inhibition of Ca2+ channel currents in sympathetic neurons; knockdown of endogenous GABBR1 via antisense markedly reduced the inhibitory effect of baclofen, and the effect was pertussis toxin-sensitive and voltage-dependent.\",\n      \"method\": \"Nuclear microinjection of sense/antisense constructs into superior cervical ganglion neurons, patch-clamp recording, pertussis toxin treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct loss-of-function (antisense) in neurons combined with electrophysiology and pharmacological controls in a rigorous study\",\n      \"pmids\": [\"10751439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"De novo GABBR2 variants found in Rett-like and epileptic encephalopathy patients reduce receptor function; EE-associated variants cause a more profound reduction in receptor activity than RTT-like variants and show greater responsiveness to agonist rescue in a Xenopus tropicalis animal model.\",\n      \"method\": \"Whole-exome sequencing, cell culture functional assays, Xenopus tropicalis in vivo model, agonist rescue experiments\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assessment in cell culture and animal model by single lab, two orthogonal systems\",\n      \"pmids\": [\"28856709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GABBR2 mediates central sensitization in chronic migraine through a GABBR2/PKA/SynCAM1 signaling pathway in the periaqueductal gray; baclofen (GABABR agonist) and PKA inhibitor H89 alleviated hyperalgesia and reduced VGLUT2, glutamate, CGRP, and c-Fos, while antagonist CGP35348 and PKA agonist had opposing effects.\",\n      \"method\": \"Rat chronic migraine model, intraventricular injection of pharmacological agents, Western blot, ELISA, immunohistochemistry\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in vivo with multiple molecular readouts, single lab\",\n      \"pmids\": [\"32931071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GABBR2 regulates post-ischemic angiogenesis through the glycolysis pathway; GABBR2 knockdown in HUVECs suppressed hypoxia-induced proliferation, migration, and tube formation, and reduced expression of glycolytic enzymes HKII, PFKFB3, and PKM1; GABBR2 downregulation in mice reduced blood flow recovery after hindlimb ischemia.\",\n      \"method\": \"Lentiviral knockdown in HUVECs, tube formation/migration/proliferation assays, XF analyzer metabolic assay, hindlimb ischemia mouse model, adenoviral overexpression, Western blot\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with metabolic mechanistic readout, single lab\",\n      \"pmids\": [\"34422926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Androgen receptor (AR) directly binds the GABBR2 promoter and drives its transcription; AR knockdown reduces GABBR2 expression, dihydrotestosterone treatment induces it, and antiandrogen hydroxyflutamide partially reverses induction. GABBR2 upregulation in cisplatin-resistant bladder cancer cells contributes to resistance, and GABBR2 knockdown or pharmacological antagonism (CGP46381) sensitizes AR-positive cells to cisplatin.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), AR knockdown/DHT treatment, GABBR2 knockdown, GABABR antagonist treatment, cisplatin cytotoxicity assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus functional pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"37762034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GABBR2 protein is expressed in rat testis and sperm with a shorter transcript than in brain (3.0 kb vs. 5.6 kb due to truncated 3'UTR); in sperm, GABBR2 protein is localized to the acrosome region of the sperm head.\",\n      \"method\": \"RT-PCR, Northern blot, Western blot, RACE-PCR, indirect immunofluorescence\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal detection methods establishing localization, single lab\",\n      \"pmids\": [\"14967916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Disease-associated GABBR2 missense variants (p.A567T, p.S695I, p.I705N) associated with epileptic encephalopathy display strong constitutive activity (50-100% of maximal GABA-induced wild-type activity) as individual subunits or heterodimers. In Gabbr2I704N/+ knock-in mice, constitutive activity increases at both pre- and postsynaptic GBRs, but receptor responsiveness to agonists is reduced; adaptive downregulation of both GB1 and GB2 subunits and G protein signaling components occurs. Positive allosteric modulator treatment normalized network activity in these mice.\",\n      \"method\": \"Luciferase reporter assay in heterologous cells, CRISPR knock-in mouse, in vitro and in vivo electrophysiology (EEG, brain slice), proteomics, positive allosteric modulator pharmacology\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reconstitution in cells, knock-in mouse, electrophysiology, proteomics) in a single rigorous study\",\n      \"pmids\": [\"40994051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"De novo missense variants in GABBR2 produce a range of gain- and loss-of-function alterations: (i) increased constitutive activity with decreased GABA efficacy, (ii) reduced GABA potency, or (iii) reduced surface expression with decreased GABA efficacy, as characterized by in vitro functional assays.\",\n      \"method\": \"In vitro functional characterization of variants in heterologous cells (luciferase reporter assay, surface expression assay)\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in heterologous cells with multiple variants, single lab\",\n      \"pmids\": [\"41803176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAp73α binds directly to HDAC2 and disassembles the HDAC2/REST repressor complex, thereby derepressing neuronal GABBR2 expression in melanoma cells; TAp73α-induced GABBR2 upregulation promotes EMT marker upregulation, cancer cell invasiveness and proliferation.\",\n      \"method\": \"Multi-omics (transcriptomics, proteomics, cistromics), 3D protein modeling, protein-protein interaction assays, functional invasion/proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with PPI and functional assays, single lab, mechanism partially inferred from binding studies\",\n      \"pmids\": [\"40505831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Global knockout of GABBR2 (via Cre-mediated conditional disruption of a floxed Gabbr2 allele) recapitulates the germline GABBR2 knockout phenotype, including spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory, abnormal neuronal architecture, increased neuronal cell death, and premature death.\",\n      \"method\": \"CRISPR loxP insertion, Cre-mediated conditional knockout (Actin-Cre), EEG, behavioral assays, histology, immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"41397015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Carbamazepine upregulates GABBR2 protein expression and activates it to suppress the AC/cAMP/PKA signaling pathway, triggering apoptosis of hypothalamic GnRH neurons; GABBR2 knockdown in GT1-7 cells attenuates CBZ-induced AC/cAMP/PKA inhibition, reduces apoptosis, and partially restores GnRH secretion.\",\n      \"method\": \"In vivo rat model (long-term CBZ dosing), GT1-7 cell line GABBR2 knockdown, Western blot, ELISA, cAMP/PKA pathway assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in cell model plus in vivo correlate, single lab\",\n      \"pmids\": [\"41571204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GABBR2 overexpression in human neuroblastoma cells (SH-SY5Y, BE(2)-M17) increases intracellular Ca2+ concentration, reactive oxygen species production, mitochondrial permeability transition pore opening, and apoptosis.\",\n      \"method\": \"Expression plasmid transfection, intracellular Ca2+ measurement, ROS assay, mitochondrial permeability assay, apoptosis assay\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment in cell lines, single lab, no mechanistic dissection of how GABBR2 causes these effects\",\n      \"pmids\": [\"39724481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GABBR2 overexpression in N2a/APP cells increased ADAM10 expression and decreased BACE1 expression, leading to upregulation of sAPPα and downregulation of sAPPβ, suggesting GABBR2 modulates APP processing toward the non-amyloidogenic pathway.\",\n      \"method\": \"Expression plasmid transfection in N2a/APP cells, Western blot for ADAM10, BACE1, sAPPα, sAPPβ\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment in one cell line, single lab, no mechanistic dissection\",\n      \"pmids\": [\"40927314\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GABBR2 encodes the GB2 subunit of the GABAB receptor, which heterodimerizes with GABBR1/GB1 to form a functional G protein-coupled receptor: GB1 binds GABA while GB2 couples to Gi/o proteins to inhibit adenylyl cyclase, suppress Ca2+ channels, and activate GIRK potassium channels; disease-associated GABBR2 missense variants confer constitutive receptor activity or loss-of-function that drives neurodevelopmental phenotypes through adaptive downregulation of receptor and G protein signaling components, and beyond the nervous system GABBR2 participates in endothelial glycolysis-dependent angiogenesis, AR-driven cisplatin resistance in bladder cancer, and APP processing modulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GABBR2 encodes the GB2 subunit of the GABA-B receptor, a Gi/o-coupled GPCR that mediates inhibitory neurotransmission: it heterodimerizes with GABBR1/GB1 to form the functional receptor, and only co-expression of both subunits confers robust activation of GIRK-type potassium channels [#0]. Within the heterodimer GB2 provides the G protein coupling and effector functions—heteromeric assembly is required for baclofen-mediated, pertussis toxin-sensitive inhibition of voltage-gated Ca2+ channel currents in neurons [#2], and the receptor negatively couples to adenylyl cyclase in response to GABA, baclofen and 3-aminopropyl(methyl)phosphinic acid, an effect blocked by GABA-B antagonists [#1]. Loss of GABBR2 in mice produces spontaneous epileptiform activity, hyperalgesia, impaired memory, abnormal neuronal architecture and premature death, establishing its essential role in CNS function [#11]. De novo GABBR2 missense variants cause neurodevelopmental disease spanning Rett-like syndrome and epileptic encephalopathy through a spectrum of functional consequences: loss of receptor activity, reduced agonist potency or surface expression, and gain-of-function constitutive activity [#3, #9]; epileptic encephalopathy variants confer strong constitutive activity that, in a Gabbr2 knock-in mouse, drives adaptive downregulation of both receptor subunits and G protein signaling components, with positive allosteric modulators normalizing network activity [#8]. Beyond the nervous system, GABBR2 acts through PKA- and cAMP-dependent signaling in diverse contexts—central sensitization in chronic migraine via a GABBR2/PKA/SynCAM1 pathway [#4], glycolysis-dependent post-ischemic angiogenesis [#5], androgen receptor-driven cisplatin resistance in bladder cancer [#6], and GnRH neuron apoptosis [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that GB2 is not an independent receptor but an obligate heterodimerization partner of GB1, resolving how the functional GABA-B receptor is assembled.\",\n      \"evidence\": \"Heterologous co-expression with GIRK channel electrophysiology and reciprocal immunoprecipitation\",\n      \"pmids\": [\"9872315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structural basis of the heterodimer not resolved\",\n        \"Did not assign which subunit performs G protein coupling versus ligand binding\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Tested whether GB2 alone can signal, finding it could reach the surface and negatively couple to adenylyl cyclase—an observation that conflicts with the later consensus of obligate heterodimerization.\",\n      \"evidence\": \"Homomeric expression in COS/CHO cells with adenylyl cyclase assay and pharmacological antagonism\",\n      \"pmids\": [\"10328880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Contradicts later consensus that homomeric GABBR2 is non-functional\",\n        \"Possible endogenous GB1 contribution not excluded\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated in native neurons that heteromeric assembly is required for the receptor's inhibition of Ca2+ channel currents, linking the heterodimer to a physiological effector through Gi/o.\",\n      \"evidence\": \"Antisense knockdown of GABBR1 in sympathetic neurons with patch-clamp and pertussis toxin controls\",\n      \"pmids\": [\"10751439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not isolate the specific role of GB2 versus GB1 in the coupling\",\n        \"Specific Gi/o subtype not identified\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended GABBR2 expression beyond brain, identifying a testis/sperm isoform with a truncated 3'UTR localized to the sperm acrosome, raising a non-neuronal role.\",\n      \"evidence\": \"RT-PCR, Northern/Western blot, RACE-PCR and immunofluorescence in rat testis and sperm\",\n      \"pmids\": [\"14967916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of acrosomal GABBR2 not established\",\n        \"No heterodimerization partner identified in sperm\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected de novo GABBR2 variants to neurodevelopmental disease, showing EE-associated variants reduce receptor function more severely than RTT-like variants and respond to agonist rescue.\",\n      \"evidence\": \"Whole-exome sequencing with cell culture functional assays and Xenopus tropicalis in vivo agonist rescue\",\n      \"pmids\": [\"28856709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not capture gain-of-function/constitutive variants identified later\",\n        \"Mechanism linking reduced activity to phenotype severity not dissected\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved that disease variants act through gain-of-function constitutive activity, not only loss of function, and showed the network response involves compensatory receptor downregulation correctable by positive allosteric modulators.\",\n      \"evidence\": \"Luciferase reporter assays, CRISPR knock-in mouse, EEG and slice electrophysiology, proteomics and PAM pharmacology\",\n      \"pmids\": [\"40994051\", \"41803176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of constitutive activity not defined\",\n        \"Whether PAM correction translates to behavioral/clinical benefit not shown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the consequences of total GABBR2 loss in vivo, confirming its essential role in neuronal survival, network excitability, nociception and memory.\",\n      \"evidence\": \"Conditional Cre-mediated knockout with EEG, behavioral, histological and immunohistochemical readouts\",\n      \"pmids\": [\"41397015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell-type-specific contributions to phenotypes not parsed\",\n        \"Molecular cause of neuronal death not identified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated GABBR2 in non-neuronal disease contexts acting through canonical cAMP/PKA and metabolic effectors, broadening its functional scope beyond synaptic inhibition.\",\n      \"evidence\": \"In vivo and cell-model loss/gain-of-function across migraine PAG, ischemic angiogenesis, bladder cancer cisplatin resistance and GnRH neuron apoptosis\",\n      \"pmids\": [\"32931071\", \"34422926\", \"37762034\", \"41571204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GB1 heterodimerization is required in these peripheral contexts is unclear\",\n        \"Direct receptor-level mechanism not established in several systems\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GABBR2 transcriptional regulation (AR, TAp73alpha/HDAC2/REST) and its reported modulation of APP processing integrate with its canonical heterodimeric signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"APP processing and Ca2+/ROS/apoptosis effects rest on single overexpression experiments without mechanistic dissection\",\n        \"Whether transcriptional control by AR or TAp73alpha operates in neurons is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"complexes\": [\"GABA-B receptor heterodimer (GB1/GB2)\"],\n    \"partners\": [\"GABBR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}