{"gene":"ADGRV1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2006,"finding":"VLGR1 protein is localized to ankle links at the base of developing stereocilia in cochlear hair bundles; targeted deletion of the transmembrane and cytoplasmic domains (Vlgr1/del7TM) abolishes ankle link formation, causes stereocilia disorganization, impairs mechanotransduction (FM1-43 loading and whole-cell recordings), and results in severe deafness.","method":"Targeted mouse knockout, immunofluorescence/mass spectrometry identification of ankle link antigen, FM1-43 dye loading, whole-cell electrophysiology, auditory brainstem recordings","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal functional readouts (electrophysiology, ABR, DPOAE, histology), replicated in multiple studies","pmids":["16775142"],"is_preprint":false},{"year":2006,"finding":"Whirlin (DFNB31) directly associates with VLGR1b via PDZ domain interactions; whirlin, USH2A isoform b, and VLGR1b co-localize at the synaptic regions of photoreceptor and outer hair cells, the connecting cilium, and the outer limiting membrane, placing whirlin in the Usher protein interactome as a PDZ scaffold.","method":"Direct binding assays, co-immunoprecipitation, immunohistochemistry, co-localization confocal microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP with functional co-localization, replicated across subsequent studies","pmids":["16434480"],"is_preprint":false},{"year":2014,"finding":"VLGR1 undergoes autocleavage at its GPCR proteolytic site (GPS) into two fragments; the cleaved β-subunit constitutively inhibits adenylate cyclase via Gαi coupling, an R6002A mutation in intracellular loop 2 abolishes Gαi coupling, and PDZD7 overexpression reduces AC inhibition by the VLGR1 β-subunit but not by the pathogenic Y6236fsX1 mutant.","method":"Heterologous expression, cAMP assay, Gαiq chimera co-expression, mutagenesis, phospholipase C/NFAT reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro signaling assay with mutagenesis and chimeric G-protein validation, multiple orthogonal methods in single study","pmids":["24962568"],"is_preprint":false},{"year":2007,"finding":"Vlgr1 protein is localized to the base of stereocilia within ~200–400 nm of the apical surface of hair cells (confirmed by immunoelectron microscopy); loss of Vlgr1 causes progressive stereocilia disorganization starting at postnatal day 8 and hearing deficit measurable by ABR and DPOAE.","method":"Immunoelectron microscopy, confocal microscopy, ABR, DPOAE, Vlgr1 knockout mice","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization by immunoelectron microscopy with correlated functional loss-of-function phenotype","pmids":["17295842"],"is_preprint":false},{"year":2004,"finding":"Loss of the transmembrane and cytoplasmic domains of VLGR1 (Vlgr1/del7TM knock-in mice) causes audiogenic seizure susceptibility, demonstrating that the intracellular signaling domain is required to suppress the seizure phenotype.","method":"Gene targeting (knock-in producing truncated ectodomain), audiogenic seizure testing, Western blot","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 — clean genetic mouse model with specific domain deletion and defined behavioral phenotype, replicated by independent Vlgr1 KO studies","pmids":["15207856"],"is_preprint":false},{"year":2012,"finding":"Specific VLGR1 variant(s) are selectively trafficked to the basal pole of auditory hair cells in association with membrane microdomains and SNAP25; co-immunoprecipitation demonstrates a physical interaction between VLGR1 and SNAP25 in organ of Corti and brain, implicating VLGR1 in vesicle docking/fusion at the basolateral domain.","method":"Confocal colocalization, sucrose density gradients, vesicle trafficking inhibitors, co-immunoprecipitation","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional trafficking context, single lab","pmids":["23035094"],"is_preprint":false},{"year":2021,"finding":"VLGR1/ADGRV1 localizes to focal adhesions (FAs) and assembles FA protein complexes in situ; depletion of VLGR1 reduces FA number and length, decreases cell spreading and migration kinetics, and impairs response to mechanical stretch, identifying VLGR1 as a metabotropic mechanosensor in FAs.","method":"Affinity proteomics, immunofluorescence co-localization in hTERT-RPE1 cells and Vlgr1 mutant mouse astrocytes, cell spreading and migration assays, mechanical stretch assay, siRNA knockdown","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — affinity proteomics plus multiple orthogonal functional assays (spreading, migration, mechanosensing) in both cultured cells and mouse tissue","pmids":["33851099"],"is_preprint":false},{"year":2022,"finding":"VLGR1/ADGRV1 localizes to mitochondria-associated ER membranes (MAMs) and interacts with key MAM proteins (confirmed by pull-down and proximity ligation assays); absence of VLGR1 in mouse tissues alters MAM architecture and dysregulates Ca2+ transients from ER to mitochondria.","method":"Affinity proteomics, in vitro pull-down, proximity ligation assay, immunocytochemistry (light and electron microscopy), Ca2+ imaging in VLGR1-deficient models","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pull-down, PLA, EM, Ca2+ imaging) in single study with KO mouse validation","pmids":["36139365"],"is_preprint":false},{"year":2023,"finding":"ADGRV1 inhibits WHRN (whirlin) phosphorylation through regional cAMP-PKA signaling; phosphorylation of WHRN regulates USH2A ubiquitination and stability via the E3 ligase WDSUB1 (identified by yeast two-hybrid); the pathogenic Y6236fsX1 mutation disrupts ADGRV1 interactions with ALC components, causes stereocilia disorganization and MET deficits, and fails to suppress WHRN phosphorylation. NMR and FlAsH-BRET provided single-residue resolution of ALC interaction motifs.","method":"Adgrv1 Y6236fsX1 knock-in mice, yeast two-hybrid, FlAsH-BRET assay, NMR spectrometry, mutagenesis, ubiquitination assays, ABR/MET recordings","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-level mechanistic dissection (NMR, BRET, mutagenesis, in vivo KI mouse, yeast two-hybrid) with multiple orthogonal validations","pmids":["37066759"],"is_preprint":false},{"year":2022,"finding":"The two N-terminal PDZ domains of PDZD7 bind the C-terminal PDZ-binding motif (PBM) of ADGRV1 and form a supramodule stabilized upon PBM binding; deafness-causing mutations in PDZD7 PDZ binding grooves reduce stability and PBM-binding affinity, defining the molecular basis by which PDZD7 regulates ADGRV1 GPCR activity in hair cells.","method":"NMR, biophysical binding assays, mutagenesis of deafness variants","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with mutagenesis of disease-associated variants and functional binding quantification","pmids":["35836927"],"is_preprint":false},{"year":2023,"finding":"VLGR1/ADGRV1 interacts with key autophagosome components (identified by affinity proteomics); VLGR1 deficiency in hTERT-RPE1 cells and USH2C patient fibroblasts evokes autophagy as shown by increased LC3 and p62 marker levels, demonstrating a role for VLGR1 in regulating autophagy at internal membranes.","method":"Affinity proteomics, whole transcriptome sequencing (Vlgr1/del7TM retina), immunoblotting and immunocytochemistry of LC3/p62 in VLGR1-deficient cells and patient fibroblasts","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2-3 — affinity proteomics plus functional autophagy assay in KO cells and patient material, single lab","pmids":["37002809"],"is_preprint":false},{"year":2023,"finding":"ADGRV1 and CIB2 (USH1J protein) mutually interact and share a high-degree overlapping interactome; both USH proteins interact with the TRiC/CCT chaperonin complex and BBS chaperonin-like proteins, and co-localize at photoreceptor cilia, implicating ADGRV1 in primary cilia function.","method":"Tandem affinity purification + mass spectrometry, co-immunoprecipitation validation, immunohistochemistry on retinal sections","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — TAP-MS with co-IP validation and histological co-localization, single lab","pmids":["37427378"],"is_preprint":false},{"year":2023,"finding":"The usherin c.2299delG mutation causes mislocalization of usherin to the photoreceptor inner segment and concomitant mislocalization of VLGR1 (and whirlin), demonstrating that usherin is required for correct localization of VLGR1 within the USH2 protein complex at the connecting cilium.","method":"Ush2a c.2299delG knock-in mouse, immunofluorescence, ERG, OCT","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean knock-in mouse with specific localization readout, single study","pmids":["36810733"],"is_preprint":false},{"year":2023,"finding":"VLGR1 regulates de novo focal adhesion assembly: live-cell imaging of paxillin-DsRed2 with nocodazole washout and FRAP experiments show that VLGR1-deficient astrocytes have significantly delayed FA assembly and reduced FA turnover kinetics, without alteration of FA disassembly.","method":"Live-cell imaging (paxillin-DsRed2), nocodazole washout assay, FRAP, Vlgr1-deficient astrocytes","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging and FRAP with direct functional consequence, single lab","pmids":["36929698"],"is_preprint":false},{"year":2025,"finding":"ADGRV1 localizes to the base of primary cilia and interacts with TRiC/CCT chaperonins and BBS chaperonin-like proteins; in the absence of TRiC/CCT-BBS complex components, ADGRV1 is depleted from primary cilia and degraded via the proteasome; knockdown of ADGRV1, CCT2/3, or BBS6 each result in reduced ciliated cells and shorter primary cilia.","method":"Affinity proteomics, immunofluorescence, siRNA knockdown, proteasome inhibitor rescue, ciliogenesis quantification in cultured cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — affinity proteomics with knockdown phenotype and proteasome rescue, single lab","pmids":["40103630"],"is_preprint":false},{"year":2025,"finding":"Super-resolution STED nanoscopy in juvenile mouse hair cells revealed highly asymmetric subcellular localization of ADGRV1 (extracellular vs. GPCR domains) and PDZD7 across stereocilia rows and between IHC and OHC; the extracellular domain of ADGRV1 disappears after postnatal day 12 while the GPCR domain persists until P21, suggesting a post-scaffolding signaling role.","method":"STED super-resolution nanoscopy, immunolabeling with domain-specific antibodies in mouse cochlea","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — high-resolution spatial mapping with temporal resolution, single study","pmids":["40836926"],"is_preprint":false},{"year":2026,"finding":"ADGRV1 controls glutamate homeostasis in hippocampal astrocytes: affinity proteomics identified astrocyte-enriched interactors; ADGRV1-deficient astrocytes show reduced glutamate uptake (colorimetric assay and live cell imaging with genetic glutamate reporter), imbalanced glutamate-glutamine cycle enzyme expression, and reduced astrocyte numbers and altered morphology in Adgrv1-mutant mouse hippocampus.","method":"Affinity proteomics, transcriptomics (USH2C patient cells and Adgrv1 KO mouse hippocampus), colorimetric glutamate uptake assay, live-cell glutamate reporter imaging, morphometric analysis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in KO model and patient-derived cells, single lab","pmids":["42002803"],"is_preprint":false},{"year":2022,"finding":"Affinity proteomics of VLGR1/ADGRV1 identified novel binding partners and placed the receptor in functional modules including transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance; selected interactions were validated in vitro and in situ.","method":"Tandem affinity purification + mass spectrometry, GO term analysis, in vitro and in situ validation of selected interactions","journal":"Molecules","confidence":"Medium","confidence_rationale":"Tier 3 — comprehensive TAP-MS with partial follow-up validation, single lab","pmids":["35630584"],"is_preprint":false},{"year":2023,"finding":"In the adgrv1 CRISPR/Cas9 zebrafish model, absence of Adgrv1 at the photoreceptor connecting cilium leads to reduced levels of usherin and Whrnb at that site, increased aberrant rhodopsin localization in photoreceptor cell bodies, and decreased ERG B-wave amplitude, demonstrating a role for ADGRV1 in USH2 complex integrity and photoreceptor function.","method":"CRISPR/Cas9 zebrafish KO (4bp deletion in exon 9), immunohistochemistry, ERG","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO in ortholog model with multiple readouts (protein localization, rhodopsin trafficking, ERG), single lab","pmids":["37371069"],"is_preprint":false}],"current_model":"ADGRV1/VLGR1 is the largest adhesion GPCR that functions as: (1) a structural scaffold at stereocilia ankle links and photoreceptor connecting cilia, where it anchors the USH2 complex (usherin, whirlin/WHRN, PDZD7) and is required for hair bundle development and mechanotransduction; (2) an active Gαi-coupled signaling receptor whose cleaved β-subunit constitutively inhibits adenylate cyclase and, through local cAMP-PKA compartmentalization, suppresses WHRN phosphorylation to stabilize USH2A via WDSUB1-mediated ubiquitination; (3) a metabotropic mechanosensor at focal adhesions controlling FA assembly, cell spreading, and migration; (4) a regulator of Ca2+ homeostasis at mitochondria-associated ER membranes; (5) a modulator of autophagy and glutamate homeostasis in astrocytes; and (6) a ciliary receptor whose trafficking to primary cilia depends on the TRiC/CCT-BBS chaperonin complex, with its intracellular signaling domain engaging PDZD7 PDZ domains via a C-terminal PDZ-binding motif to regulate GPCR activity."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that the intracellular signaling domain of VLGR1 is required to suppress audiogenic seizures revealed that VLGR1 is not merely an extracellular adhesion molecule but actively signals intracellularly in the CNS.","evidence":"Vlgr1/del7TM knock-in mice lacking transmembrane and cytoplasmic domains tested with audiogenic seizure paradigm","pmids":["15207856"],"confidence":"High","gaps":["Downstream signaling pathway mediating seizure suppression not identified","Brain regions and cell types responsible not mapped"]},{"year":2006,"claim":"Identification of VLGR1 as the ankle link antigen in cochlear stereocilia and demonstration that its loss abolishes ankle links, disorganizes hair bundles, and eliminates mechanotransduction established the core structural role of VLGR1 in hair cell development.","evidence":"Vlgr1/del7TM knockout mice analyzed by immunoelectron microscopy, FM1-43 dye loading, whole-cell recordings, and ABR","pmids":["16775142","17295842"],"confidence":"High","gaps":["Molecular composition of the ankle link filament beyond VLGR1 ectodomain not determined","Whether VLGR1 signals at stereocilia or acts only as a scaffold was unresolved"]},{"year":2006,"claim":"Demonstration that whirlin directly binds VLGR1b via PDZ domains and co-localizes with USH2A at photoreceptor and hair cell synapses placed VLGR1 at the center of an Usher syndrome protein interactome.","evidence":"Direct binding assays, reciprocal co-immunoprecipitation, and confocal co-localization in retina and cochlea","pmids":["16434480"],"confidence":"High","gaps":["Stoichiometry and assembly order of the USH2 complex not defined","Functional consequence of whirlin–VLGR1 interaction for signaling not tested"]},{"year":2012,"claim":"Discovery that a VLGR1 splice variant traffics to the basolateral pole of hair cells and physically interacts with SNAP25 suggested a role in polarized vesicle docking beyond the stereocilia apex.","evidence":"Confocal co-localization, sucrose density gradients, co-immunoprecipitation in organ of Corti and brain","pmids":["23035094"],"confidence":"Medium","gaps":["No functional rescue or loss-of-function vesicle trafficking assay performed","Interaction not validated by reciprocal pulldown with tagged SNAP25","Single lab finding"]},{"year":2014,"claim":"Demonstrating that the GPS-cleaved VLGR1 β-subunit constitutively inhibits adenylate cyclase via Gαi, with PDZD7 modulating this activity, resolved whether VLGR1 is an active GPCR rather than an inert adhesion molecule.","evidence":"Heterologous cAMP assays with Gαiq chimeras, ICL2 R6002A mutagenesis abolishing coupling, PDZD7 co-expression reducing AC inhibition","pmids":["24962568"],"confidence":"High","gaps":["Whether Gαi coupling occurs in native hair cells not shown","Endogenous ligand or activation trigger unknown"]},{"year":2021,"claim":"Localization of VLGR1 to focal adhesions and demonstration that its depletion impairs FA number, cell spreading, migration, and mechanical stretch response extended VLGR1 function from sensory epithelia to general metabotropic mechanosensing.","evidence":"Affinity proteomics, siRNA knockdown in hTERT-RPE1, and Vlgr1-mutant mouse astrocytes with cell spreading, migration, and stretch assays","pmids":["33851099"],"confidence":"High","gaps":["Signaling pathway downstream of VLGR1 at focal adhesions not identified","Whether Gαi coupling mediates the FA phenotype not tested"]},{"year":2022,"claim":"Structural determination of the PDZD7 PDZ1-2 supramodule binding the ADGRV1 C-terminal PBM, with deafness mutations reducing affinity, defined the molecular basis of PDZD7-mediated regulation of ADGRV1 GPCR activity.","evidence":"NMR structure, biophysical binding assays, mutagenesis of deafness-associated PDZD7 variants","pmids":["35836927"],"confidence":"High","gaps":["In vivo consequences of disrupting PDZ–PBM interaction in animal models not tested","Whether other PDZ proteins compete for the same motif unknown"]},{"year":2022,"claim":"Localization of VLGR1 to mitochondria-associated ER membranes and demonstration that its absence dysregulates ER-to-mitochondria Ca²⁺ transfer uncovered a novel role in intracellular Ca²⁺ homeostasis.","evidence":"Pull-down, proximity ligation assay, immunoelectron microscopy, and Ca²⁺ imaging in Vlgr1-deficient mouse tissues and cells","pmids":["36139365"],"confidence":"High","gaps":["Mechanism by which VLGR1 organizes MAM tethering complexes not delineated","Downstream consequences for mitochondrial function (respiration, apoptosis) not measured"]},{"year":2023,"claim":"Reconstitution of a cAMP-PKA-WHRN phosphorylation-WDSUB1 ubiquitination axis downstream of ADGRV1, disrupted by the pathogenic Y6236fsX1 mutation, provided the first complete signaling pathway from ADGRV1 to USH2A protein stability in stereocilia.","evidence":"Adgrv1 Y6236fsX1 knock-in mice, NMR, FlAsH-BRET, yeast two-hybrid identification of WDSUB1, ubiquitination and ABR/MET recordings","pmids":["37066759"],"confidence":"High","gaps":["Whether WDSUB1-mediated ubiquitination of USH2A is degradative or regulatory not resolved","Spatial compartmentalization of PKA at ankle links not directly imaged"]},{"year":2023,"claim":"Zebrafish adgrv1 knockout confirmed ADGRV1 is required for USH2 complex integrity at the connecting cilium and for rhodopsin trafficking, validating the receptor's conserved role in photoreceptor function across vertebrates.","evidence":"CRISPR/Cas9 zebrafish KO with immunohistochemistry showing reduced usherin/Whrnb at connecting cilium and aberrant rhodopsin, plus decreased ERG B-wave","pmids":["37371069"],"confidence":"Medium","gaps":["Mouse photoreceptor degeneration phenotype from Adgrv1 loss alone is mild; whether complete loss in mammalian retina suffices for RP is unclear","Single lab, single allele"]},{"year":2023,"claim":"Demonstrating that VLGR1 deficiency evokes autophagy (increased LC3/p62) in RPE cells and USH2C patient fibroblasts linked ADGRV1 to membrane stress responses beyond adhesion and signaling.","evidence":"Affinity proteomics identifying autophagosome components, immunoblotting of LC3/p62 in VLGR1-KO cells and patient fibroblasts","pmids":["37002809"],"confidence":"Medium","gaps":["Whether autophagy induction is a direct effect or secondary to ER/MAM Ca²⁺ disruption not distinguished","Flux assays (bafilomycin block) not performed"]},{"year":2025,"claim":"Identification of TRiC/CCT-BBS chaperonins as required for ADGRV1 ciliary trafficking and ciliogenesis revealed the quality-control pathway that delivers ADGRV1 to primary cilia.","evidence":"Affinity proteomics, siRNA knockdown of CCT2/3 and BBS6 causing ADGRV1 proteasomal degradation and reduced cilia number/length, proteasome inhibitor rescue","pmids":["40103630"],"confidence":"Medium","gaps":["Direct client–chaperone binding not demonstrated by in vitro reconstitution","Whether this pathway operates in photoreceptor connecting cilia in vivo not tested"]},{"year":2025,"claim":"Super-resolution STED imaging revealed that ADGRV1 extracellular and GPCR domains are asymmetrically distributed across stereocilia rows and temporally uncoupled—the ectodomain disappears by P12 while the GPCR domain persists—supporting a transition from structural scaffolding to post-scaffolding signaling.","evidence":"STED nanoscopy with domain-specific antibodies in postnatal mouse cochlea at multiple time points","pmids":["40836926"],"confidence":"Medium","gaps":["Functional consequence of retained GPCR domain after ectodomain loss not tested","Whether GPS cleavage produces the observed temporal pattern not verified"]},{"year":2026,"claim":"Discovery that ADGRV1 controls glutamate uptake and glutamate–glutamine cycle enzyme expression in hippocampal astrocytes expanded its function to CNS neurotransmitter homeostasis.","evidence":"Affinity proteomics, transcriptomics, colorimetric glutamate uptake assay and live-cell glutamate reporter in Adgrv1-KO astrocytes and USH2C patient cells","pmids":["42002803"],"confidence":"Medium","gaps":["Signaling pathway connecting ADGRV1 to glutamate transporter regulation not identified","Whether glutamate homeostasis defect contributes to seizure susceptibility not tested"]},{"year":null,"claim":"The endogenous ligand or mechanical stimulus that activates ADGRV1 signaling in any tissue remains unknown, and it is unresolved whether the Gαi pathway demonstrated in heterologous cells operates at focal adhesions, MAMs, or cilia in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous ligand identified","In vivo Gαi coupling in native tissues not demonstrated","How ADGRV1 integrates its multiple subcellular signaling pools is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,9]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,11,12,14,18]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,6,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,9]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,3,4,18]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,6,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[11,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,16]}],"complexes":["USH2 complex (usherin/USH2A, whirlin/WHRN, PDZD7, ADGRV1)"],"partners":["WHRN","USH2A","PDZD7","WDSUB1","CIB2","SNAP25","CCT2","BBS6"],"other_free_text":[]},"mechanistic_narrative":"ADGRV1 (VLGR1) is the largest adhesion G protein-coupled receptor, functioning as a structural scaffold and active signaling receptor essential for sensory hair cell mechanotransduction, photoreceptor maintenance, ciliary biology, and astrocyte homeostasis. At developing cochlear stereocilia, ADGRV1 forms ankle links and organizes the Usher type 2 (USH2) protein complex with usherin, whirlin (WHRN), and PDZD7; its targeted deletion abolishes ankle links, disorganizes hair bundles, eliminates mechanotransduction, and causes deafness and audiogenic seizure susceptibility [PMID:16775142, PMID:15207856]. Following GPS autocleavage, the ADGRV1 β-subunit constitutively inhibits adenylate cyclase via Gαi coupling, and through compartmentalized cAMP-PKA signaling suppresses WHRN phosphorylation to stabilize USH2A via the E3 ligase WDSUB1; PDZD7 modulates this signaling through a PDZ supramodule that engages the ADGRV1 C-terminal PDZ-binding motif [PMID:24962568, PMID:37066759, PMID:35836927]. Beyond the inner ear and retina, ADGRV1 localizes to focal adhesions where it controls de novo FA assembly and mechanosensing, to mitochondria-associated ER membranes where it regulates ER-to-mitochondria Ca²⁺ transfer, and to primary cilia where its trafficking depends on TRiC/CCT-BBS chaperonins; in hippocampal astrocytes it maintains glutamate uptake and the glutamate–glutamine cycle [PMID:33851099, PMID:36139365, PMID:40103630, PMID:42002803]."},"prefetch_data":{"uniprot":{"accession":"Q8WXG9","full_name":"Adhesion G-protein coupled receptor V1","aliases":["G-protein coupled receptor 98","Monogenic audiogenic seizure susceptibility protein 1 homolog","Usher syndrome type-2C protein","Very large G-protein coupled receptor 1"],"length_aa":6306,"mass_kda":693.1,"function":"G-protein coupled receptor which has an essential role in the development of hearing and vision. Couples to G-alpha(i)-proteins, GNAI1/2/3, G-alpha(q)-proteins, GNAQ, as well as G-alpha(s)-proteins, GNAS, inhibiting adenylate cyclase (AC) activity and cAMP production. Required for the hair bundle ankle formation, which connects growing stereocilia in developing cochlear hair cells of the inner ear. In response to extracellular calcium, activates kinases PKA and PKC to regulate myelination by inhibiting the ubiquitination of MAG, thus enhancing the stability of this protein in myelin-forming cells of the auditory pathway. In retina photoreceptors, the USH2 complex is required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport. Involved in the regulation of bone metabolism Cleaved ADGRV1 beta-subunit couples with G-alpha(i)-proteins, GNAI1/2/3, and constitutively inhibits adenylate cyclase (AC) activity with a stronger effect than full ADGRV1","subcellular_location":"Cell membrane; Cell projection, stereocilium membrane; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/Q8WXG9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRV1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRV1","total_profiled":1310},"omim":[{"mim_id":"620802","title":"WD REPEAT-, STERILE ALPHA MOTIF-, AND U-BOX DOMAIN-CONTAINING PROTEIN 1; WDSUB1","url":"https://www.omim.org/entry/620802"},{"mim_id":"619332","title":"LYSOSOMAL ENZYME TRAFFICKING FACTOR; LYSET","url":"https://www.omim.org/entry/619332"},{"mim_id":"618190","title":"LUNG CANCER-ASSOCIATED TRANSCRIPT 1, NONCODING; LUCAT1","url":"https://www.omim.org/entry/618190"},{"mim_id":"612971","title":"PDZ DOMAIN-CONTAINING 7; PDZD7","url":"https://www.omim.org/entry/612971"},{"mim_id":"605472","title":"USHER SYNDROME, TYPE IIC; USH2C","url":"https://www.omim.org/entry/605472"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":494.7}],"url":"https://www.proteinatlas.org/search/ADGRV1"},"hgnc":{"alias_symbol":["DKFZp761P0710","KIAA0686","FEB4","VLGR1"],"prev_symbol":["USH2C","MASS1","GPR98"]},"alphafold":{"accession":"Q8WXG9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXG9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXG9-4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXG9-4-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADGRV1","jax_strain_url":"https://www.jax.org/strain/search?query=ADGRV1"},"sequence":{"accession":"Q8WXG9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXG9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXG9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXG9"}},"corpus_meta":[{"pmid":"14740321","id":"PMC_14740321","title":"Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14740321","citation_count":271,"is_preprint":false},{"pmid":"16775142","id":"PMC_16775142","title":"The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16775142","citation_count":172,"is_preprint":false},{"pmid":"16434480","id":"PMC_16434480","title":"The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.","date":"2006","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16434480","citation_count":156,"is_preprint":false},{"pmid":"15207856","id":"PMC_15207856","title":"Loss of the transmembrane and cytoplasmic domains 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targeted deletion of the transmembrane and cytoplasmic domains (Vlgr1/del7TM) abolishes ankle link formation, causes stereocilia disorganization, impairs mechanotransduction (FM1-43 loading and whole-cell recordings), and results in severe deafness.\",\n      \"method\": \"Targeted mouse knockout, immunofluorescence/mass spectrometry identification of ankle link antigen, FM1-43 dye loading, whole-cell electrophysiology, auditory brainstem recordings\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal functional readouts (electrophysiology, ABR, DPOAE, histology), replicated in multiple studies\",\n      \"pmids\": [\"16775142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Whirlin (DFNB31) directly associates with VLGR1b via PDZ domain interactions; whirlin, USH2A isoform b, and VLGR1b co-localize at the synaptic regions of photoreceptor and outer hair cells, the connecting cilium, and the outer limiting membrane, placing whirlin in the Usher protein interactome as a PDZ scaffold.\",\n      \"method\": \"Direct binding assays, co-immunoprecipitation, immunohistochemistry, co-localization confocal microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with functional co-localization, replicated across subsequent studies\",\n      \"pmids\": [\"16434480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VLGR1 undergoes autocleavage at its GPCR proteolytic site (GPS) into two fragments; the cleaved β-subunit constitutively inhibits adenylate cyclase via Gαi coupling, an R6002A mutation in intracellular loop 2 abolishes Gαi coupling, and PDZD7 overexpression reduces AC inhibition by the VLGR1 β-subunit but not by the pathogenic Y6236fsX1 mutant.\",\n      \"method\": \"Heterologous expression, cAMP assay, Gαiq chimera co-expression, mutagenesis, phospholipase C/NFAT reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro signaling assay with mutagenesis and chimeric G-protein validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24962568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Vlgr1 protein is localized to the base of stereocilia within ~200–400 nm of the apical surface of hair cells (confirmed by immunoelectron microscopy); loss of Vlgr1 causes progressive stereocilia disorganization starting at postnatal day 8 and hearing deficit measurable by ABR and DPOAE.\",\n      \"method\": \"Immunoelectron microscopy, confocal microscopy, ABR, DPOAE, Vlgr1 knockout mice\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by immunoelectron microscopy with correlated functional loss-of-function phenotype\",\n      \"pmids\": [\"17295842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss of the transmembrane and cytoplasmic domains of VLGR1 (Vlgr1/del7TM knock-in mice) causes audiogenic seizure susceptibility, demonstrating that the intracellular signaling domain is required to suppress the seizure phenotype.\",\n      \"method\": \"Gene targeting (knock-in producing truncated ectodomain), audiogenic seizure testing, Western blot\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic mouse model with specific domain deletion and defined behavioral phenotype, replicated by independent Vlgr1 KO studies\",\n      \"pmids\": [\"15207856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Specific VLGR1 variant(s) are selectively trafficked to the basal pole of auditory hair cells in association with membrane microdomains and SNAP25; co-immunoprecipitation demonstrates a physical interaction between VLGR1 and SNAP25 in organ of Corti and brain, implicating VLGR1 in vesicle docking/fusion at the basolateral domain.\",\n      \"method\": \"Confocal colocalization, sucrose density gradients, vesicle trafficking inhibitors, co-immunoprecipitation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional trafficking context, single lab\",\n      \"pmids\": [\"23035094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VLGR1/ADGRV1 localizes to focal adhesions (FAs) and assembles FA protein complexes in situ; depletion of VLGR1 reduces FA number and length, decreases cell spreading and migration kinetics, and impairs response to mechanical stretch, identifying VLGR1 as a metabotropic mechanosensor in FAs.\",\n      \"method\": \"Affinity proteomics, immunofluorescence co-localization in hTERT-RPE1 cells and Vlgr1 mutant mouse astrocytes, cell spreading and migration assays, mechanical stretch assay, siRNA knockdown\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — affinity proteomics plus multiple orthogonal functional assays (spreading, migration, mechanosensing) in both cultured cells and mouse tissue\",\n      \"pmids\": [\"33851099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VLGR1/ADGRV1 localizes to mitochondria-associated ER membranes (MAMs) and interacts with key MAM proteins (confirmed by pull-down and proximity ligation assays); absence of VLGR1 in mouse tissues alters MAM architecture and dysregulates Ca2+ transients from ER to mitochondria.\",\n      \"method\": \"Affinity proteomics, in vitro pull-down, proximity ligation assay, immunocytochemistry (light and electron microscopy), Ca2+ imaging in VLGR1-deficient models\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pull-down, PLA, EM, Ca2+ imaging) in single study with KO mouse validation\",\n      \"pmids\": [\"36139365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADGRV1 inhibits WHRN (whirlin) phosphorylation through regional cAMP-PKA signaling; phosphorylation of WHRN regulates USH2A ubiquitination and stability via the E3 ligase WDSUB1 (identified by yeast two-hybrid); the pathogenic Y6236fsX1 mutation disrupts ADGRV1 interactions with ALC components, causes stereocilia disorganization and MET deficits, and fails to suppress WHRN phosphorylation. NMR and FlAsH-BRET provided single-residue resolution of ALC interaction motifs.\",\n      \"method\": \"Adgrv1 Y6236fsX1 knock-in mice, yeast two-hybrid, FlAsH-BRET assay, NMR spectrometry, mutagenesis, ubiquitination assays, ABR/MET recordings\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level mechanistic dissection (NMR, BRET, mutagenesis, in vivo KI mouse, yeast two-hybrid) with multiple orthogonal validations\",\n      \"pmids\": [\"37066759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The two N-terminal PDZ domains of PDZD7 bind the C-terminal PDZ-binding motif (PBM) of ADGRV1 and form a supramodule stabilized upon PBM binding; deafness-causing mutations in PDZD7 PDZ binding grooves reduce stability and PBM-binding affinity, defining the molecular basis by which PDZD7 regulates ADGRV1 GPCR activity in hair cells.\",\n      \"method\": \"NMR, biophysical binding assays, mutagenesis of deafness variants\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis of disease-associated variants and functional binding quantification\",\n      \"pmids\": [\"35836927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VLGR1/ADGRV1 interacts with key autophagosome components (identified by affinity proteomics); VLGR1 deficiency in hTERT-RPE1 cells and USH2C patient fibroblasts evokes autophagy as shown by increased LC3 and p62 marker levels, demonstrating a role for VLGR1 in regulating autophagy at internal membranes.\",\n      \"method\": \"Affinity proteomics, whole transcriptome sequencing (Vlgr1/del7TM retina), immunoblotting and immunocytochemistry of LC3/p62 in VLGR1-deficient cells and patient fibroblasts\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — affinity proteomics plus functional autophagy assay in KO cells and patient material, single lab\",\n      \"pmids\": [\"37002809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADGRV1 and CIB2 (USH1J protein) mutually interact and share a high-degree overlapping interactome; both USH proteins interact with the TRiC/CCT chaperonin complex and BBS chaperonin-like proteins, and co-localize at photoreceptor cilia, implicating ADGRV1 in primary cilia function.\",\n      \"method\": \"Tandem affinity purification + mass spectrometry, co-immunoprecipitation validation, immunohistochemistry on retinal sections\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — TAP-MS with co-IP validation and histological co-localization, single lab\",\n      \"pmids\": [\"37427378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The usherin c.2299delG mutation causes mislocalization of usherin to the photoreceptor inner segment and concomitant mislocalization of VLGR1 (and whirlin), demonstrating that usherin is required for correct localization of VLGR1 within the USH2 protein complex at the connecting cilium.\",\n      \"method\": \"Ush2a c.2299delG knock-in mouse, immunofluorescence, ERG, OCT\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knock-in mouse with specific localization readout, single study\",\n      \"pmids\": [\"36810733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VLGR1 regulates de novo focal adhesion assembly: live-cell imaging of paxillin-DsRed2 with nocodazole washout and FRAP experiments show that VLGR1-deficient astrocytes have significantly delayed FA assembly and reduced FA turnover kinetics, without alteration of FA disassembly.\",\n      \"method\": \"Live-cell imaging (paxillin-DsRed2), nocodazole washout assay, FRAP, Vlgr1-deficient astrocytes\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging and FRAP with direct functional consequence, single lab\",\n      \"pmids\": [\"36929698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADGRV1 localizes to the base of primary cilia and interacts with TRiC/CCT chaperonins and BBS chaperonin-like proteins; in the absence of TRiC/CCT-BBS complex components, ADGRV1 is depleted from primary cilia and degraded via the proteasome; knockdown of ADGRV1, CCT2/3, or BBS6 each result in reduced ciliated cells and shorter primary cilia.\",\n      \"method\": \"Affinity proteomics, immunofluorescence, siRNA knockdown, proteasome inhibitor rescue, ciliogenesis quantification in cultured cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity proteomics with knockdown phenotype and proteasome rescue, single lab\",\n      \"pmids\": [\"40103630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Super-resolution STED nanoscopy in juvenile mouse hair cells revealed highly asymmetric subcellular localization of ADGRV1 (extracellular vs. GPCR domains) and PDZD7 across stereocilia rows and between IHC and OHC; the extracellular domain of ADGRV1 disappears after postnatal day 12 while the GPCR domain persists until P21, suggesting a post-scaffolding signaling role.\",\n      \"method\": \"STED super-resolution nanoscopy, immunolabeling with domain-specific antibodies in mouse cochlea\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — high-resolution spatial mapping with temporal resolution, single study\",\n      \"pmids\": [\"40836926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADGRV1 controls glutamate homeostasis in hippocampal astrocytes: affinity proteomics identified astrocyte-enriched interactors; ADGRV1-deficient astrocytes show reduced glutamate uptake (colorimetric assay and live cell imaging with genetic glutamate reporter), imbalanced glutamate-glutamine cycle enzyme expression, and reduced astrocyte numbers and altered morphology in Adgrv1-mutant mouse hippocampus.\",\n      \"method\": \"Affinity proteomics, transcriptomics (USH2C patient cells and Adgrv1 KO mouse hippocampus), colorimetric glutamate uptake assay, live-cell glutamate reporter imaging, morphometric analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in KO model and patient-derived cells, single lab\",\n      \"pmids\": [\"42002803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Affinity proteomics of VLGR1/ADGRV1 identified novel binding partners and placed the receptor in functional modules including transcriptional regulation, splicing, cell cycle regulation, ciliogenesis, cell adhesion, neuronal development, and retinal maintenance; selected interactions were validated in vitro and in situ.\",\n      \"method\": \"Tandem affinity purification + mass spectrometry, GO term analysis, in vitro and in situ validation of selected interactions\",\n      \"journal\": \"Molecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — comprehensive TAP-MS with partial follow-up validation, single lab\",\n      \"pmids\": [\"35630584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the adgrv1 CRISPR/Cas9 zebrafish model, absence of Adgrv1 at the photoreceptor connecting cilium leads to reduced levels of usherin and Whrnb at that site, increased aberrant rhodopsin localization in photoreceptor cell bodies, and decreased ERG B-wave amplitude, demonstrating a role for ADGRV1 in USH2 complex integrity and photoreceptor function.\",\n      \"method\": \"CRISPR/Cas9 zebrafish KO (4bp deletion in exon 9), immunohistochemistry, ERG\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in ortholog model with multiple readouts (protein localization, rhodopsin trafficking, ERG), single lab\",\n      \"pmids\": [\"37371069\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRV1/VLGR1 is the largest adhesion GPCR that functions as: (1) a structural scaffold at stereocilia ankle links and photoreceptor connecting cilia, where it anchors the USH2 complex (usherin, whirlin/WHRN, PDZD7) and is required for hair bundle development and mechanotransduction; (2) an active Gαi-coupled signaling receptor whose cleaved β-subunit constitutively inhibits adenylate cyclase and, through local cAMP-PKA compartmentalization, suppresses WHRN phosphorylation to stabilize USH2A via WDSUB1-mediated ubiquitination; (3) a metabotropic mechanosensor at focal adhesions controlling FA assembly, cell spreading, and migration; (4) a regulator of Ca2+ homeostasis at mitochondria-associated ER membranes; (5) a modulator of autophagy and glutamate homeostasis in astrocytes; and (6) a ciliary receptor whose trafficking to primary cilia depends on the TRiC/CCT-BBS chaperonin complex, with its intracellular signaling domain engaging PDZD7 PDZ domains via a C-terminal PDZ-binding motif to regulate GPCR activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADGRV1 (VLGR1) is the largest adhesion G protein-coupled receptor, functioning as a structural scaffold and active signaling receptor essential for sensory hair cell mechanotransduction, photoreceptor maintenance, ciliary biology, and astrocyte homeostasis. At developing cochlear stereocilia, ADGRV1 forms ankle links and organizes the Usher type 2 (USH2) protein complex with usherin, whirlin (WHRN), and PDZD7; its targeted deletion abolishes ankle links, disorganizes hair bundles, eliminates mechanotransduction, and causes deafness and audiogenic seizure susceptibility [PMID:16775142, PMID:15207856]. Following GPS autocleavage, the ADGRV1 β-subunit constitutively inhibits adenylate cyclase via Gαi coupling, and through compartmentalized cAMP-PKA signaling suppresses WHRN phosphorylation to stabilize USH2A via the E3 ligase WDSUB1; PDZD7 modulates this signaling through a PDZ supramodule that engages the ADGRV1 C-terminal PDZ-binding motif [PMID:24962568, PMID:37066759, PMID:35836927]. Beyond the inner ear and retina, ADGRV1 localizes to focal adhesions where it controls de novo FA assembly and mechanosensing, to mitochondria-associated ER membranes where it regulates ER-to-mitochondria Ca²⁺ transfer, and to primary cilia where its trafficking depends on TRiC/CCT-BBS chaperonins; in hippocampal astrocytes it maintains glutamate uptake and the glutamate–glutamine cycle [PMID:33851099, PMID:36139365, PMID:40103630, PMID:42002803].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that the intracellular signaling domain of VLGR1 is required to suppress audiogenic seizures revealed that VLGR1 is not merely an extracellular adhesion molecule but actively signals intracellularly in the CNS.\",\n      \"evidence\": \"Vlgr1/del7TM knock-in mice lacking transmembrane and cytoplasmic domains tested with audiogenic seizure paradigm\",\n      \"pmids\": [\"15207856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway mediating seizure suppression not identified\", \"Brain regions and cell types responsible not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of VLGR1 as the ankle link antigen in cochlear stereocilia and demonstration that its loss abolishes ankle links, disorganizes hair bundles, and eliminates mechanotransduction established the core structural role of VLGR1 in hair cell development.\",\n      \"evidence\": \"Vlgr1/del7TM knockout mice analyzed by immunoelectron microscopy, FM1-43 dye loading, whole-cell recordings, and ABR\",\n      \"pmids\": [\"16775142\", \"17295842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular composition of the ankle link filament beyond VLGR1 ectodomain not determined\", \"Whether VLGR1 signals at stereocilia or acts only as a scaffold was unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that whirlin directly binds VLGR1b via PDZ domains and co-localizes with USH2A at photoreceptor and hair cell synapses placed VLGR1 at the center of an Usher syndrome protein interactome.\",\n      \"evidence\": \"Direct binding assays, reciprocal co-immunoprecipitation, and confocal co-localization in retina and cochlea\",\n      \"pmids\": [\"16434480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the USH2 complex not defined\", \"Functional consequence of whirlin–VLGR1 interaction for signaling not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that a VLGR1 splice variant traffics to the basolateral pole of hair cells and physically interacts with SNAP25 suggested a role in polarized vesicle docking beyond the stereocilia apex.\",\n      \"evidence\": \"Confocal co-localization, sucrose density gradients, co-immunoprecipitation in organ of Corti and brain\",\n      \"pmids\": [\"23035094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue or loss-of-function vesicle trafficking assay performed\", \"Interaction not validated by reciprocal pulldown with tagged SNAP25\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that the GPS-cleaved VLGR1 β-subunit constitutively inhibits adenylate cyclase via Gαi, with PDZD7 modulating this activity, resolved whether VLGR1 is an active GPCR rather than an inert adhesion molecule.\",\n      \"evidence\": \"Heterologous cAMP assays with Gαiq chimeras, ICL2 R6002A mutagenesis abolishing coupling, PDZD7 co-expression reducing AC inhibition\",\n      \"pmids\": [\"24962568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Gαi coupling occurs in native hair cells not shown\", \"Endogenous ligand or activation trigger unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Localization of VLGR1 to focal adhesions and demonstration that its depletion impairs FA number, cell spreading, migration, and mechanical stretch response extended VLGR1 function from sensory epithelia to general metabotropic mechanosensing.\",\n      \"evidence\": \"Affinity proteomics, siRNA knockdown in hTERT-RPE1, and Vlgr1-mutant mouse astrocytes with cell spreading, migration, and stretch assays\",\n      \"pmids\": [\"33851099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of VLGR1 at focal adhesions not identified\", \"Whether Gαi coupling mediates the FA phenotype not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural determination of the PDZD7 PDZ1-2 supramodule binding the ADGRV1 C-terminal PBM, with deafness mutations reducing affinity, defined the molecular basis of PDZD7-mediated regulation of ADGRV1 GPCR activity.\",\n      \"evidence\": \"NMR structure, biophysical binding assays, mutagenesis of deafness-associated PDZD7 variants\",\n      \"pmids\": [\"35836927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequences of disrupting PDZ–PBM interaction in animal models not tested\", \"Whether other PDZ proteins compete for the same motif unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localization of VLGR1 to mitochondria-associated ER membranes and demonstration that its absence dysregulates ER-to-mitochondria Ca²⁺ transfer uncovered a novel role in intracellular Ca²⁺ homeostasis.\",\n      \"evidence\": \"Pull-down, proximity ligation assay, immunoelectron microscopy, and Ca²⁺ imaging in Vlgr1-deficient mouse tissues and cells\",\n      \"pmids\": [\"36139365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which VLGR1 organizes MAM tethering complexes not delineated\", \"Downstream consequences for mitochondrial function (respiration, apoptosis) not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reconstitution of a cAMP-PKA-WHRN phosphorylation-WDSUB1 ubiquitination axis downstream of ADGRV1, disrupted by the pathogenic Y6236fsX1 mutation, provided the first complete signaling pathway from ADGRV1 to USH2A protein stability in stereocilia.\",\n      \"evidence\": \"Adgrv1 Y6236fsX1 knock-in mice, NMR, FlAsH-BRET, yeast two-hybrid identification of WDSUB1, ubiquitination and ABR/MET recordings\",\n      \"pmids\": [\"37066759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WDSUB1-mediated ubiquitination of USH2A is degradative or regulatory not resolved\", \"Spatial compartmentalization of PKA at ankle links not directly imaged\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Zebrafish adgrv1 knockout confirmed ADGRV1 is required for USH2 complex integrity at the connecting cilium and for rhodopsin trafficking, validating the receptor's conserved role in photoreceptor function across vertebrates.\",\n      \"evidence\": \"CRISPR/Cas9 zebrafish KO with immunohistochemistry showing reduced usherin/Whrnb at connecting cilium and aberrant rhodopsin, plus decreased ERG B-wave\",\n      \"pmids\": [\"37371069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mouse photoreceptor degeneration phenotype from Adgrv1 loss alone is mild; whether complete loss in mammalian retina suffices for RP is unclear\", \"Single lab, single allele\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that VLGR1 deficiency evokes autophagy (increased LC3/p62) in RPE cells and USH2C patient fibroblasts linked ADGRV1 to membrane stress responses beyond adhesion and signaling.\",\n      \"evidence\": \"Affinity proteomics identifying autophagosome components, immunoblotting of LC3/p62 in VLGR1-KO cells and patient fibroblasts\",\n      \"pmids\": [\"37002809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether autophagy induction is a direct effect or secondary to ER/MAM Ca²⁺ disruption not distinguished\", \"Flux assays (bafilomycin block) not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of TRiC/CCT-BBS chaperonins as required for ADGRV1 ciliary trafficking and ciliogenesis revealed the quality-control pathway that delivers ADGRV1 to primary cilia.\",\n      \"evidence\": \"Affinity proteomics, siRNA knockdown of CCT2/3 and BBS6 causing ADGRV1 proteasomal degradation and reduced cilia number/length, proteasome inhibitor rescue\",\n      \"pmids\": [\"40103630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct client–chaperone binding not demonstrated by in vitro reconstitution\", \"Whether this pathway operates in photoreceptor connecting cilia in vivo not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Super-resolution STED imaging revealed that ADGRV1 extracellular and GPCR domains are asymmetrically distributed across stereocilia rows and temporally uncoupled—the ectodomain disappears by P12 while the GPCR domain persists—supporting a transition from structural scaffolding to post-scaffolding signaling.\",\n      \"evidence\": \"STED nanoscopy with domain-specific antibodies in postnatal mouse cochlea at multiple time points\",\n      \"pmids\": [\"40836926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of retained GPCR domain after ectodomain loss not tested\", \"Whether GPS cleavage produces the observed temporal pattern not verified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery that ADGRV1 controls glutamate uptake and glutamate–glutamine cycle enzyme expression in hippocampal astrocytes expanded its function to CNS neurotransmitter homeostasis.\",\n      \"evidence\": \"Affinity proteomics, transcriptomics, colorimetric glutamate uptake assay and live-cell glutamate reporter in Adgrv1-KO astrocytes and USH2C patient cells\",\n      \"pmids\": [\"42002803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway connecting ADGRV1 to glutamate transporter regulation not identified\", \"Whether glutamate homeostasis defect contributes to seizure susceptibility not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous ligand or mechanical stimulus that activates ADGRV1 signaling in any tissue remains unknown, and it is unresolved whether the Gαi pathway demonstrated in heterologous cells operates at focal adhesions, MAMs, or cilia in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous ligand identified\", \"In vivo Gαi coupling in native tissues not demonstrated\", \"How ADGRV1 integrates its multiple subcellular signaling pools is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 11, 12, 14, 18]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 6, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 9]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 3, 4, 18]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 6, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [11, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"complexes\": [\n      \"USH2 complex (usherin/USH2A, whirlin/WHRN, PDZD7, ADGRV1)\"\n    ],\n    \"partners\": [\n      \"WHRN\",\n      \"USH2A\",\n      \"PDZD7\",\n      \"WDSUB1\",\n      \"CIB2\",\n      \"SNAP25\",\n      \"CCT2\",\n      \"BBS6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}