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Showing ADGRB3 — BAI3 is a alias.

ADGRB3

Adhesion G protein-coupled receptor B3 · UniProt O60242

Length
1522 aa
Mass
171.5 kDa
Annotated
2026-06-09
23 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADGRB3 (BAI3) is an adhesion-GPCR that functions as a high-affinity receptor for the secreted C1q-like proteins (C1ql1–4), coupling extracellular C1ql recognition to intracellular Rac1-dependent cytoskeletal and adhesive remodeling across neuronal, muscle, and metabolic tissues (PMID:21262840, PMID:23628982, PMID:30367035). The four C1ql proteins bind the extracellular thrombospondin-repeat domain of BAI3 through their globular C1q domains, and cryo-EM reveals that this interaction is calcium-mediated: a central C1ql homotrimer captures three BAI3 molecules into the grooves of the trimeric C1q domains, with C1ql further undergoing calcium-modulated domain-swapping to form hexamers and linear clusters that scaffold and accumulate BAI3 receptors at the plasma membrane (PMID:40316654, PMID:41372137). Downstream, BAI3 binds ELMO1/2 directly at the cell surface and activates Rac1, a module that drives dendritic arborization in Purkinje cells and is required for vertebrate myoblast fusion, with ELMO-binding-deficient BAI3 mutants failing to rescue either phenotype (PMID:24567399, PMID:23628982). In muscle, BAI3 GPCR activity is bidirectionally controlled — repressed by C1ql proteins and activated by Stabilin-2, which triggers heterotrimeric G-protein and ELMO recruitment to promote fusion and efficient muscle regeneration (PMID:30367035). At cerebellar synapses, C1ql1–BAI3 signaling organizes the stereotyped connectivity of climbing and parallel fiber excitatory afferents onto Purkinje cells and regulates activity-dependent climbing fiber synaptogenesis downstream of GluD2 (PMID:25660030, PMID:37488606). Beyond the nervous system and muscle, BAI3 mediates C1ql3-dependent inhibition of cAMP-stimulated insulin secretion in pancreatic β-cells and regulates adaptive thermogenesis, with knockout mice showing increased energy expenditure and thermogenic gene induction in brown adipose tissue (PMID:30228187, PMID:37367869).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Low

    Established BAI3 as a brain-specific transcript distinct from its paralog BAI1, setting the stage for tissue-targeted functional study.

    Evidence Northern blot, chromosomal mapping to 6q12, and cell-line expression analysis

    PMID:9533023

    Open questions at the time
    • No mechanistic assay beyond transcriptional regulation comparison
    • No ligand or signaling function identified
    • Reduced expression in glioblastoma lines left mechanistically unexplained
  2. 2011 High

    Identified the C1q-like proteins as BAI3 ligands and mapped the binding interface, answering what BAI3 recognizes and linking it to synapse regulation.

    Evidence Pulldown binding assay with domain mapping and neuronal culture synapse-density competition assay

    PMID:21262840

    Open questions at the time
    • Did not resolve downstream signaling from the receptor
    • Synapse effect direction (decrease) not yet reconciled with later synaptogenic roles
  3. 2013 High

    Connected BAI3 to an intracellular effector pathway, showing it drives dendrite morphogenesis through direct ELMO1 binding and Rac1 activation.

    Evidence shRNA knockdown, overexpression, transgenic Purkinje-cell dominant-negative, and Rac1 activation assay

    PMID:23628982

    Open questions at the time
    • Did not link ELMO/Rac1 output to a defined ligand input
    • DOCK1 involvement not directly demonstrated here
  4. 2014 High

    Extended the BAI3–ELMO module beyond neurons, demonstrating it is required for vertebrate myoblast fusion and that the ELMO interaction is functionally essential.

    Evidence Reciprocal Co-IP, loss-of-function, and in vivo rescue with ELMO-binding-deficient mutant

    PMID:24567399

    Open questions at the time
    • Upstream activator of BAI3 in muscle not yet identified
    • GPCR signaling step between receptor and ELMO not resolved
  5. 2015 High

    Placed the C1QL1–BAI3 axis in vivo as an organizer of stereotyped cerebellar afferent connectivity.

    Evidence In vivo knockout/knockdown, electrophysiology, and immunohistochemistry in mouse cerebellum

    PMID:25660030

    Open questions at the time
    • Molecular mechanism of synaptic territory specification not fully resolved
    • Did not establish the structural basis of C1QL1–BAI3 binding
  6. 2018 High

    Resolved the bidirectional regulation of BAI3 GPCR activity in muscle, identifying Stabilin-2 as an activator and C1ql proteins as repressors upstream of G-protein/ELMO recruitment.

    Evidence Proteomic interactome, Co-IP, BRET GPCR activity assay, and BAI3 knockout cardiotoxin injury model

    PMID:30367035

    Open questions at the time
    • Identity of coupled G-protein subtype not fully defined
    • How C1ql binding mechanically represses G-protein coupling unresolved
  7. 2018 Medium

    Demonstrated a non-neuronal endocrine role, showing BAI3 transduces C1ql3 inhibition of cAMP-stimulated insulin secretion in β-cells.

    Evidence siRNA knockdown in INS1 cells, soluble receptor-fragment competition, and insulin/cAMP secretion assays

    PMID:30228187

    Open questions at the time
    • Single lab, two complementary methods
    • Signaling link between BAI3 and cAMP machinery not mapped
    • No in vivo confirmation in β-cells
  8. 2019 Medium

    Implicated BAI3 in testicular steroidogenesis as a C1QL4 receptor regulating StAR expression, while revealing it is not the sole receptor.

    Evidence siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay

    PMID:30608882

    Open questions at the time
    • Incomplete suppression indicates an additional unidentified C1QL4 receptor
    • Single lab
    • ERK1/2 and cAMP changes not mechanistically connected to receptor activation
  9. 2021 Medium

    Expanded the synaptic adhesion model by showing C1QL3 bridges ADGRB3 to neuronal pentraxins NPTX1/NPTXR in a trans-synaptic complex.

    Evidence In vivo Co-IP/MS interactome, cell-cell adhesion assay, and single-cell RNA-seq co-expression

    PMID:33337553

    Open questions at the time
    • Single lab
    • Functional consequence of the BAI3–pentraxin complex at synapses not established
    • Stoichiometry of the multi-protein complex undefined
  10. 2023 High

    Positioned Bai3 within the molecular logic of activity-dependent cerebellar synaptogenesis, downstream of GluD2 in climbing fiber synapse regulation.

    Evidence Bai3 KO × GluD2 KO epistasis, overexpression, electrophysiology, Ca2+ imaging, and IHC

    PMID:37488606

    Open questions at the time
    • Mechanistic link between GluD2 and C1ql1–Bai3 not defined
    • How neuronal activity gates the pathway unresolved
  11. 2023 Medium

    Defined organism-level consequences of BAI3 loss, revealing social-interaction deficits and a role in adaptive thermogenesis.

    Evidence CRISPR/Cas9 whole-body knockout mice with behavioral testing, CLAMS metabolic monitoring, MRI, and BAT gene expression

    PMID:37337931 PMID:37367869

    Open questions at the time
    • Single lab for each phenotype
    • Cell-type and ligand responsible for thermogenic and behavioral phenotypes not pinpointed
    • Direct link to the C1ql–BAI3 axis not established for these phenotypes
  12. 2025 High

    Provided the structural mechanism of C1ql–BAI3 recognition, showing calcium-mediated hexameric assembly and domain-swapping that clusters receptors for synapse maintenance.

    Evidence Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, biochemical reconstitution, and in vivo studies

    PMID:40316654 PMID:41372137

    Open questions at the time
    • How ligand clustering is transduced to GPCR/G-protein activation not resolved
    • Structural basis of activating vs repressive signaling not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How extracellular C1ql binding and clustering is mechanically coupled to BAI3 GPCR activation, G-protein subtype selection, and the switch between repressive (C1ql) and activating (Stabilin-2) inputs remains unresolved.
  • No structure of an activated, G-protein-coupled BAI3 state
  • G-protein subtype coupling not defined
  • Mechanism reconciling synapse-reducing and synapse-organizing effects of C1ql unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2 GO:0060089 molecular transducer activity 1 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1500931 Cell-Cell communication 1
Partners
C1QL1C1QL3ELMO1ELMO2NPTX1NPTXRSTAB2
Complex memberships
C1QL3–ADGRB3–NPTX1/NPTXR trans-synaptic adhesion complexC1ql3–BAI3 hexameric complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 All four C1q-like proteins (C1ql1-C1ql4) bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, mediated by the globular C1q domains of the C1ql proteins; addition of submicromolar C1ql proteins to cultured neurons decreased synapse density, and this was prevented by the thrombospondin-repeat fragment of BAI3. Biochemical binding assay (pulldown), neuronal culture synapse density assay with recombinant protein competition Proceedings of the National Academy of Sciences of the United States of America High 21262840
2014 BAI3 interacts with ELMO1/2 at the cell surface and is required for myoblast fusion in vertebrates; loss of BAI3 or ELMO1/2 severely impairs myoblast fusion without affecting differentiation, and BAI3 mutants deficient in ELMO binding cannot rescue the fusion defect; BAI1 cannot functionally substitute for BAI3 in this process. Co-immunoprecipitation, loss-of-function (siRNA/dominant-negative), in vivo embryonic muscle expression of ELMO-binding-deficient BAI3 mutant Proceedings of the National Academy of Sciences of the United States of America High 24567399
2013 BAI3 controls dendritic arborization growth and branching in neurons via activation of the RhoGTPase Rac1 and requires direct binding to ELMO1; knockdown of BAI3 or expression of ELMO-binding-deficient BAI3 in Purkinje cells in vivo impairs dendrite morphogenesis. Expression knockdown (shRNA/lentivirus), overexpression, transgenic mouse Purkinje cell-specific dominant-negative, Rac1 activation assay Molecular psychiatry High 23628982
2015 The C1QL1–BAI3 signaling pathway controls the stereotyped synaptic connectivity of excitatory afferents (parallel fibers and climbing fibers) on cerebellar Purkinje cells; restricted expression of C1QL1 in inferior olivary neurons determines proper climbing fiber synaptic territory. In vivo loss-of-function (knockout/knockdown), electrophysiology, immunohistochemistry in mouse cerebellum Cell reports High 25660030
2018 Stabilin-2 interacts with BAI3 and activates its GPCR activity, leading to recruitment of heterotrimeric G-proteins; activated G-proteins contribute to initial recruitment of ELMO proteins to the membrane, which are then stabilized on BAI3 through direct interaction, promoting myoblast fusion. C1q-like proteins (C1ql1-4) repress BAI3-mediated fusion by specifically interacting with BAI3. Mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after injury. Proteomic interactome screen, Co-IP, GPCR activity assay (BRET), BAI3 knockout mouse (cardiotoxin injury model), loss-of-function in myoblasts Nature communications High 30367035
2018 BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells; C1ql3 inhibits primarily cAMP-stimulated insulin secretion, and siRNA-mediated Bai3 knockdown increases glucose-stimulated insulin secretion; the soluble C1ql3-binding fragment of BAI3 blocks C1ql3's inhibitory effects on cAMP-stimulated insulin secretion. siRNA knockdown in INS1(832/13) cells, recombinant protein competition assay, insulin secretion assay, cAMP measurement The Journal of biological chemistry Medium 30228187
2021 C1QL3 mediates formation of a novel trans-synaptic adhesion complex involving ADGRB3/BAI3 and neuronal pentraxins NPTX1 and NPTXR; C1QL3 bridges ADGRB3 and the pentraxins in a cell-cell adhesion complex identified by in vivo interactome study. In vivo interactome (co-IP/MS), cell-cell adhesion assay, single-cell RNA-seq co-expression analysis FASEB journal Medium 33337553
2019 BAI3 (as a putative C1QL4 receptor) is expressed in seminiferous tubules and Leydig cells of the testis; Bai3 knockdown in Leydig cells reduces StAR expression and alters ERK1/2 phosphorylation and cAMP levels, indicating a role in steroidogenesis; C1QL4-induced StAR expression was not completely suppressed in Bai3-deficient cells, suggesting an additional unidentified receptor. siRNA knockdown in TM3 Leydig cells, Western blot, cAMP measurement, StAR expression assay FASEB journal Medium 30608882
2023 C1ql1–Bai3 signaling in adult cerebellum regulates climbing fiber synaptogenesis in mature Purkinje cells; overexpression of C1ql1 or Bai3 caused CF transverse branches to elongate and synapse on distal PC dendrites; GluD2 knockout-induced CF reinnervation was absent in Bai3 knockout PCs, placing Bai3 downstream of GluD2; C1ql1 levels increased in GluD2 KO CF, suggesting endogenous C1ql1-Bai3 signaling regulates reinnervation; effects required neuronal activity in both PCs and CFs. Genetic epistasis (Bai3 KO × GluD2 KO double mutant), overexpression, electrophysiology, Ca2+-imaging, immunohistochemistry in mouse cerebellum Molecular brain High 37488606
2025 Cryo-EM structure of the C1ql3–BAI3 complex at 2.8 Å resolution reveals a hexameric configuration: a central C1ql3 homotrimer captures three BAI3 molecules that fit into the grooves between trimeric C1q domains via calcium ion (Ca2+)-mediated interactions; mutant analysis confirmed essential contact residues. Single-particle cryo-EM (2.8 Å), site-directed mutagenesis, cell surface staining Communications biology High 40316654
2025 The trimeric gC1q domain of C1ql1 undergoes a calcium-modulated domain-swapping event to form a hexamer; cryo-EM structure reveals calcium ions stabilize the C1ql1 gC1q hexamer in complex with the extended CUB domain of BAI3; full-length C1ql1 further assembles into linear clusters to scaffold and accumulate BAI3 receptors on the plasma membrane; in vivo data support a role for gC1q-mediated dynamic assembly in receptor accumulation and synapse maintenance. Cryo-EM, biochemical reconstitution, computational analysis, cellular and in vivo studies Nature communications High 41372137
2023 Whole-body BAI3 knockout mice (CRISPR/Cas9, 7-bp deletion in exon 10) lack full-length ADGRB3 protein and display reduced brain and body weights and deficits in social interaction; locomotor function, olfaction, anxiety, and prepulse inhibition were not significantly different from wild-type. CRISPR/Cas9 knockout mouse, Western blot, behavioral testing Basic & clinical pharmacology & toxicology Medium 37337931
2023 Whole-body BAI3 knockout mice show increased energy expenditure and reduced body weight, with increased mRNA of thermogenic genes (Ucp1, Pgc1α, Prdm16, Elov3) in brown adipose tissue; energy expenditure differences were abolished at thermoneutrality (30°C), indicating a role for BAI3 in adaptive thermogenesis. CRISPR/Cas9 whole-body KO mouse, CLAMS metabolic monitoring, quantitative MRI, gene expression analysis Metabolites Medium 37367869
1997 BAI3 (then named BAI3) is specifically expressed in brain and maps to chromosomal locus 6q12; unlike BAI1, BAI3 expression is not transcriptionally regulated by p53; BAI3 expression is absent or significantly reduced in multiple glioblastoma cell lines. Northern blot, chromosomal mapping, cell line expression analysis Cytogenetics and cell genetics Low 9533023

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. Proceedings of the National Academy of Sciences of the United States of America 151 21262840
2015 The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells. Cell reports 112 25660030
2014 G-protein coupled receptor BAI3 promotes myoblast fusion in vertebrates. Proceedings of the National Academy of Sciences of the United States of America 98 24567399
1997 Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). Cytogenetics and cell genetics 93 9533023
2013 The adhesion-GPCR BAI3, a gene linked to psychiatric disorders, regulates dendrite morphogenesis in neurons. Molecular psychiatry 75 23628982
2004 Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma. FEBS letters 61 15225653
2018 Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. Nature communications 50 30367035
2013 BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas. Histopathology 43 24266897
2018 Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3. The Journal of biological chemistry 42 30228187
2021 C1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 33337553
2010 A multi-stage multi-design strategy provides strong evidence that the BAI3 locus is associated with early-onset venous thromboembolism. Journal of thrombosis and haemostasis : JTH 35 20946148
2019 Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder. European journal of human genetics : EJHG 25 30659260
2021 miR-142 downregulation alleviates the impairment of spatial learning and memory, reduces the level of apoptosis, and upregulates the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice. Behavioural brain research 18 34302879
2023 C1ql1-Bai3 signaling is necessary for climbing fiber synapse formation in mature Purkinje cells in coordination with neuronal activity. Molecular brain 17 37488606
2021 Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene. Translational psychiatry 16 34075027
2019 Expression patterns of C1ql4 and its cell-adhesion GPCR Bai3 in the murine testis and functional roles in steroidogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 30608882
2021 Perinatal SSRI Exposure Disrupts G Protein-coupled Receptor BAI3 in Developing Dentate Gyrus and Adult Emotional Behavior: Relevance to Psychiatric Disorders. Neuroscience 15 34293414
2022 Variants Within Genes EDIL3 and ADGRB3 are Associated With Divergent Fecal Egg Counts in Katahdin Sheep at Weaning. Frontiers in genetics 12 35360858
2023 Generation and initial characterization of mice lacking full-length BAI3 (ADGRB3) expression. Basic & clinical pharmacology & toxicology 10 37337931
2023 Loss of Brain Angiogenesis Inhibitor-3 (BAI3) G-Protein Coupled Receptor in Mice Regulates Adaptive Thermogenesis by Enhancing Energy Expenditure. Metabolites 10 37367869
2025 Structure of the complex of C1q-like 3 protein with adhesion-GPCR BAI3. Communications biology 7 40316654
2017 An investigation into the potential role of brain angiogenesis inhibitor protein 3 (BAI3) in the tumorigenesis of small-cell carcinoma: a review of the surrounding literature. Journal of receptor and signal transduction research 7 28537194
2025 Structural basis of calcium-dependent C1ql1/BAI3 assemblies in synaptic connectivity. Nature communications 1 41372137

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