GABBR2 encodes the GABA-B receptor subunit that couples a GABBR1–GABBR2 heterodimer to inhibitory heterotrimeric G proteins. Its extracellular Venus-flytrap domain and seven-transmembrane region form interfaces with GABBR1, relaying agonist-dependent conformational changes from the orthosteric ligand-binding GABBR1 subunit toward G-protein activation. At neuronal plasma membranes, receptor signaling inhibits adenylyl cyclase and regulates potassium and calcium channels through downstream G-protein subunits. Presynaptic receptors inhibit transmitter release, while postsynaptic receptors contribute to slow inhibition; extrasynaptic populations coexist with synaptic receptors. The distal GABBR2 tail binds KCTD auxiliary proteins that shape signaling kinetics. GABBR2 also supports receptor assembly and surface expression.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004888 transmembrane signaling receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: The inherited transmembrane receptor function can be specified as G protein-coupled GABA receptor activity. Reason: Actual PTHR10519 tree and alignment place human O75899 at AN139/PTN002471337 below the GO:0004888 IBD origin AN0/PTN000828857. Literal donor membership and target sequence were checked, with no retained negative assertion on this lineage; the target's own donor occurrence is legitimate experimental grounding. This phylogenetic assertion is sound. Human receptor experiments independently establish the more informative GO:0004965, an is_a descendant through GO:0004930. The refinement expresses the known GABA-B receptor role rather than alleging loss of ancestral receptor activity. GABBR2 supplies the coupling subunit of the heterodimer. The proposed activity is intended as GABBR2 contributing to the assembled heterodimer, consistent with the contributes_to core; the literal upstream relationship field is preserved as provenance, not interpreted as evidence for autonomous receptor activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000828857 SUPPORTS TRANSFER The retained PTHR10519 IBD places receptor activity at AN0, above human O75899 at AN139/PTN002471337. The ancestral receptor assertion is supported; the refinement specifies the independently established GABA-B receptor function without asserting loss or faulty propagation. Proposed replacements: G protein-coupled GABA receptor activity |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro GPCR assignment can be refined to the experimentally established GABA-B receptor activity. Reason: IPR000337/IPR017978/IPR017979 support the class-C seven-transmembrane receptor architecture, but GO:0004930 does not identify the receptor system. The retained human extracellular-domain structures and receptor signaling experiments support GO:0004965, a direct is_a child. The proposed specificity relies on the literature as well as the domain mapping; it does not imply that every protein sharing a broad InterPro entry recognizes GABA or that GABBR2 alone binds the orthosteric agonist. The proposed activity is intended as GABBR2 contributing to the assembled heterodimer, consistent with the contributes_to core; the literal upstream relationship field is preserved as provenance, not interpreted as evidence for autonomous receptor activity. Proposed replacements: G protein-coupled GABA receptor activity |
| GO:0004965 G protein-coupled GABA receptor activity | IDA PMID:9872316 Heterodimerization is required for the formation of a functi... | ACCEPT | Summary: GABBR2 contributes to G protein-coupled GABA receptor activity in the GABBR1–GABBR2 heterodimer. Reason: The original contributes_to qualifier is essential to the interpretation and is retained. PMID:9872316 reports receptor-subunit association, cell-surface delivery and functional GABA responses after coexpression. Human structural and functional studies distinguish the orthosteric ligand-binding GABBR1 subunit from the G-protein-coupling GABBR2 subunit (PMID:22660477, PMID:24305054, PMID:32581365). This supports a contributing receptor subunit, without assigning an autonomous GABA-binding site or ion-conducting pore to GABBR2. |
| GO:0004965 G protein-coupled GABA receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: The GABA-B-specific InterPro mapping agrees with the established heterodimeric receptor function. Reason: The IPR002455/IPR002457 mapping names the experimentally established G protein-coupled GABA receptor system. Human GABBR2 participates through G-protein coupling and intersubunit communication, while GABBR1 supplies the orthosteric GABA site. The correct molecular activity is retained with this subunit scope, supported independently by PMID:9872316 and the human structural studies; no ion-channel or autonomous ligand-binding function is inferred from the electronic annotation. The accepted biological claim is GABBR2 contribution to the assembled receptor, as represented in the contributes_to core. The literal upstream relationship field remains unchanged; this review does not independently establish a qualifier defect. |
| GO:0004965 G protein-coupled GABA receptor activity | TAS PMID:10328880 Molecular identification of the human GABABR2: cell surface ... | ACCEPT | Summary: GABBR2 has a core GABA-B receptor role, while this early autonomous-receptor interpretation remains disputed. Reason: PMID:10328880 explicitly reports human GABBR2-dependent adenylyl-cyclase inhibition in CHO cells described as lacking GABBR1. That is the actual historical report and is not rewritten as a heterodimer experiment. Subsequent work shows functional responses requiring both subunits, and human structures place orthosteric agonists in GABBR1 (PMID:10075644, PMID:10773016, PMID:24305054). The gene-level GABA-B receptor activity is firmly supported in the heterodimer. Accepting it does not endorse the paper's proposed physiological GABBR2 homomer; the reference assessment records that conflict separately. The accepted biological claim is GABBR2 contribution to the assembled receptor, as represented in the contributes_to core. The literal upstream relationship field remains unchanged; this review does not independently establish a qualifier defect. |
| GO:0005515 protein binding | IPI PMID:16724110 Coordinated action of NSF and PKC regulates GABAB receptor s... | KEEP AS NON CORE | Summary: NSF associates with GABA-B receptor complexes and modulates receptor desensitization. Reason: The PMID:16724110 abstract explicitly reports NSF interaction with the receptor heterodimer in rat synaptosomes and CHO cells, and a GABBR2-derived peptide that interferes with NSF binding and agonist-promoted desensitization. This is positive source-specific association evidence, not a misleading paralog title. The exact human construct and full assay details were not recovered. Retain the P46459 interaction as noncore under the project's generic-binding policy; do not assign NSF ATPase activity or a new trafficking mechanism to GABBR2. |
| GO:0005515 protein binding | IPI PMID:16724110 Coordinated action of NSF and PKC regulates GABAB receptor s... | MODIFY | Summary: The GABBR1 interaction is more informatively represented as receptor heterodimerization. Reason: PMID:16724110 describes a receptor heterodimer within an NSF-containing ternary complex, while the human studies independently establish direct GABBR1–GABBR2 heterodimer interfaces and 1:1 extracellular-domain association (PMID:22660477, PMID:24305054). GO:0046982 specifies the known role of this named GABBR1 pair and is an is_a descendant of protein binding through protein dimerization activity. The original IPI partner Q9UBS5 is retained. The refinement does not claim that the inaccessible full 2006 experiment independently measured purified-human affinity or stoichiometry. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | UNDECIDED | Summary: The particular GABBR2–GLP-1R interaction remains unresolved from the accessible target evidence. Reason: The PMID:23864651 cache is marked full-text available but contains abstract and Discussion rather than the target Results/table. The accessible material describes full-length human GLP-1R MYTH screening and CHO follow-up, including overexpression limitations, but does not expose the literal GABBR2–P43220 pair or tested GABBR2 construct. The general assay and other validated candidates cannot substitute for that target row. Preserve the IPI claim without asserting contamination, wrong-gene assignment or absence; the insulin-secretion experiments on other hits are not assigned to GABBR2. |
| GO:0005515 protein binding | IPI PMID:24305054 Structural mechanism of ligand activation in human GABA(B) r... | MODIFY | Summary: Human GABBR1b and GABBR2 extracellular domains directly form a receptor heterodimer. Reason: PMID:24305054 directly resolves noncovalent human GBR1b–GBR2 extracellular heterodimers in apo, antagonist-bound and agonist-bound states and tests interface mutations. This supports GO:0046982 rather than generic protein binding. The incoming Q9UBS5-2 partner remains literal; it specifies the GABBR1 product in this context, not a GABBR2 isoform. Purified ectodomains and engineered full-length receptor tests are distinguished, and orthosteric ligand contacts belong to GBR1b. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | MODIFY | Summary: The named GABBR1–GABBR2 positive control supports the established heterodimeric interaction. Reason: Authentic PMID:24658140 supplementary Figures 3e and 6b explicitly assay GABBR1-Cub reporter fusions with GABBR2-Nub in HEK293T cells. Thus the EGFR-focused abstract does not invalidate this receptor-pair annotation. The MaMTH signal establishes association in engineered cells; human purified-domain and structural studies independently identify the pair as a heterodimer (PMID:22660477, PMID:24305054), supporting GO:0046982. No exact natural GABBR1 splice product, endogenous neuronal co-IP or affinity value is inferred from the reporter experiment. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:30814734 Structural basis for KCTD-mediated rapid desensitization of ... | KEEP AS NON CORE | Summary: The GABBR2 distal tail directly binds the KCTD16 auxiliary-subunit assembly. Reason: PMID:30814734 directly resolves human GABBR2 residues 876–913 bound within an asymmetric KCTD16 BTB pentamer and tests interface disruption. This is strong positive evidence for the literal Q68DU8 interaction. It is retained as a source-specific noncore binding annotation; the precise tail/BTB interface is more informative in the rationale than the bare GO term. KCTD12 H1 binding to Gbeta-gamma and the proposed stripping mechanism are separate experiments and are not activities of the GABBR2 tail. These engineered fragments are not natural alternative products. |
| GO:0005515 protein binding | IPI PMID:32555460 Structural basis of the activation of a metabotropic GABA re... | MODIFY | Summary: Human receptor structures directly establish GABBR1–GABBR2 heterodimerization. Reason: PMID:32555460 resolves the human GB1–GB2 complex through inactive and agonist/PAM-bound activation states. This is direct heterodimer-interface evidence for GO:0046982. Although the broad framing calls the receptor full-length, the structural Methods specifies GB1 165–920 and GB2 42–821 with expression tags; these are engineered constructs. HEK293 signaling assays use Galpha-qi9 and do not prove physiological Gq coupling. The literal Q9UBS5 partner and original IPI context are preserved. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:32580208 Structures of metabotropic GABA(B) receptor. | MODIFY | Summary: The GABBR1b–GABBR2 cryo-EM complex supports specific receptor heterodimerization. Reason: PMID:32580208 combines human receptor structures with functional and interface-mutant assays, supporting GO:0046982 for the incoming Q9UBS5-2 pair. Signal-peptide replacements and the reported construct boundaries are experimental details, not a new natural GABBR2 isoform. The separately purified homodimer in this study is GABBR1b, and it must not be represented as a physiological GABBR2 homomer. Engineered Galpha-q/o5 signaling also does not establish native Gq specificity. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:32581365 Structure of human GABA(B) receptor in an inactive state. | MODIFY | Summary: The human inactive receptor contains a directly resolved GABBR1b–GABBR2 heterodimer interface. Reason: PMID:32581365 resolves the human heterodimer and tests its transmembrane intersubunit latch, giving direct support for GO:0046982. The structural proteins retain the coiled-coil but truncate flexible tails: GABBR2 1–819 and GABBR1b 1–802. Preserve the incoming Q9UBS5-2 identity while distinguishing those engineered proteins from natural products. Ligand density, lipid modulation and Gi-related receptor biology are not evidence that GABBR2 itself forms an ion pore. Proposed replacements: protein heterodimerization activity |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | UNDECIDED | Summary: The precise Q86UR5 interaction has not been independently resolved from the retained neuronal interactome evidence. Reason: PMID:37207277 names GABBR2 among genetically prioritized network interactors and provides neuronal IP-MS methods, but the retained selected text does not expose the exact O75899–Q86UR5 target row, differentiation time point or pair-specific validation. The six-protein networks and enrichment/QC criteria establish the experimental class, not this pair. Retain the original IPI record with uncertainty; IP-MS would support co-complex association rather than necessarily direct binary binding, and the separate tagged-TCF4 assay cannot be generalized to this context. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific cytoplasmic localization claim remains unresolved because its mouse donor panel was not recovered. Reason: The electronic transfer traces to mouse Q80T41/ENSMUSP00000103378 and an IDA annotation citing PMID:15013631. The accessible abstract establishes receptor–ATF4 association and neuronal/glial colocalization in neonatal mouse brain, but it does not identify the exact cytoplasmic compartment or recover the supporting GABBR2 localization panel. General membrane-receptor trafficking is not positive evidence for this particular assertion. The ER accumulation in PMID:14657159 and PMID:15617512 concerns GABBR1 and is not reassigned to GABBR2. Keep the original donor assertion pending its primary localization evidence; this uncertainty neither establishes soluble cytosol nor refutes a possible intracellular receptor pool. |
| GO:0005886 plasma membrane | EXP PMID:15617512 Subcellular distribution of GABA(B) receptor homo- and heter... | ACCEPT | Summary: Imaging and interaction assays place GABBR2-containing assemblies at the plasma membrane. Reason: The PMID:15617512 abstract explicitly reports co-IP/BRET/FRET and confocal localization: GBR2 homodimers and GBR1–GBR2 heterodimers occur at the plasma membrane, whereas GBR1 homodimers are retained in ER/ERGIC. The positive GABBR2 location supports this EXP annotation. It does not establish physiological signaling by GABBR2 homomers, and the GBR1 ER-retention result is not transferred to GABBR2. Only the available abstract, not full original imaging panels, was inspected. |
| GO:0005886 plasma membrane | IDA PMID:15304491 Structural analysis of the complement control protein (CCP) ... | ACCEPT | Summary: Plasma-membrane localization is valid, with the specific 2004 experiment not independently recovered. Reason: The PMID:15304491 abstract concentrates on GABBR1 CCP domains and does not expose the GABBR2 surface-expression assay underlying this IDA annotation. It is not evidence of a paralog error. The same gene-level plasma-membrane location is independently demonstrated by human GABBR2 expression and receptor reconstitution studies (PMID:10328880, PMID:9872316) and receptor-subunit imaging in PMID:15617512. Accept the established location while retaining the source-specific access limitation rather than claiming to have read this particular assay. |
| GO:0005886 plasma membrane | IDA PMID:9872316 Heterodimerization is required for the formation of a functi... | ACCEPT | Summary: Reconstituted GABBR1–GABBR2 receptors function at the cell surface. Reason: PMID:9872316 directly reports GABBR1 terminal glycosylation and cell-surface expression when coexpressed with GABBR2, together with functional high-affinity GABA receptor responses. This supports plasma-membrane residence of the functional receptor assembly. It does not imply that GABBR2 is the GABA-binding subunit or that intracellular receptor pools are absent. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane is an established functional location of GABBR2-containing receptors. Reason: The SL-0039 mapping agrees with independent receptor surface-expression experiments, functional reconstitution and human receptor studies. GABBR2 can reach the surface in the tested expression systems and forms a functional surface receptor with GABBR1. This is a positive, nonexclusive location claim; it does not imply that every receptor molecule is permanently at the surface or that trafficking intermediates are absent. |
| GO:0005886 plasma membrane | TAS PMID:10328880 Molecular identification of the human GABABR2: cell surface ... | ACCEPT | Summary: The early human GABBR2 study directly reports cell-surface expression. Reason: PMID:10328880 explicitly places human GABBR2 at the cell surface in transfected COS cells. This localization result is separable from the paper's disputed interpretation of GABBR2-only signaling. Independent GABBR1–GABBR2 surface-expression and functional experiments corroborate the same cellular location, so the historical signaling disagreement is not a reason to discard this positive location assertion. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1013012 | ACCEPT | Summary: The modeled GABA-B receptor complex is at the plasma membrane during G-protein signaling. Reason: The official R-HSA-1013012 participant/catalyst chain reaches ligand-bound GABBR1–GABBR2 complex 420698 and mature human GABBR2 entity 420747/O75899 residues 42–941 at the plasma membrane. Catalyst 1013016 assigns the GABA receptor activity to the complex. This directly checks target membership and compartment in the model, without treating the processed chain as a separate splice isoform or assigning the receptor complex's functions to an ion-conducting GABBR2 pore. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1013013 | ACCEPT | Summary: The Reactome GABA-B effector-complex event retains the receptor at the plasma membrane. Reason: The official R-HSA-1013013 chain contains the ligand-bound receptor complex and explicitly reaches GABBR2 entity 420747/O75899 in the plasma membrane. The modeled Gbeta-gamma and channel-associated assemblies do not change that receptor compartment. This supports the location assertion; membership of a larger effector assembly does not make GABBR2 itself the G-protein subunit or the conducting potassium-channel protein. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1013020 | ACCEPT | Summary: GABBR2 remains a plasma-membrane component of the modeled receptor–G-protein–Kir assembly. Reason: R-HSA-1013020 uses catalyst 1013015 linked to the receptor/Gbeta-gamma/Kir assembly, whose explicit participant chain reaches O75899 entity 420747 at the plasma membrane. The inward-rectifier channel activity assigned to the larger assembly is not intrinsic GABBR2 pore activity. The present annotation asserts only receptor location, which is supported by the actual model membership and independent receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: The generic Gi activation model explicitly includes plasma-membrane GABBR2. Reason: Official R-HSA-380073 connects inactive Gi-bound complex 749455, through catalyst 380101, to activated counterpart 749445. Defined receptor set 380091 explicitly includes GABA-bound complex 420698, which contains mature GABBR2 entity 420747/O75899 in the plasma membrane. This verifies that GABBR2 is a modeled member of the generic event rather than relying on its title alone. Cytosolic nucleotides in the reaction do not relocate the receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-420688 | ACCEPT | Summary: The GABA–GABA-B receptor binding model places GABBR2 in the plasma membrane. Reason: R-HSA-420688 joins GABA with GABBR1–GABBR2 complex 420748 to form ligand-bound complex 420698. The component chain explicitly includes entity 420747, mature O75899 residues 42–941, assigned to the plasma membrane. The event models ligand binding to the heterodimer and does not identify an independent orthosteric GABA-binding site in GABBR2. The location is also supported by receptor surface-expression experiments. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: GABBR2 is an explicitly included plasma-membrane receptor in the Gi dissociation model. Reason: Official R-HSA-749454 acts on the activated Gi/receptor counterpart 749445. Its receptor set includes complex 420698 and target entity 420747/O75899 at the plasma membrane. The membership chain supplies the specific target connection missing from a generic event summary. The annotation is accepted as receptor location, without assigning the released G-protein subunits' compartment or enzymatic roles to GABBR2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: The modeled association with Gi includes GABBR2 in a plasma-membrane receptor complex. Reason: Official R-HSA-749456 forms inactive Gi-bound receptor complex 749455. The receptor set 380091 includes the GABA-B receptor through complex 420698, whose component 420747 is mature human GABBR2 in the plasma membrane. This directly supports the modeled location and agrees with independent receptor surface-expression studies. It is model membership evidence, not a newly inspected receptor-binding experiment or proof of a particular neuronal expression pattern. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: The broad InterPro GPCR pathway can be specified as the adenylate-cyclase-inhibiting receptor pathway. Reason: GABBR2 couples the GABA-B heterodimer to inhibitory heterotrimeric G proteins; receptor coexpression experiments include direct cAMP readouts and human structural/interface studies support activation (PMID:10075644, PMID:10773016, PMID:24305054). GO:0007193 is an is_a descendant of GO:0007186 through GO:0007188. This identifies a demonstrated branch rather than treating GABBR2 as the enzyme that hydrolyzes cAMP. The refinement does not assert that all GABA-B effects are mediated by cAMP, since Gbeta-gamma-dependent channel regulation is also supported. Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:9872316 Heterodimerization is required for the formation of a functi... | MODIFY | Summary: GABA-B receptor signaling can be represented by its demonstrated adenylate-cyclase-inhibiting branch. Reason: PMID:9872316 establishes functional GABBR1–GABBR2 receptor assembly. The more specific downstream branch is supported independently by coexpression/cAMP experiments in PMID:10075644 and PMID:10773016, with human Gi-response interface tests in PMID:24305054. GO:0007193 descends from the original GPCR pathway through GO:0007188. The original TAS reference is retained, and the rationale does not invent a cAMP experiment in the abstract of PMID:9872316 or exclude other receptor effectors. Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:987231 [Methylation of phenols using metal-salt catalysts (author's... | ACCEPT | Summary: GABBR2 participates in inhibitory G-protein signaling to adenylyl cyclase, despite an incorrect source PMID. Reason: The biological claim is supported by receptor coexpression/cAMP experiments and the distinct coupling role of GABBR2 (PMID:10075644, PMID:10773016, PMID:24305054). The incoming ComplexPortal citation PMID:987231 instead resolves to a 1976 phenol-methylation chemistry paper and cannot support this IDA assignment. Keep the original record unchanged and report its reference defect for source correction. PMID:9872316 is a relevant separate receptor paper, but its resemblance to the malformed identifier is not proof of the curator's intended replacement. Accepting the biological process does not validate the original citation or evidence attribution. |
| GO:0007194 negative regulation of adenylate cyclase activity | TAS PMID:10328880 Molecular identification of the human GABABR2: cell surface ... | ACCEPT | Summary: GABBR2 contributes to receptor-mediated reduction of adenylyl-cyclase activity. Reason: PMID:10328880 explicitly reports agonist-sensitive adenylyl-cyclase inhibition by human GABBR2 in CHO cells described as lacking GABBR1. Preserve that historical result while distinguishing its disputed autonomous-receptor interpretation from the well-established inhibitory GABBR1–GABBR2 pathway. Independent coexpression studies support functional cAMP inhibition requiring the heterodimer (PMID:10075644, PMID:10773016). The retained process is a receptor-mediated regulatory role, not intrinsic adenylyl-cyclase catalytic activity or endorsement of physiological GABBR2-only signaling. |
| GO:0007214 gamma-aminobutyric acid signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GABA signaling is a conserved core role of the GABBR2 receptor subunit. Reason: Human O75899 AN139/PTN002471337 lies below the actual GABA-signaling IBD at AN1/PTN000054983 in PTHR10519. The retained literal IBD, donor identities and target path agree; no lineage-loss assertion was found in the retained family record. Self-donor O75899 is expected because its experimental annotation helped ground the ancestral placement. Human GABBR1–GABBR2 functional evidence independently supports this core signaling role. The claim concerns inherited participation in GABA reception and transduction, not autonomous GABBR2 ligand recognition. |
| GO:0007214 gamma-aminobutyric acid signaling pathway | IDA PMID:987231 [Methylation of phenols using metal-salt catalysts (author's... | ACCEPT | Summary: GABBR2 has a well-established GABA signaling role, with the incoming ComplexPortal reference requiring correction. Reason: PMID:987231 is an unrelated chemistry paper and is not evidence for the asserted IDA context. The GABA signaling claim itself is independently established by PMID:9872316, PMID:22660477 and PMID:24305054, as well as the separately inspected ancestral assertion. Retain the biological annotation and its immutable incoming reference while recording a CHECK request to the responsible ComplexPortal source. No verified canonical replacement is asserted, and no inference is made that the erroneous reference arose through a particular transcription mechanism. |
| GO:0007214 gamma-aminobutyric acid signaling pathway | IDA PMID:9872316 Heterodimerization is required for the formation of a functi... | ACCEPT | Summary: Functional receptor reconstitution directly supports GABBR2 participation in GABA signaling. Reason: PMID:9872316 reports intracellular-tail association of the two subunits, GABBR1 surface maturation after coexpression and functional high-affinity receptor responses. These experiments establish GABBR2 as a participant in the receptor's GABA signaling machinery. Later human structures clarify that agonists bind GABBR1 while GABBR2 transduces the allosteric change toward G-protein activation; that division of labor supports rather than negates process participation. |
| GO:0007268 chemical synaptic transmission | TAS PMID:9872316 Heterodimerization is required for the formation of a functi... | MODIFY | Summary: The chemical-synaptic-transmission annotation can be specified as GABAergic transmission. Reason: The original functional GABA-B receptor study supports a receptor for inhibitory GABA transmission, and the conserved receptor mechanism and neuronal localization corroborate this role. GO:0051932 is a verified direct is_a child of chemical synaptic transmission and includes postsynaptic GABA receptor activation, not just presynaptic vesicle exocytosis. The refinement therefore identifies the transmitter system without asserting that GABBR2 itself releases transmitter or forms a conducting channel. Proposed replacements: synaptic transmission, GABAergic |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The broad membrane annotation can be specified as plasma membrane. Reason: The InterPro entries support the integral-membrane receptor architecture, while independent surface-expression and functional reconstitution experiments establish plasma-membrane location. GO:0005886 is a verified direct is_a child of GO:0016020 and already has multiple supported incoming contexts. The refinement identifies the functional receptor compartment without denying intracellular trafficking pools or deriving membrane topology solely from domain labels. Proposed replacements: plasma membrane |
| GO:0016917 GABA receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: The ARBA GABA-receptor activity can be refined to the metabotropic G protein-coupled subtype. Reason: GO:0016917 covers both ionotropic and metabotropic GABA receptor systems. GABBR2 is the coupling subunit of the GABBR1–GABBR2 metabotropic receptor, supported by human functional and structural evidence. GO:0004965 is a verified direct is_a descendant and is already represented in the incoming annotation set. The refinement is based on the experimentally established receptor type, without assigning GABA-A channel activity or an isolated GABBR2 orthosteric site. The proposed activity is intended as GABBR2 contributing to the assembled heterodimer, consistent with the contributes_to core; the literal upstream relationship field is preserved as provenance, not interpreted as evidence for autonomous receptor activity. Proposed replacements: G protein-coupled GABA receptor activity |
| GO:0038039 G protein-coupled receptor heterodimeric complex | IBA GO_REF:0000033 | ACCEPT | Summary: GABBR2 is a conserved component of a GPCR heterodimeric complex. Reason: The current official name of GO:0038039 is G protein-coupled receptor heterodimeric complex. Human AN139/PTN002471337 descends from the inspected AN0/PTN000828857 IBD for this term, and the literal donor/target joins agree. No retained lineage loss was found; the target's own experimental donor occurrence is appropriate. Human structures independently establish the GABBR1–GABBR2 heterodimer. This compositional claim is retained alongside the function-defined GABA receptor complex; an unverified ontology edge between those two complex terms is not invented. |
| GO:0038039 G protein-coupled receptor heterodimeric complex | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA heterodimeric GPCR-complex assignment agrees with the directly characterized receptor assembly. Reason: ARBA00088008 assigns membership in GO:0038039, whose current definition specifies two different GPCR subtypes. GABBR1 and GABBR2 form the experimentally characterized heterodimer in human structural studies, supporting this compositional annotation independently of the automated rule. The term is not relabeled from memory as a GABA-specific complex, and no physiological GABBR2 homomer function is inferred. |
| GO:0038039 G protein-coupled receptor heterodimeric complex | IPI PMID:9872316 Heterodimerization is required for the formation of a functi... | ACCEPT | Summary: The original cloning study supports GABBR1–GABBR2 heterodimeric-complex membership. Reason: PMID:9872316 reports tail-mediated interaction and a fully functional surface receptor after coexpression of the two subunits. This directly supports membership in the heterodimeric GPCR complex with literal partner Q9UBS5. Later human extracellular and transmembrane structures corroborate the assembly while distinguishing ligand binding on GABBR1 from coupling through GABBR2. The original IPI context is retained unchanged. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | ACCEPT | Summary: Neuronal projections are supported locations for GABBR2-containing receptors. Reason: The mouse Q80T41/ENSMUSP00000103378 transfer traces to PMID:15013631, whose abstract reports neuronal/glial receptor colocalization and development-dependent ATF4 association; the exact projection panel remains inaccessible. Independent rat receptor-subunit immunoelectron microscopy in PMID:14657159 directly places GABBR2 on dendritic and axonal elements, supporting the conserved neuronal-projection location. Accept the anatomical occurrence without claiming that all receptor is synaptic or assigning ATF4 transcriptional activity to GABBR2. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The curated postsynaptic-membrane mapping agrees with receptor-subunit localization evidence. Reason: SL-0219 is consistent with the directly read rat GABBR2 localization in PMID:14657159 and the receptor's postsynaptic signaling role. The positive location is nonexclusive: presynaptic and extrasynaptic populations are also reported. Accept the mapping without asserting that a broad subcellular-location label establishes every synaptic subdomain or a human isoform-specific distribution. |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Rat donor imaging supports both postsynaptic and presynaptic GABBR2 membrane populations. Reason: The ISS donor O88871 traces to PMID:14657159. Original Methods and Results describe subunit-specific immunoelectron microscopy in adult male Wistar rat hippocampus. GABBR2 labeling occurs at pre- and postsynaptic plasma membranes, predominantly extrasynaptically, with occasional presynaptic and postsynaptic specializations; Figures 3 and 5 and the corresponding Results distinguish these populations. The source Discussion relates presynaptic receptors to inhibition of transmitter release through calcium-channel suppression, citing earlier physiology. This supports the nonexclusive postsynaptic annotation and the broader pre/postsynaptic core location, without claiming human imaging or a new functional experiment in this localization study. Quantitative distance measurements specifically analyzed GABBR1a/b and are not transferred to GABBR2. |
| GO:0046982 protein heterodimerization activity | IPI PMID:15304491 Structural analysis of the complement control protein (CCP) ... | ACCEPT | Summary: Heterodimerization is an established molecular role of GABBR2, with this particular source assay still incompletely accessible. Reason: The PMID:15304491 abstract foregrounds GABBR1a CCP domains and fibulin binding; the precise GABBR2 experiment underlying this IPI row with rat GABBR1 Q9Z0U4 was not recovered. That does not establish misattribution. Independent human GABBR1–GABBR2 purified-domain and structural experiments directly establish the same heterodimerization activity (PMID:22660477, PMID:24305054). Accept the well-established gene-level activity while retaining the original partner and explicitly withholding a claim that the particular cross-species assay was independently checked. |
| GO:0051932 synaptic transmission, GABAergic | NAS PMID:987231 [Methylation of phenols using metal-salt catalysts (author's... | ACCEPT | Summary: The receptor subunit participates in GABAergic transmission, although the cited chemistry PMID is invalid support. Reason: The definition includes postsynaptic GABA receptor activation and consequent changes in membrane potential, so it applies to the receptor's signaling role rather than requiring GABBR2 to perform vesicle fusion. Functional receptor assembly, neuronal localization and mechanistic receptor studies independently support this role (PMID:9872316, PMID:14657159, PMID:30814734). PMID:987231 is unrelated phenol-methylation chemistry; the literal NAS citation is retained and flagged for ComplexPortal review rather than silently replaced by a similar identifier. |
| GO:0150099 neuron-glial cell signaling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The rat donor supports a contextual receptor role in signaling from neurons to astrocytes. Reason: The literal ISS donor O88871 traces to rat IGI PMID:10196584 with the same two-cell extension conjunction. Its abstract reports interneuron-evoked potentiation, blockade by a GABA-B antagonist and dependence on astrocytic calcium signaling, supporting a GABA-B receptor-mediated neuron-to-astrocyte route. This is a contextual receptor function rather than the universal identity of GABBR2. The original full text and a subunit-isolated assay were not recovered; the interpretation preserves the curated donor attribution and does not claim a direct human experiment. Both has_start_location CL:0011005 and has_end_location CL:0000127 atoms remain together. |
| GO:1902710 GABA receptor complex | IDA PMID:15304491 Structural analysis of the complement control protein (CCP) ... | MODIFY | Summary: The known GABBR2 complex is specifically the G protein-coupled GABA receptor complex. Reason: GO:1902710 includes both ionotropic and metabotropic GABA receptor assemblies. Human receptor structures and functional reconstitution directly establish the metabotropic GABBR1–GABBR2 complex, represented by its verified is_a child GO:1902712. The exact GABBR2 experiment in PMID:15304491 was not recovered from its GABBR1 CCP-focused abstract, so the refinement uses independent PMID:22660477 and PMID:24305054 support rather than alleging a wrong-paralog citation or inventing that paper's assay. Proposed replacements: G protein-coupled GABA receptor complex |
| GO:1902712 G protein-coupled GABA receptor complex | IPI PMID:24305054 Structural mechanism of ligand activation in human GABA(B) r... | ACCEPT | Summary: Human GABBR2 directly participates in the structurally characterized G protein-coupled GABA receptor complex. Reason: PMID:24305054 resolves human GABBR1b and GABBR2 extracellular domains as a heterodimer in ligand-free, antagonist-bound and agonist-bound conformations and functionally tests interfaces. This directly supports the specific receptor complex. The defined orthosteric site is in GABBR1b; GABBR2 participates in the coupling interface, so complex membership does not imply identical ligand-binding roles or a distinct natural product corresponding to the engineered domains. |
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Download this section (compressed HTML)Q: Which original ComplexPortal evidence was intended by the three annotations carrying the unrelated PMID:987231, and can the responsible source verify a replacement rather than infer one from identifier similarity?
Q: What target-level constructs and data support the GABBR2–GLP-1R and GABBR2–Q86UR5 interaction records whose exact tables were unavailable in the retained source text?
Q: Under which expression and assay conditions did the early GABBR2-alone adenylyl-cyclase responses occur, and how do those conditions compare with later evidence for the physiological heterodimer?
Experiment: Compare matched full-length human GABBR1–GABBR2 receptors with defined KCTD combinations using surface-expression controls, direct Gi activation and cAMP or GIRK readouts. Keep engineered chimeric-G-protein assays separate from native-coupling conclusions.
Hypothesis: Receptor–auxiliary-protein composition tunes signaling kinetics without changing the orthosteric division of labor between GABBR1 and GABBR2.
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