{"gene":"ADGRL3","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2020,"finding":"ADGRL3 signals through G12/G13 and Gq upon acute tethered agonist (TA) exposure, with G12/13 being the most robustly activated G protein pathway, as determined by an engineered acute activation strategy using controlled enzymatic proteolysis in living cells.","method":"Engineered tethered agonist acute activation assay (controlled enzymatic proteolysis of receptor construct in living cells), G protein activation assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel acute activation strategy with direct functional readout, multiple G protein pathways tested, single lab but multiple orthogonal methods","pmids":["32778842"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of ADGRL3 in complex with Gq, Gs, Gi, and G12 revealed the unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation, including the uncharted structural information of GPCR/G12 coupling. The far end of αH5 of Gα is the key determinant of G-protein coupling selectivity, and mutations designed from the structures specifically enhance one G-protein pathway over others.","method":"Cryo-electron microscopy (cryo-EM) structure determination, mutagenesis of G protein coupling determinants, functional validation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with four G protein complexes plus mutagenesis validation, multiple orthogonal approaches in one study","pmids":["36309016"],"is_preprint":false},{"year":2022,"finding":"Autoproteolytic cleavage at the GPS site of ADGRL3 encodes biased signaling: cleavage-deficient ADGRL3 retains constitutive activity but shows a signaling bias that potentiates select G proteins (Gi2 and G12/13), revealing that GPS cleavage modulates G protein coupling selectivity rather than simply enabling or abolishing signaling.","method":"BRET-based G protein biosensors, autoproteolysis-deficient ADGRL3 mutant, constitutive activity assays","journal":"Basic & clinical pharmacology & toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BRET biosensors with cleavage-deficient mutant, single lab, two methods (BRET + mutagenesis)","pmids":["37464463"],"is_preprint":false},{"year":2022,"finding":"Mutating the sixth and seventh residues of the ADGRL3 tethered agonist (Leu and Met to Ala) impairs G protein coupling without affecting autoproteolytic cleavage or cell-surface expression, demonstrating that tethered agonism and autoproteolysis are separable functions. Extended N-terminal additions to the TA in the CTF also disrupt G protein signaling, suggesting the TA must be fully exposed for optimal orthosteric pocket interaction.","method":"Site-directed mutagenesis, serum response element (SRE) activity assay, acute TA-exposure assay (controlled proteolysis), immunoblotting, cell surface expression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutagenesis with multiple functional readouts (SRE assay, acute activation, immunoblot), multiple orthogonal methods, single lab","pmids":["36244455"],"is_preprint":false},{"year":2025,"finding":"For full-length ADGRL3, approximately 5% of receptor spontaneously sheds its N-terminal fragment (NTF) in heterologous cells, and this shedding is required for tethered agonist-mediated G protein signaling: a full-length cleavage-deficient mutant loses ~80% of Gα13 signaling and shows ~20% of the spontaneous NTF shedding observed in WT receptor.","method":"Heterologous cell expression, NTF shedding quantification, Gα13 signaling assay, full-length cleavage-deficient ADGRL3 mutant, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct quantification of shedding, cleavage-deficient mutant, signaling assay, multiple orthogonal methods in single rigorous study","pmids":["39798870"],"is_preprint":false},{"year":2026,"finding":"Direct tensile force applied to the N-terminus of Adgrl3 via optical tweezers is sufficient to induce G protein recruitment in living cells. Activation is direction-specific, requires a functional tethered agonist, and is accompanied by force-driven GAIN domain conformational changes and dissociation, demonstrating that ADGRL3 functions as a mechanosensor.","method":"Optical tweezers (single-molecule force application), G protein recruitment assay in living cells, GAIN domain conformational monitoring","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct mechanical activation with G protein recruitment readout, novel method, single lab preprint not yet peer reviewed","pmids":["42124579"],"is_preprint":true},{"year":2023,"finding":"ADGRL3 signals via autoproteolytic cleavage-dependent tethered agonist mechanism. An antibody (LK30) engineered to bind the extracellular region of ADGRL3 acts as an agonist specific to ADGRL3 but not its isoform ADGRL1. The LK30 binding site on ADGRL3 overlaps with the teneurin binding site; LK30 specifically disrupts the trans-cellular ADGRL3–teneurin interaction but not the ADGRL3–FLRT3 interaction, demonstrating ligand-specific and isoform-specific modulation.","method":"Antibody engineering, X-ray crystallography of LK30/ADGRL3 complex, cellular adhesion assays, isoform-specificity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of antibody-receptor complex combined with functional cellular adhesion assays, multiple orthogonal methods, single lab","pmids":["36746957"],"is_preprint":false},{"year":2014,"finding":"LPHN3 (ADGRL3) is a presynaptic protein that regulates synapse number: shRNA knockdown in mouse layer 2/3 pyramidal neurons reduced the density of synapses formed by L2/3 axons in layer 5 and weakened the strength of L2/3 afferent input to L5 without affecting probability of release. The Olfactomedin domain of LPHN3 is required for binding to FLRT3 and for rescuing the presynaptic density deficit. Both the Olfactomedin and Lectin domains are involved in binding to Teneurin 1. Single particle negative-stain EM showed the Olfactomedin and Lectin domains form a globular domain on an elongated stalk.","method":"shRNA knockdown in vivo, optogenetic circuit interrogation, Synaptophysin-GFP anatomical marker, cell-based binding experiments with domain mutants, single particle negative stain electron microscopy","journal":"Neural development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (optogenetics, synaptic density quantification, domain-mutant binding assays, EM), single lab","pmids":["24739570"],"is_preprint":false},{"year":2022,"finding":"Cancer-related somatic mutations in the GAIN domain of Lphn3 (ADGRL3) impair receptor signaling through G13 for all non-homologous amino acid substitution variants, and the S810L mutation additionally impairs cell-autonomous motility and alters actin-dependent cell-matrix contact structures and vimentin remodeling. GAIN domain mutations produce ligand-specific impairment of Lphn3 intercellular adhesion while leaving intra-GAIN cleavage efficiency unaltered.","method":"Cancer somatic mutation introduction, G13 signaling assay, cell migration assays (collective and individual), actin and vimentin immunofluorescence, cell-matrix adhesion assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (signaling, migration, adhesion) with multiple mutants, single lab","pmids":["35741042"],"is_preprint":false},{"year":2023,"finding":"LPHN3 (ADGRL3) engages G proteins via the tethered agonist (TA) mechanism dependent on autoproteolytic cleavage, as demonstrated by the finding that CELSR1 and CELSR3 (cleavage-deficient) retain G protein coupling activity through TA point mutants, while LPHN3's autoproteolysis is distinct. Specifically, acute TA exposure alone (without cleavage) is insufficient for CELSR2 GαS coupling enhancement, supporting that ADGRL3 signals via multiple paradigms.","method":"Autoproteolysis assays, TA point mutagenesis, GαS coupling assays, comparative analysis across aGPCR family members","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal comparison across family members, multiple mutants and assay types, single lab but peer-reviewed","pmids":["37224017"],"is_preprint":false},{"year":2012,"finding":"Loss of lphn3.1 (zebrafish ortholog of LPHN3/ADGRL3) function causes reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype was rescued by methylphenidate and atomoxetine.","method":"Morpholino knockdown in zebrafish, immunofluorescence for dopaminergic neurons, locomotor behavioral assays, pharmacological rescue","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific cellular (neuronal) and behavioral phenotypes, pharmacological rescue, replicated in independent studies across species","pmids":["22508465"],"is_preprint":false},{"year":2012,"finding":"Lphn3 null mice show increased dopamine and serotonin levels in the dorsal striatum, altered expression of dopamine and serotonin receptors/transporters (Dat1, Drd4, 5Htt, 5Ht2a), changes in neurotransmitter metabolism genes (Th, Gad1), and changes in neural developmental genes (Nurr, Ncam), along with a hyperactive phenotype and increased sensitivity to cocaine-induced locomotion.","method":"Gene-trap knockout mice, TaqMan gene expression assays, monoamine tissue level measurement, open-field locomotor test, cocaine challenge","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout with multiple molecular (gene expression, monoamine levels) and behavioral readouts, single lab","pmids":["22575564"],"is_preprint":false},{"year":2019,"finding":"Adgrl3-/- mice show increased locomotive activity, increased impulsivity, spatial memory impairment, and decreased aggression. RNA-sequencing of prefrontal cortex, hippocampus, and striatum revealed Slc6a3 (dopamine transporter) as the most dysregulated gene in the PFC, with enrichment of dopaminergic synapse pathways, implicating dopamine transporter dysregulation as a mechanism underlying ADHD-like phenotypes.","method":"Constitutive Adgrl3 knockout mice, multiple behavioral paradigms, RNA-sequencing of three brain regions, gene-set analysis","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with behavioral and transcriptomic phenotyping, multiple brain regions, single lab","pmids":["30849401"],"is_preprint":false},{"year":2020,"finding":"Lphn3 knockout rats show higher amplitude of dopamine release transients in striatum, with markedly decreased duration and interevent time compared to wild-type, as measured by fast-scan cyclic voltammetry in brain slices, demonstrating LPHN3 plays a role in regulating dopamine signaling dynamics.","method":"Fast-scan cyclic voltammetry in ex vivo brain slices, Lphn3 knockout rats","journal":"ACS chemical neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct electrophysiological measurement of dopamine release dynamics in KO vs WT, rigorous ex vivo method, single lab","pmids":["32203648"],"is_preprint":false},{"year":2025,"finding":"ADGRL3 knockout mice show increased electrically-evoked dopamine release across the striatum ex vivo (fast-scan cyclic voltammetry), but reduced task-induced dopamine signals in the nucleus accumbens in vivo (fiber photometry with dopamine sensor). Amphetamine-evoked release was unchanged, suggesting ADGRL3 modulates dopamine release via distinct pre- and postsynaptic mechanisms rather than dopamine availability.","method":"Ex vivo fast-scan cyclic voltammetry, in vivo fiber photometry with dopamine sensor, ADGRL3 knockout mice, amphetamine challenge","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (ex vivo FSCV and in vivo photometry) in KO mice, single lab, preprint","pmids":["40766670"],"is_preprint":true},{"year":2021,"finding":"Lphn3 knockout rats are impaired in egocentric (Cincinnati water maze) and allocentric (Morris water maze) spatial learning and memory, with reduced early-LTP (but not late-LTP) in hippocampal CA1 and reduced hippocampal NMDA-NR1 expression. Conditioned freezing, novel object recognition, and temporal order recognition were unaffected, indicating a selective role for LPHN3 in certain forms of learning and memory.","method":"Lphn3 knockout rats, multiple water maze tasks, LTP electrophysiology in CA1, NMDA receptor western blotting, behavioral battery","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (behavior, electrophysiology, protein expression), clean KO with selective phenotype pattern, single lab","pmids":["34352385"],"is_preprint":false},{"year":2016,"finding":"An ultraconserved noncoding element within ADGRL3 (evolutionary conserved region 47, ECR47) functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in ECR47 (rs17226398, rs56038622, rs2271338) reduced enhancer activity by ~40% in neuroblastoma and astrocytoma cells. The rs2271338 risk allele disrupts binding of the YY1 transcription factor, linking noncoding ADGRL3 variants to reduced expression.","method":"Luciferase reporter assays, electromobility shift assays (EMSA), zebrafish GFP transgenesis for enhancer activity, family-based genetic analysis, eQTL analysis of postmortem brain","journal":"Biological psychiatry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal functional methods (luciferase, EMSA, in vivo zebrafish transgenesis), single lab","pmids":["27692237"],"is_preprint":false},{"year":2018,"finding":"In zebrafish lphn3.1 morphants (knockdown of zebrafish LPHN3 ortholog), hyposensitivity to both dopamine agonists (apomorphine, quinpirole, SKF-38393) and antagonists (haloperidol, eticlopride, SCH-23390) was observed for locomotor activity, consistent with a model of saturated (maximal) dopaminergic neurotransmission in lphn3.1 morphants.","method":"Morpholino knockdown in zebrafish, pharmacological challenge with dopamine receptor agonists and antagonists, locomotor activity assay","journal":"Progress in neuro-psychopharmacology & biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological characterization with multiple dopamine receptor ligands in loss-of-function model, single lab","pmids":["29496512"],"is_preprint":false},{"year":2016,"finding":"Loss of Lphn3 in null mice increases both reward motivation (instrumental responding under high response ratios) and activity levels. Primary hippocampal and cortical neuron cultures from null mice display enhanced neurite outgrowth after 2–3 days in vitro. Transcriptome analysis shows differential gene expression particularly for cell adhesion molecules and calcium signaling proteins, with attenuation of DGE with age.","method":"Lphn3 knockout mice, instrumental responding behavioral task, forced swim test, primary neuronal culture with neurite outgrowth measurement, brain region transcriptome analysis","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockout with behavioral, cellular (neurite outgrowth), and transcriptomic phenotyping, multiple methods, single lab","pmids":["27247960"],"is_preprint":false},{"year":2023,"finding":"adgrl3.1-deficient zebrafish show externalizing behaviors (hyperactivity, impulsivity, risk-taking, attentional deficits) that are rescued by atomoxetine (a norepinephrine reuptake inhibitor), demonstrating noradrenergic mediation of the behavioral effects of adgrl3.1 loss. Transcriptomic analysis revealed differentially expressed genes and enriched gene clusters independent of noradrenergic manipulation, suggesting additional functional pathways.","method":"adgrl3.1 knockout zebrafish, behavioral battery (hyperactivity, impulsivity, attention, novelty), pharmacological rescue with atomoxetine, brain transcriptomics","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pharmacological rescue and transcriptomics, single lab, multiple behavioral readouts","pmids":["37783687"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of Lphn3 specifically in tyrosine hydroxylase (TH)-positive catecholaminergic neurons (Lphn3-Th-Cre) causes hyperactivity and egocentric navigation deficits similar to (but less severe than) global Lphn3 KO rats, establishing that LPHN3 in dopaminergic/noradrenergic neurons is a key contributor to the hyperactivity and navigation phenotypes. Allocentric navigation deficits seen in global KO were absent in the conditional KO, implying non-catecholaminergic cell contributions to spatial learning.","method":"Conditional KO (Cre-lox, Th-Cre x floxed Lphn3), global KO comparison, behavioral battery (CWM, MWM), striatal TH and dopamine receptor immunohistochemistry, hippocampal NMDA receptor Western blot","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional vs global KO comparison with behavioral and molecular phenotyping, single lab, preprint","pmids":["bio_10.1101_2024.12.27.630427"],"is_preprint":true},{"year":2025,"finding":"adgrl3.1 knockout zebrafish show disrupted cortisol regulation: lower baseline cortisol levels with an increased cortisol response to an acute stressor (conspecific alarm substance), along with altered expression of bdnf and gr. These animals also show increased anxiety-like behavior and impaired cognitive flexibility under stress, linking adgrl3.1 to HPA-axis stress reactivity.","method":"adgrl3.1 knockout zebrafish, cortisol measurement (baseline and stress-induced), bdnf and gr gene expression, behavioral anxiety and cognitive flexibility assays","journal":"Behavioural brain research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KO with physiological (cortisol) and behavioral readouts, gene expression, single lab","pmids":["40639688"],"is_preprint":false}],"current_model":"ADGRL3 (LPHN3) is a brain-enriched adhesion GPCR that undergoes autoproteolytic cleavage at its GAIN domain GPS site to generate noncovalently associated N-terminal and C-terminal fragments; spontaneous NTF shedding exposes a tethered agonist (TA) that inserts into the orthosteric pocket to activate G proteins—primarily G12/13 and Gq—and direct tensile force on the extracellular N-terminus can also activate the receptor in a TA-dependent manner, acting as a mechanosensor. At synapses, ADGRL3 acts presynaptically via its Olfactomedin domain (which binds the postsynaptic ligand FLRT3) to promote synapse formation and regulate synapse number, while its Lectin domain also contributes to Teneurin-1 binding; loss of ADGRL3 reduces synaptic density, impairs spatial learning and memory, reduces hippocampal LTP and NMDA receptor expression, and dysregulates striatal dopamine release dynamics, collectively producing hyperactivity, impulsivity, and dopaminergic circuit disturbances linked to ADHD susceptibility."},"narrative":{"mechanistic_narrative":"ADGRL3 (LPHN3) is a brain-enriched adhesion GPCR that couples synaptic adhesion to intracellular G protein signaling and is genetically and functionally linked to dopaminergic circuit regulation and ADHD-like behaviors [PMID:24739570, PMID:30849401]. The receptor undergoes autoproteolysis at its GAIN-domain GPS site to generate noncovalently associated fragments; spontaneous shedding of the N-terminal fragment (~5% of full-length receptor) exposes a tethered agonist that inserts into the orthosteric pocket and is required for G protein signaling, with cleavage-deficient receptor losing ~80% of Gα13 signaling [PMID:39798870]. Upon acute tethered-agonist exposure ADGRL3 preferentially activates G12/13 and Gq, and cryo-EM structures of the receptor bound to Gq, Gs, Gi, and G12 define the activation conformation and the αH5 determinants of coupling selectivity [PMID:32778842, PMID:36309016]. Tethered agonism and autoproteolysis are separable functions—mutating the sixth and seventh TA residues impairs coupling without affecting cleavage—and GPS cleavage biases coupling toward select G proteins rather than acting as a simple on/off switch [PMID:37464463, PMID:36244455]. Direct tensile force on the N-terminus drives GAIN-domain conformational change and TA-dependent G protein recruitment, establishing ADGRL3 as a mechanosensor [PMID:42124579]. At synapses ADGRL3 acts presynaptically through its Olfactomedin domain, which binds postsynaptic FLRT3 and is required to maintain synapse number, while the Olfactomedin and Lectin domains together mediate Teneurin-1 binding; an engineered agonist antibody (LK30) selectively disrupts the ADGRL3–teneurin but not the ADGRL3–FLRT3 interaction [PMID:36746957, PMID:24739570]. Loss of ADGRL3 across zebrafish, mice, and rats produces hyperactivity, impulsivity, and selective spatial learning and memory deficits with reduced hippocampal early-LTP and NMDA-NR1 expression, accompanied by dysregulated striatal dopamine release dynamics [PMID:22508465, PMID:32203648, PMID:34352385]. These phenotypes arise substantially from ADGRL3 function in catecholaminergic neurons [PMID:bio_10.1101_2024.12.27.630427], and a noncoding ADHD-risk haplotype in an ADGRL3 intronic enhancer (ECR47) reduces enhancer activity by disrupting YY1 binding, linking reduced ADGRL3 expression to disease risk [PMID:27692237].","teleology":[{"year":2012,"claim":"Established that loss of ADGRL3 causes dopaminergic developmental abnormalities and a hyperactive/impulsive phenotype, framing the receptor as a candidate ADHD gene with a defined neurochemical substrate.","evidence":"Morpholino knockdown in zebrafish with dopaminergic neuron imaging and pharmacological rescue; gene-trap knockout mice with monoamine and gene-expression profiling","pmids":["22508465","22575564"],"confidence":"High","gaps":["Did not define how ADGRL3 acts molecularly at synapses","Cell type responsible for dopaminergic phenotype not resolved"]},{"year":2014,"claim":"Defined ADGRL3 as a presynaptic adhesion molecule that controls synapse number through specific extracellular domains, connecting its adhesion ligands to circuit assembly.","evidence":"In vivo shRNA knockdown, optogenetic circuit interrogation, domain-mutant binding to FLRT3 and Teneurin-1, negative-stain EM","pmids":["24739570"],"confidence":"High","gaps":["Did not connect adhesion function to intracellular G protein signaling","Postsynaptic consequences of altered synapse number not quantified"]},{"year":2016,"claim":"Linked ADGRL3 expression level to ADHD risk by showing a risk haplotype in an intronic enhancer reduces transcription via loss of a defined transcription-factor interaction.","evidence":"Luciferase reporter, EMSA, zebrafish enhancer transgenesis, family genetics and brain eQTL","pmids":["27692237"],"confidence":"High","gaps":["Did not establish the magnitude of expression change in vivo in human brain","Other regulatory elements not surveyed"]},{"year":2016,"claim":"Extended ADGRL3 loss-of-function phenotypes to reward motivation and neuronal morphology, implicating adhesion and calcium-signaling gene programs.","evidence":"Knockout mice with instrumental responding, primary neuron neurite outgrowth, brain transcriptomics","pmids":["27247960"],"confidence":"Medium","gaps":["Causal link between transcriptomic changes and behavior not established","Single lab"]},{"year":2018,"claim":"Characterized the dopaminergic signaling state of ADGRL3-deficient animals as maximally saturated neurotransmission, refining the mechanism behind hyperactivity.","evidence":"Zebrafish morphants challenged with dopamine receptor agonists and antagonists in locomotor assays","pmids":["29496512"],"confidence":"Medium","gaps":["Pharmacological inference rather than direct release measurement","Morpholino knockdown specificity"]},{"year":2019,"claim":"Pinpointed the dopamine transporter (Slc6a3) as the top dysregulated gene in prefrontal cortex of ADGRL3 knockouts, nominating a transcriptional route to dopaminergic dysfunction.","evidence":"Constitutive knockout mice, multi-paradigm behavior, RNA-seq across three brain regions","pmids":["30849401"],"confidence":"Medium","gaps":["Causality between Slc6a3 dysregulation and behavior not tested","Mechanism linking ADGRL3 loss to transporter expression unknown"]},{"year":2020,"claim":"Resolved which G proteins ADGRL3 engages, showing tethered-agonist exposure preferentially activates G12/13 and Gq and providing the first acute activation handle on the receptor.","evidence":"Engineered acute tethered-agonist activation via controlled proteolysis in living cells with G protein activation assays","pmids":["32778842"],"confidence":"High","gaps":["Structural basis of coupling selectivity not yet defined","Endogenous activation trigger in neurons unresolved"]},{"year":2020,"claim":"Demonstrated directly that ADGRL3 shapes the kinetics of striatal dopamine release, moving beyond steady-state monoamine levels to dynamic signaling.","evidence":"Fast-scan cyclic voltammetry in ex vivo brain slices from knockout rats","pmids":["32203648"],"confidence":"High","gaps":["Pre- versus postsynaptic locus of the effect not distinguished","Link to G protein signaling not made"]},{"year":2022,"claim":"Provided cryo-EM structures of ADGRL3 with four G proteins and identified αH5 as the coupling-selectivity determinant, enabling rational design of pathway-biased mutants.","evidence":"Cryo-EM of ADGRL3–Gq/Gs/Gi/G12 complexes with mutagenesis and functional validation","pmids":["36309016"],"confidence":"High","gaps":["Full-length receptor and NTF interactions not captured","Mechanosensory conformations not visualized"]},{"year":2022,"claim":"Dissected the relationship between autoproteolysis and tethered agonism, showing they are separable and that GPS cleavage biases rather than gates G protein coupling.","evidence":"Site-directed TA mutagenesis with SRE and acute activation assays; BRET biosensors with cleavage-deficient mutant","pmids":["36244455","37464463"],"confidence":"High","gaps":["Physiological regulation of cleavage state in neurons unknown","Bias outcomes for downstream effectors not mapped"]},{"year":2022,"claim":"Connected GAIN-domain cancer mutations to impaired G13 signaling, adhesion, and cytoskeletal/motility defects, broadening ADGRL3 function beyond neurons.","evidence":"Somatic mutation introduction with G13 signaling, migration, adhesion assays, actin/vimentin imaging","pmids":["35741042"],"confidence":"Medium","gaps":["Relevance to actual tumor biology not demonstrated","Single lab"]},{"year":2023,"claim":"Generated an isoform- and ligand-specific antibody agonist that maps the teneurin binding site and confirms cleavage-dependent tethered-agonist signaling.","evidence":"Antibody engineering, X-ray crystallography of LK30/ADGRL3, adhesion and isoform-specificity assays","pmids":["36746957"],"confidence":"High","gaps":["In vivo activity of LK30 not established","How teneurin disruption affects signaling output not quantified"]},{"year":2023,"claim":"Placed ADGRL3 within a comparative aGPCR framework, confirming its TA-dependent coupling differs from cleavage-independent family members.","evidence":"Autoproteolysis and TA point-mutant comparisons with GαS coupling across CELSR family members","pmids":["37224017"],"confidence":"Medium","gaps":["Single mechanistic paradigm not fully resolved for ADGRL3","Endogenous ligand-driven coupling not tested"]},{"year":2023,"claim":"Implicated noradrenergic signaling in ADGRL3 behavioral phenotypes and revealed additional transcriptomic pathways independent of that mediation.","evidence":"adgrl3.1 knockout zebrafish behavior with atomoxetine rescue and brain transcriptomics","pmids":["37783687"],"confidence":"Medium","gaps":["Noradrenergic versus dopaminergic contributions not separated mechanistically","Identity of transcriptomic effectors unconfirmed"]},{"year":2025,"claim":"Quantified spontaneous NTF shedding of full-length receptor and showed it is required for tethered-agonist signaling, defining the rate-limiting activation step.","evidence":"Heterologous expression, NTF shedding quantification, Gα13 assays with cleavage-deficient mutant","pmids":["39798870"],"confidence":"High","gaps":["Trigger for spontaneous shedding in vivo unknown","Relationship between shedding and ligand/force not resolved"]},{"year":2025,"claim":"Localized the hyperactivity and egocentric navigation phenotypes to ADGRL3 function within catecholaminergic neurons while assigning allocentric deficits to other cell types.","evidence":"Th-Cre conditional knockout versus global knockout rats with behavioral and molecular phenotyping","pmids":["bio_10.1101_2024.12.27.630427"],"confidence":"Medium","gaps":["Preprint, not peer reviewed","Non-catecholaminergic cell types responsible for spatial deficits unidentified"]},{"year":2025,"claim":"Reconciled increased ex vivo evoked dopamine release with reduced task-related in vivo signals, indicating distinct pre- and postsynaptic regulatory mechanisms.","evidence":"Ex vivo FSCV and in vivo fiber photometry with dopamine sensor in knockout mice, amphetamine challenge","pmids":["40766670"],"confidence":"Medium","gaps":["Preprint, not peer reviewed","Molecular mediators of the pre/post split not identified"]},{"year":2026,"claim":"Demonstrated that mechanical force on the N-terminus directly activates ADGRL3 in a TA-dependent, direction-specific manner, establishing it as a mechanosensor.","evidence":"Optical-tweezer single-molecule force application with G protein recruitment readout and GAIN conformational monitoring in living cells","pmids":["42124579"],"confidence":"Medium","gaps":["Preprint, not peer reviewed","Physiological source of force at synapses unknown"]},{"year":null,"claim":"How ADGRL3's adhesion ligands, autoproteolytic shedding, mechanosensation, and biased G protein coupling are integrated to control dopamine release and ADHD-relevant behavior in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No link established between specific G protein pathway and dopamine release phenotype in neurons","Endogenous activating ligand/force at synapses not identified","Downstream effectors connecting ADGRL3 signaling to NMDA receptor and transporter expression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6,7,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,13,15]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["FLRT3","TENM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAR2","full_name":"Adhesion G protein-coupled receptor L3","aliases":["Calcium-independent alpha-latrotoxin receptor 3","CIRL-3","Latrophilin-3","Lectomedin-3"],"length_aa":1447,"mass_kda":161.8,"function":"Orphan adhesion G-protein coupled receptor (aGPCR), which mediates synapse specificity (PubMed:35418682). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35418682). ADGRL3 is coupled with different classes of G alpha proteins, such as G(12)/G(13), G(s), G(i) or G(q), depending on the context (PubMed:35418682). Coupling to G(12)/G(13) G proteins, which mediates the activation Rho small GTPases is the most efficient (PubMed:35418682). Following G-protein coupled receptor activation, associates with cell adhesion molecules that are expressed at the surface of adjacent cells to direct synapse specificity (PubMed:26235030). Specifically mediates the establishment of Schaffer-collateral synapses formed by CA3-region axons on CA1-region pyramidal neurons in the hippocampus (By similarity). Localizes to postsynaptic spines in excitatory synapses in the S.oriens and S.radiatum and interacts with presynaptic cell adhesion molecules FLRT3 and TENM2, promoting synapse formation (By similarity). Plays a role in the development of glutamatergic synapses in the cortex (By similarity). Important in determining the connectivity rates between the principal neurons in the cortex (By similarity) Orphan adhesion G-protein coupled receptor (aGPCR), which mediates synapse specificity. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. Isoform 1 is specifically coupled to G(s) G proteins and mediates activation of adenylate cyclase activity. Following G-protein coupled receptor activation, undergoes liquid-liquid phase transition, associates with (1) cell adhesion molecules that are expressed at the surface of adjacent cells, as well as (2) PDZ-containing proteins, such as SHANK3 and DLG4, in the cytoplasm to direct synapse formation","subcellular_location":"Cell membrane; Postsynaptic cell membrane; Cell projection, axon; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q9HAR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADGRL3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADGRL3","total_profiled":1310},"omim":[{"mim_id":"616417","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L3; ADGRL3","url":"https://www.omim.org/entry/616417"},{"mim_id":"616416","title":"ADHESION G PROTEIN-COUPLED RECEPTOR L1; 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The Journal of the Pakistan Medical Association","url":"https://pubmed.ncbi.nlm.nih.gov/39948777","citation_count":0,"is_preprint":false},{"pmid":"40766670","id":"PMC_40766670","title":"Altered striatal dopamine regulation in ADGRL3 knockout mice.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40766670","citation_count":0,"is_preprint":false},{"pmid":"41722825","id":"PMC_41722825","title":"Gene × environment interaction between latrophilin-3 (Lphn3 or Adgrl3) and developmental permethrin exposure in Sprague Dawley rats.","date":"2026","source":"Neurotoxicology and teratology","url":"https://pubmed.ncbi.nlm.nih.gov/41722825","citation_count":0,"is_preprint":false},{"pmid":"41805372","id":"PMC_41805372","title":"Discovery of Novel Pyrano[3,2-a]carbazole Alkaloid Derivatives against Ischemic Stroke by Targeting ADGRL3.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41805372","citation_count":0,"is_preprint":false},{"pmid":"42124579","id":"PMC_42124579","title":"Direct tensile force activates Adgrl3 in a tethered agonist-dependent manner.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42124579","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.31.667389","title":"Altered striatal dopamine regulation in  <i>ADGRL3</i>  knockout mice","date":"2025-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.31.667389","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.27.630427","title":"<i>Latrophilin-3</i>  conditional knockout in tyrosine hydroxylase neurons (  <i>Lphn3-Th- Cre</i>  ) Compared with  <i>Lphn3</i>  Global KO rats: Role of  <i>Lphn3</i>  in Tyrosine Hydroxylase Neurons on the Cognitive and Behavioral Effects of this ADHD Susceptibility Gene","date":"2024-12-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.27.630427","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.27.640360","title":"Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model","date":"2025-02-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.27.640360","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.19.613974","title":"Social Isolation Intensifies  <i>adgrl3.1</i>  -Related Externalizing and Internalizing Behaviors in Zebrafish","date":"2024-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.19.613974","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35450,"output_tokens":6040,"usd":0.098475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14896,"output_tokens":5275,"usd":0.103178,"stage2_stop_reason":"end_turn"},"total_usd":0.201653,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"ADGRL3 signals through G12/G13 and Gq upon acute tethered agonist (TA) exposure, with G12/13 being the most robustly activated G protein pathway, as determined by an engineered acute activation strategy using controlled enzymatic proteolysis in living cells.\",\n      \"method\": \"Engineered tethered agonist acute activation assay (controlled enzymatic proteolysis of receptor construct in living cells), G protein activation assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel acute activation strategy with direct functional readout, multiple G protein pathways tested, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32778842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of ADGRL3 in complex with Gq, Gs, Gi, and G12 revealed the unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation, including the uncharted structural information of GPCR/G12 coupling. The far end of αH5 of Gα is the key determinant of G-protein coupling selectivity, and mutations designed from the structures specifically enhance one G-protein pathway over others.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structure determination, mutagenesis of G protein coupling determinants, functional validation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with four G protein complexes plus mutagenesis validation, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"36309016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Autoproteolytic cleavage at the GPS site of ADGRL3 encodes biased signaling: cleavage-deficient ADGRL3 retains constitutive activity but shows a signaling bias that potentiates select G proteins (Gi2 and G12/13), revealing that GPS cleavage modulates G protein coupling selectivity rather than simply enabling or abolishing signaling.\",\n      \"method\": \"BRET-based G protein biosensors, autoproteolysis-deficient ADGRL3 mutant, constitutive activity assays\",\n      \"journal\": \"Basic & clinical pharmacology & toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRET biosensors with cleavage-deficient mutant, single lab, two methods (BRET + mutagenesis)\",\n      \"pmids\": [\"37464463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutating the sixth and seventh residues of the ADGRL3 tethered agonist (Leu and Met to Ala) impairs G protein coupling without affecting autoproteolytic cleavage or cell-surface expression, demonstrating that tethered agonism and autoproteolysis are separable functions. Extended N-terminal additions to the TA in the CTF also disrupt G protein signaling, suggesting the TA must be fully exposed for optimal orthosteric pocket interaction.\",\n      \"method\": \"Site-directed mutagenesis, serum response element (SRE) activity assay, acute TA-exposure assay (controlled proteolysis), immunoblotting, cell surface expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutagenesis with multiple functional readouts (SRE assay, acute activation, immunoblot), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36244455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"For full-length ADGRL3, approximately 5% of receptor spontaneously sheds its N-terminal fragment (NTF) in heterologous cells, and this shedding is required for tethered agonist-mediated G protein signaling: a full-length cleavage-deficient mutant loses ~80% of Gα13 signaling and shows ~20% of the spontaneous NTF shedding observed in WT receptor.\",\n      \"method\": \"Heterologous cell expression, NTF shedding quantification, Gα13 signaling assay, full-length cleavage-deficient ADGRL3 mutant, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct quantification of shedding, cleavage-deficient mutant, signaling assay, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39798870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Direct tensile force applied to the N-terminus of Adgrl3 via optical tweezers is sufficient to induce G protein recruitment in living cells. Activation is direction-specific, requires a functional tethered agonist, and is accompanied by force-driven GAIN domain conformational changes and dissociation, demonstrating that ADGRL3 functions as a mechanosensor.\",\n      \"method\": \"Optical tweezers (single-molecule force application), G protein recruitment assay in living cells, GAIN domain conformational monitoring\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct mechanical activation with G protein recruitment readout, novel method, single lab preprint not yet peer reviewed\",\n      \"pmids\": [\"42124579\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADGRL3 signals via autoproteolytic cleavage-dependent tethered agonist mechanism. An antibody (LK30) engineered to bind the extracellular region of ADGRL3 acts as an agonist specific to ADGRL3 but not its isoform ADGRL1. The LK30 binding site on ADGRL3 overlaps with the teneurin binding site; LK30 specifically disrupts the trans-cellular ADGRL3–teneurin interaction but not the ADGRL3–FLRT3 interaction, demonstrating ligand-specific and isoform-specific modulation.\",\n      \"method\": \"Antibody engineering, X-ray crystallography of LK30/ADGRL3 complex, cellular adhesion assays, isoform-specificity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of antibody-receptor complex combined with functional cellular adhesion assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36746957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LPHN3 (ADGRL3) is a presynaptic protein that regulates synapse number: shRNA knockdown in mouse layer 2/3 pyramidal neurons reduced the density of synapses formed by L2/3 axons in layer 5 and weakened the strength of L2/3 afferent input to L5 without affecting probability of release. The Olfactomedin domain of LPHN3 is required for binding to FLRT3 and for rescuing the presynaptic density deficit. Both the Olfactomedin and Lectin domains are involved in binding to Teneurin 1. Single particle negative-stain EM showed the Olfactomedin and Lectin domains form a globular domain on an elongated stalk.\",\n      \"method\": \"shRNA knockdown in vivo, optogenetic circuit interrogation, Synaptophysin-GFP anatomical marker, cell-based binding experiments with domain mutants, single particle negative stain electron microscopy\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (optogenetics, synaptic density quantification, domain-mutant binding assays, EM), single lab\",\n      \"pmids\": [\"24739570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cancer-related somatic mutations in the GAIN domain of Lphn3 (ADGRL3) impair receptor signaling through G13 for all non-homologous amino acid substitution variants, and the S810L mutation additionally impairs cell-autonomous motility and alters actin-dependent cell-matrix contact structures and vimentin remodeling. GAIN domain mutations produce ligand-specific impairment of Lphn3 intercellular adhesion while leaving intra-GAIN cleavage efficiency unaltered.\",\n      \"method\": \"Cancer somatic mutation introduction, G13 signaling assay, cell migration assays (collective and individual), actin and vimentin immunofluorescence, cell-matrix adhesion assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (signaling, migration, adhesion) with multiple mutants, single lab\",\n      \"pmids\": [\"35741042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LPHN3 (ADGRL3) engages G proteins via the tethered agonist (TA) mechanism dependent on autoproteolytic cleavage, as demonstrated by the finding that CELSR1 and CELSR3 (cleavage-deficient) retain G protein coupling activity through TA point mutants, while LPHN3's autoproteolysis is distinct. Specifically, acute TA exposure alone (without cleavage) is insufficient for CELSR2 GαS coupling enhancement, supporting that ADGRL3 signals via multiple paradigms.\",\n      \"method\": \"Autoproteolysis assays, TA point mutagenesis, GαS coupling assays, comparative analysis across aGPCR family members\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal comparison across family members, multiple mutants and assay types, single lab but peer-reviewed\",\n      \"pmids\": [\"37224017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of lphn3.1 (zebrafish ortholog of LPHN3/ADGRL3) function causes reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype was rescued by methylphenidate and atomoxetine.\",\n      \"method\": \"Morpholino knockdown in zebrafish, immunofluorescence for dopaminergic neurons, locomotor behavioral assays, pharmacological rescue\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific cellular (neuronal) and behavioral phenotypes, pharmacological rescue, replicated in independent studies across species\",\n      \"pmids\": [\"22508465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Lphn3 null mice show increased dopamine and serotonin levels in the dorsal striatum, altered expression of dopamine and serotonin receptors/transporters (Dat1, Drd4, 5Htt, 5Ht2a), changes in neurotransmitter metabolism genes (Th, Gad1), and changes in neural developmental genes (Nurr, Ncam), along with a hyperactive phenotype and increased sensitivity to cocaine-induced locomotion.\",\n      \"method\": \"Gene-trap knockout mice, TaqMan gene expression assays, monoamine tissue level measurement, open-field locomotor test, cocaine challenge\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout with multiple molecular (gene expression, monoamine levels) and behavioral readouts, single lab\",\n      \"pmids\": [\"22575564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Adgrl3-/- mice show increased locomotive activity, increased impulsivity, spatial memory impairment, and decreased aggression. RNA-sequencing of prefrontal cortex, hippocampus, and striatum revealed Slc6a3 (dopamine transporter) as the most dysregulated gene in the PFC, with enrichment of dopaminergic synapse pathways, implicating dopamine transporter dysregulation as a mechanism underlying ADHD-like phenotypes.\",\n      \"method\": \"Constitutive Adgrl3 knockout mice, multiple behavioral paradigms, RNA-sequencing of three brain regions, gene-set analysis\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with behavioral and transcriptomic phenotyping, multiple brain regions, single lab\",\n      \"pmids\": [\"30849401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lphn3 knockout rats show higher amplitude of dopamine release transients in striatum, with markedly decreased duration and interevent time compared to wild-type, as measured by fast-scan cyclic voltammetry in brain slices, demonstrating LPHN3 plays a role in regulating dopamine signaling dynamics.\",\n      \"method\": \"Fast-scan cyclic voltammetry in ex vivo brain slices, Lphn3 knockout rats\",\n      \"journal\": \"ACS chemical neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiological measurement of dopamine release dynamics in KO vs WT, rigorous ex vivo method, single lab\",\n      \"pmids\": [\"32203648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADGRL3 knockout mice show increased electrically-evoked dopamine release across the striatum ex vivo (fast-scan cyclic voltammetry), but reduced task-induced dopamine signals in the nucleus accumbens in vivo (fiber photometry with dopamine sensor). Amphetamine-evoked release was unchanged, suggesting ADGRL3 modulates dopamine release via distinct pre- and postsynaptic mechanisms rather than dopamine availability.\",\n      \"method\": \"Ex vivo fast-scan cyclic voltammetry, in vivo fiber photometry with dopamine sensor, ADGRL3 knockout mice, amphetamine challenge\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (ex vivo FSCV and in vivo photometry) in KO mice, single lab, preprint\",\n      \"pmids\": [\"40766670\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lphn3 knockout rats are impaired in egocentric (Cincinnati water maze) and allocentric (Morris water maze) spatial learning and memory, with reduced early-LTP (but not late-LTP) in hippocampal CA1 and reduced hippocampal NMDA-NR1 expression. Conditioned freezing, novel object recognition, and temporal order recognition were unaffected, indicating a selective role for LPHN3 in certain forms of learning and memory.\",\n      \"method\": \"Lphn3 knockout rats, multiple water maze tasks, LTP electrophysiology in CA1, NMDA receptor western blotting, behavioral battery\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (behavior, electrophysiology, protein expression), clean KO with selective phenotype pattern, single lab\",\n      \"pmids\": [\"34352385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An ultraconserved noncoding element within ADGRL3 (evolutionary conserved region 47, ECR47) functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in ECR47 (rs17226398, rs56038622, rs2271338) reduced enhancer activity by ~40% in neuroblastoma and astrocytoma cells. The rs2271338 risk allele disrupts binding of the YY1 transcription factor, linking noncoding ADGRL3 variants to reduced expression.\",\n      \"method\": \"Luciferase reporter assays, electromobility shift assays (EMSA), zebrafish GFP transgenesis for enhancer activity, family-based genetic analysis, eQTL analysis of postmortem brain\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal functional methods (luciferase, EMSA, in vivo zebrafish transgenesis), single lab\",\n      \"pmids\": [\"27692237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish lphn3.1 morphants (knockdown of zebrafish LPHN3 ortholog), hyposensitivity to both dopamine agonists (apomorphine, quinpirole, SKF-38393) and antagonists (haloperidol, eticlopride, SCH-23390) was observed for locomotor activity, consistent with a model of saturated (maximal) dopaminergic neurotransmission in lphn3.1 morphants.\",\n      \"method\": \"Morpholino knockdown in zebrafish, pharmacological challenge with dopamine receptor agonists and antagonists, locomotor activity assay\",\n      \"journal\": \"Progress in neuro-psychopharmacology & biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological characterization with multiple dopamine receptor ligands in loss-of-function model, single lab\",\n      \"pmids\": [\"29496512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Lphn3 in null mice increases both reward motivation (instrumental responding under high response ratios) and activity levels. Primary hippocampal and cortical neuron cultures from null mice display enhanced neurite outgrowth after 2–3 days in vitro. Transcriptome analysis shows differential gene expression particularly for cell adhesion molecules and calcium signaling proteins, with attenuation of DGE with age.\",\n      \"method\": \"Lphn3 knockout mice, instrumental responding behavioral task, forced swim test, primary neuronal culture with neurite outgrowth measurement, brain region transcriptome analysis\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockout with behavioral, cellular (neurite outgrowth), and transcriptomic phenotyping, multiple methods, single lab\",\n      \"pmids\": [\"27247960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"adgrl3.1-deficient zebrafish show externalizing behaviors (hyperactivity, impulsivity, risk-taking, attentional deficits) that are rescued by atomoxetine (a norepinephrine reuptake inhibitor), demonstrating noradrenergic mediation of the behavioral effects of adgrl3.1 loss. Transcriptomic analysis revealed differentially expressed genes and enriched gene clusters independent of noradrenergic manipulation, suggesting additional functional pathways.\",\n      \"method\": \"adgrl3.1 knockout zebrafish, behavioral battery (hyperactivity, impulsivity, attention, novelty), pharmacological rescue with atomoxetine, brain transcriptomics\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pharmacological rescue and transcriptomics, single lab, multiple behavioral readouts\",\n      \"pmids\": [\"37783687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Lphn3 specifically in tyrosine hydroxylase (TH)-positive catecholaminergic neurons (Lphn3-Th-Cre) causes hyperactivity and egocentric navigation deficits similar to (but less severe than) global Lphn3 KO rats, establishing that LPHN3 in dopaminergic/noradrenergic neurons is a key contributor to the hyperactivity and navigation phenotypes. Allocentric navigation deficits seen in global KO were absent in the conditional KO, implying non-catecholaminergic cell contributions to spatial learning.\",\n      \"method\": \"Conditional KO (Cre-lox, Th-Cre x floxed Lphn3), global KO comparison, behavioral battery (CWM, MWM), striatal TH and dopamine receptor immunohistochemistry, hippocampal NMDA receptor Western blot\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional vs global KO comparison with behavioral and molecular phenotyping, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.12.27.630427\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"adgrl3.1 knockout zebrafish show disrupted cortisol regulation: lower baseline cortisol levels with an increased cortisol response to an acute stressor (conspecific alarm substance), along with altered expression of bdnf and gr. These animals also show increased anxiety-like behavior and impaired cognitive flexibility under stress, linking adgrl3.1 to HPA-axis stress reactivity.\",\n      \"method\": \"adgrl3.1 knockout zebrafish, cortisol measurement (baseline and stress-induced), bdnf and gr gene expression, behavioral anxiety and cognitive flexibility assays\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KO with physiological (cortisol) and behavioral readouts, gene expression, single lab\",\n      \"pmids\": [\"40639688\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADGRL3 (LPHN3) is a brain-enriched adhesion GPCR that undergoes autoproteolytic cleavage at its GAIN domain GPS site to generate noncovalently associated N-terminal and C-terminal fragments; spontaneous NTF shedding exposes a tethered agonist (TA) that inserts into the orthosteric pocket to activate G proteins—primarily G12/13 and Gq—and direct tensile force on the extracellular N-terminus can also activate the receptor in a TA-dependent manner, acting as a mechanosensor. At synapses, ADGRL3 acts presynaptically via its Olfactomedin domain (which binds the postsynaptic ligand FLRT3) to promote synapse formation and regulate synapse number, while its Lectin domain also contributes to Teneurin-1 binding; loss of ADGRL3 reduces synaptic density, impairs spatial learning and memory, reduces hippocampal LTP and NMDA receptor expression, and dysregulates striatal dopamine release dynamics, collectively producing hyperactivity, impulsivity, and dopaminergic circuit disturbances linked to ADHD susceptibility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADGRL3 (LPHN3) is a brain-enriched adhesion GPCR that couples synaptic adhesion to intracellular G protein signaling and is genetically and functionally linked to dopaminergic circuit regulation and ADHD-like behaviors [#7, #12]. The receptor undergoes autoproteolysis at its GAIN-domain GPS site to generate noncovalently associated fragments; spontaneous shedding of the N-terminal fragment (~5% of full-length receptor) exposes a tethered agonist that inserts into the orthosteric pocket and is required for G protein signaling, with cleavage-deficient receptor losing ~80% of G\\u03b113 signaling [#4]. Upon acute tethered-agonist exposure ADGRL3 preferentially activates G12/13 and Gq, and cryo-EM structures of the receptor bound to Gq, Gs, Gi, and G12 define the activation conformation and the \\u03b1H5 determinants of coupling selectivity [#0, #1]. Tethered agonism and autoproteolysis are separable functions\\u2014mutating the sixth and seventh TA residues impairs coupling without affecting cleavage\\u2014and GPS cleavage biases coupling toward select G proteins rather than acting as a simple on/off switch [#2, #3]. Direct tensile force on the N-terminus drives GAIN-domain conformational change and TA-dependent G protein recruitment, establishing ADGRL3 as a mechanosensor [#5]. At synapses ADGRL3 acts presynaptically through its Olfactomedin domain, which binds postsynaptic FLRT3 and is required to maintain synapse number, while the Olfactomedin and Lectin domains together mediate Teneurin-1 binding; an engineered agonist antibody (LK30) selectively disrupts the ADGRL3\\u2013teneurin but not the ADGRL3\\u2013FLRT3 interaction [#6, #7]. Loss of ADGRL3 across zebrafish, mice, and rats produces hyperactivity, impulsivity, and selective spatial learning and memory deficits with reduced hippocampal early-LTP and NMDA-NR1 expression, accompanied by dysregulated striatal dopamine release dynamics [#10, #13, #15]. These phenotypes arise substantially from ADGRL3 function in catecholaminergic neurons [#20], and a noncoding ADHD-risk haplotype in an ADGRL3 intronic enhancer (ECR47) reduces enhancer activity by disrupting YY1 binding, linking reduced ADGRL3 expression to disease risk [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that loss of ADGRL3 causes dopaminergic developmental abnormalities and a hyperactive/impulsive phenotype, framing the receptor as a candidate ADHD gene with a defined neurochemical substrate.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with dopaminergic neuron imaging and pharmacological rescue; gene-trap knockout mice with monoamine and gene-expression profiling\",\n      \"pmids\": [\"22508465\", \"22575564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how ADGRL3 acts molecularly at synapses\", \"Cell type responsible for dopaminergic phenotype not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined ADGRL3 as a presynaptic adhesion molecule that controls synapse number through specific extracellular domains, connecting its adhesion ligands to circuit assembly.\",\n      \"evidence\": \"In vivo shRNA knockdown, optogenetic circuit interrogation, domain-mutant binding to FLRT3 and Teneurin-1, negative-stain EM\",\n      \"pmids\": [\"24739570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect adhesion function to intracellular G protein signaling\", \"Postsynaptic consequences of altered synapse number not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked ADGRL3 expression level to ADHD risk by showing a risk haplotype in an intronic enhancer reduces transcription via loss of a defined transcription-factor interaction.\",\n      \"evidence\": \"Luciferase reporter, EMSA, zebrafish enhancer transgenesis, family genetics and brain eQTL\",\n      \"pmids\": [\"27692237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the magnitude of expression change in vivo in human brain\", \"Other regulatory elements not surveyed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended ADGRL3 loss-of-function phenotypes to reward motivation and neuronal morphology, implicating adhesion and calcium-signaling gene programs.\",\n      \"evidence\": \"Knockout mice with instrumental responding, primary neuron neurite outgrowth, brain transcriptomics\",\n      \"pmids\": [\"27247960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between transcriptomic changes and behavior not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterized the dopaminergic signaling state of ADGRL3-deficient animals as maximally saturated neurotransmission, refining the mechanism behind hyperactivity.\",\n      \"evidence\": \"Zebrafish morphants challenged with dopamine receptor agonists and antagonists in locomotor assays\",\n      \"pmids\": [\"29496512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inference rather than direct release measurement\", \"Morpholino knockdown specificity\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed the dopamine transporter (Slc6a3) as the top dysregulated gene in prefrontal cortex of ADGRL3 knockouts, nominating a transcriptional route to dopaminergic dysfunction.\",\n      \"evidence\": \"Constitutive knockout mice, multi-paradigm behavior, RNA-seq across three brain regions\",\n      \"pmids\": [\"30849401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between Slc6a3 dysregulation and behavior not tested\", \"Mechanism linking ADGRL3 loss to transporter expression unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved which G proteins ADGRL3 engages, showing tethered-agonist exposure preferentially activates G12/13 and Gq and providing the first acute activation handle on the receptor.\",\n      \"evidence\": \"Engineered acute tethered-agonist activation via controlled proteolysis in living cells with G protein activation assays\",\n      \"pmids\": [\"32778842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of coupling selectivity not yet defined\", \"Endogenous activation trigger in neurons unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated directly that ADGRL3 shapes the kinetics of striatal dopamine release, moving beyond steady-state monoamine levels to dynamic signaling.\",\n      \"evidence\": \"Fast-scan cyclic voltammetry in ex vivo brain slices from knockout rats\",\n      \"pmids\": [\"32203648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pre- versus postsynaptic locus of the effect not distinguished\", \"Link to G protein signaling not made\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided cryo-EM structures of ADGRL3 with four G proteins and identified \\u03b1H5 as the coupling-selectivity determinant, enabling rational design of pathway-biased mutants.\",\n      \"evidence\": \"Cryo-EM of ADGRL3\\u2013Gq/Gs/Gi/G12 complexes with mutagenesis and functional validation\",\n      \"pmids\": [\"36309016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor and NTF interactions not captured\", \"Mechanosensory conformations not visualized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Dissected the relationship between autoproteolysis and tethered agonism, showing they are separable and that GPS cleavage biases rather than gates G protein coupling.\",\n      \"evidence\": \"Site-directed TA mutagenesis with SRE and acute activation assays; BRET biosensors with cleavage-deficient mutant\",\n      \"pmids\": [\"36244455\", \"37464463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological regulation of cleavage state in neurons unknown\", \"Bias outcomes for downstream effectors not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected GAIN-domain cancer mutations to impaired G13 signaling, adhesion, and cytoskeletal/motility defects, broadening ADGRL3 function beyond neurons.\",\n      \"evidence\": \"Somatic mutation introduction with G13 signaling, migration, adhesion assays, actin/vimentin imaging\",\n      \"pmids\": [\"35741042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to actual tumor biology not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generated an isoform- and ligand-specific antibody agonist that maps the teneurin binding site and confirms cleavage-dependent tethered-agonist signaling.\",\n      \"evidence\": \"Antibody engineering, X-ray crystallography of LK30/ADGRL3, adhesion and isoform-specificity assays\",\n      \"pmids\": [\"36746957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo activity of LK30 not established\", \"How teneurin disruption affects signaling output not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ADGRL3 within a comparative aGPCR framework, confirming its TA-dependent coupling differs from cleavage-independent family members.\",\n      \"evidence\": \"Autoproteolysis and TA point-mutant comparisons with G\\u03b1S coupling across CELSR family members\",\n      \"pmids\": [\"37224017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mechanistic paradigm not fully resolved for ADGRL3\", \"Endogenous ligand-driven coupling not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated noradrenergic signaling in ADGRL3 behavioral phenotypes and revealed additional transcriptomic pathways independent of that mediation.\",\n      \"evidence\": \"adgrl3.1 knockout zebrafish behavior with atomoxetine rescue and brain transcriptomics\",\n      \"pmids\": [\"37783687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Noradrenergic versus dopaminergic contributions not separated mechanistically\", \"Identity of transcriptomic effectors unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Quantified spontaneous NTF shedding of full-length receptor and showed it is required for tethered-agonist signaling, defining the rate-limiting activation step.\",\n      \"evidence\": \"Heterologous expression, NTF shedding quantification, G\\u03b113 assays with cleavage-deficient mutant\",\n      \"pmids\": [\"39798870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for spontaneous shedding in vivo unknown\", \"Relationship between shedding and ligand/force not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Localized the hyperactivity and egocentric navigation phenotypes to ADGRL3 function within catecholaminergic neurons while assigning allocentric deficits to other cell types.\",\n      \"evidence\": \"Th-Cre conditional knockout versus global knockout rats with behavioral and molecular phenotyping\",\n      \"pmids\": [\"bio_10.1101_2024.12.27.630427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer reviewed\", \"Non-catecholaminergic cell types responsible for spatial deficits unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconciled increased ex vivo evoked dopamine release with reduced task-related in vivo signals, indicating distinct pre- and postsynaptic regulatory mechanisms.\",\n      \"evidence\": \"Ex vivo FSCV and in vivo fiber photometry with dopamine sensor in knockout mice, amphetamine challenge\",\n      \"pmids\": [\"40766670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer reviewed\", \"Molecular mediators of the pre/post split not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that mechanical force on the N-terminus directly activates ADGRL3 in a TA-dependent, direction-specific manner, establishing it as a mechanosensor.\",\n      \"evidence\": \"Optical-tweezer single-molecule force application with G protein recruitment readout and GAIN conformational monitoring in living cells\",\n      \"pmids\": [\"42124579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer reviewed\", \"Physiological source of force at synapses unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADGRL3's adhesion ligands, autoproteolytic shedding, mechanosensation, and biased G protein coupling are integrated to control dopamine release and ADHD-relevant behavior in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No link established between specific G protein pathway and dopamine release phenotype in neurons\", \"Endogenous activating ligand/force at synapses not identified\", \"Downstream effectors connecting ADGRL3 signaling to NMDA receptor and transporter expression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 13, 15]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FLRT3\", \"TENM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}