Affinage

Showing ADGRL3 — LPHN3 is a alias.

ADGRL3

Adhesion G protein-coupled receptor L3 · UniProt Q9HAR2

Length
1447 aa
Mass
161.8 kDa
Annotated
2026-06-09
64 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2012 High

    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

    PMID:22508465 PMID:22575564

    Open questions at the time
    • Did not define how ADGRL3 acts molecularly at synapses
    • Cell type responsible for dopaminergic phenotype not resolved
  2. 2014 High

    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

    PMID:24739570

    Open questions at the time
    • Did not connect adhesion function to intracellular G protein signaling
    • Postsynaptic consequences of altered synapse number not quantified
  3. 2016 High

    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

    PMID:27692237

    Open questions at the time
    • Did not establish the magnitude of expression change in vivo in human brain
    • Other regulatory elements not surveyed
  4. 2016 Medium

    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

    PMID:27247960

    Open questions at the time
    • Causal link between transcriptomic changes and behavior not established
    • Single lab
  5. 2018 Medium

    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

    PMID:29496512

    Open questions at the time
    • Pharmacological inference rather than direct release measurement
    • Morpholino knockdown specificity
  6. 2019 Medium

    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

    PMID:30849401

    Open questions at the time
    • Causality between Slc6a3 dysregulation and behavior not tested
    • Mechanism linking ADGRL3 loss to transporter expression unknown
  7. 2020 High

    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

    PMID:32778842

    Open questions at the time
    • Structural basis of coupling selectivity not yet defined
    • Endogenous activation trigger in neurons unresolved
  8. 2020 High

    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

    PMID:32203648

    Open questions at the time
    • Pre- versus postsynaptic locus of the effect not distinguished
    • Link to G protein signaling not made
  9. 2022 High

    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

    PMID:36309016

    Open questions at the time
    • Full-length receptor and NTF interactions not captured
    • Mechanosensory conformations not visualized
  10. 2022 High

    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

    PMID:36244455 PMID:37464463

    Open questions at the time
    • Physiological regulation of cleavage state in neurons unknown
    • Bias outcomes for downstream effectors not mapped
  11. 2022 Medium

    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

    PMID:35741042

    Open questions at the time
    • Relevance to actual tumor biology not demonstrated
    • Single lab
  12. 2023 High

    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

    PMID:36746957

    Open questions at the time
    • In vivo activity of LK30 not established
    • How teneurin disruption affects signaling output not quantified
  13. 2023 Medium

    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

    PMID:37224017

    Open questions at the time
    • Single mechanistic paradigm not fully resolved for ADGRL3
    • Endogenous ligand-driven coupling not tested
  14. 2023 Medium

    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

    PMID:37783687

    Open questions at the time
    • Noradrenergic versus dopaminergic contributions not separated mechanistically
    • Identity of transcriptomic effectors unconfirmed
  15. 2025 High

    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

    PMID:39798870

    Open questions at the time
    • Trigger for spontaneous shedding in vivo unknown
    • Relationship between shedding and ligand/force not resolved
  16. 2025 Medium

    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

    PMID:bio_10.1101_2024.12.27.630427

    Open questions at the time
    • Preprint, not peer reviewed
    • Non-catecholaminergic cell types responsible for spatial deficits unidentified
  17. 2025 Medium

    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

    PMID:40766670

    Open questions at the time
    • Preprint, not peer reviewed
    • Molecular mediators of the pre/post split not identified
  18. 2026 Medium

    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

    PMID:42124579

    Open questions at the time
    • Preprint, not peer reviewed
    • Physiological source of force at synapses unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2
Partners
FLRT3TENM1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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. Engineered tethered agonist acute activation assay (controlled enzymatic proteolysis of receptor construct in living cells), G protein activation assays Nature chemical biology High 32778842
2022 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. Cryo-electron microscopy (cryo-EM) structure determination, mutagenesis of G protein coupling determinants, functional validation Molecular cell High 36309016
2022 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. BRET-based G protein biosensors, autoproteolysis-deficient ADGRL3 mutant, constitutive activity assays Basic & clinical pharmacology & toxicology Medium 37464463
2022 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. Site-directed mutagenesis, serum response element (SRE) activity assay, acute TA-exposure assay (controlled proteolysis), immunoblotting, cell surface expression assay The Journal of biological chemistry High 36244455
2025 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. Heterologous cell expression, NTF shedding quantification, Gα13 signaling assay, full-length cleavage-deficient ADGRL3 mutant, immunoblotting The Journal of biological chemistry High 39798870
2026 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. Optical tweezers (single-molecule force application), G protein recruitment assay in living cells, GAIN domain conformational monitoring bioRxivpreprint Medium 42124579
2023 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. Antibody engineering, X-ray crystallography of LK30/ADGRL3 complex, cellular adhesion assays, isoform-specificity assays Nature communications High 36746957
2014 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. shRNA knockdown in vivo, optogenetic circuit interrogation, Synaptophysin-GFP anatomical marker, cell-based binding experiments with domain mutants, single particle negative stain electron microscopy Neural development High 24739570
2022 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. Cancer somatic mutation introduction, G13 signaling assay, cell migration assays (collective and individual), actin and vimentin immunofluorescence, cell-matrix adhesion assays Cells Medium 35741042
2023 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. Autoproteolysis assays, TA point mutagenesis, GαS coupling assays, comparative analysis across aGPCR family members Cell reports Medium 37224017
2012 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. Morpholino knockdown in zebrafish, immunofluorescence for dopaminergic neurons, locomotor behavioral assays, pharmacological rescue Molecular psychiatry High 22508465
2012 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. Gene-trap knockout mice, TaqMan gene expression assays, monoamine tissue level measurement, open-field locomotor test, cocaine challenge Brain research Medium 22575564
2019 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. Constitutive Adgrl3 knockout mice, multiple behavioral paradigms, RNA-sequencing of three brain regions, gene-set analysis Neuropharmacology Medium 30849401
2020 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. Fast-scan cyclic voltammetry in ex vivo brain slices, Lphn3 knockout rats ACS chemical neuroscience High 32203648
2025 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. Ex vivo fast-scan cyclic voltammetry, in vivo fiber photometry with dopamine sensor, ADGRL3 knockout mice, amphetamine challenge bioRxivpreprint Medium 40766670
2021 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. Lphn3 knockout rats, multiple water maze tasks, LTP electrophysiology in CA1, NMDA receptor western blotting, behavioral battery Neurobiology of disease High 34352385
2016 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. Luciferase reporter assays, electromobility shift assays (EMSA), zebrafish GFP transgenesis for enhancer activity, family-based genetic analysis, eQTL analysis of postmortem brain Biological psychiatry High 27692237
2018 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. Morpholino knockdown in zebrafish, pharmacological challenge with dopamine receptor agonists and antagonists, locomotor activity assay Progress in neuro-psychopharmacology & biological psychiatry Medium 29496512
2016 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. Lphn3 knockout mice, instrumental responding behavioral task, forced swim test, primary neuronal culture with neurite outgrowth measurement, brain region transcriptome analysis Molecular genetics & genomic medicine Medium 27247960
2023 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. adgrl3.1 knockout zebrafish, behavioral battery (hyperactivity, impulsivity, attention, novelty), pharmacological rescue with atomoxetine, brain transcriptomics Translational psychiatry Medium 37783687
2025 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. 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 bioRxivpreprint Medium bio_10.1101_2024.12.27.630427
2025 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. adgrl3.1 knockout zebrafish, cortisol measurement (baseline and stress-induced), bdnf and gr gene expression, behavioral anxiety and cognitive flexibility assays Behavioural brain research Medium 40639688

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Molecular psychiatry 225 20157310
2012 The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development. Molecular psychiatry 138 22508465
2010 Contribution of LPHN3 to the genetic susceptibility to ADHD in adulthood: a replication study. Genes, brain, and behavior 98 21040458
2012 Initial characterization of mice null for Lphn3, a gene implicated in ADHD and addiction. Brain research 76 22575564
2020 G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. Nature chemical biology 64 32778842
2014 LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5. Neural development 62 24739570
2010 Screening of human LPHN3 for variants with a potential impact on ADHD susceptibility. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 58 21184580
2015 LPHN3 and attention-deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study. Genes, brain, and behavior 54 25989180
2011 A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular psychiatry 51 21606926
2016 An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility. Biological psychiatry 50 27692237
2012 LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy. Journal of child psychology and psychiatry, and allied disciplines 47 22486528
2016 Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction. Molecular genetics & genomic medicine 45 27247960
2022 Structural insights into adhesion GPCR ADGRL3 activation and Gq, Gs, Gi, and G12 coupling. Molecular cell 43 36309016
2019 Dissociation of impulsivity and aggression in mice deficient for the ADHD risk gene Adgrl3: Evidence for dopamine transporter dysregulation. Neuropharmacology 40 30849401
2012 Refining psychiatric phenotypes for response to treatment: contribution of LPHN3 in ADHD. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 38 22851411
2018 Pharmacological analysis of zebrafish lphn3.1 morphant larvae suggests that saturated dopaminergic signaling could underlie the ADHD-like locomotor hyperactivity. Progress in neuro-psychopharmacology & biological psychiatry 35 29496512
2018 LPHN3 gene variations and susceptibility to ADHD in Chinese Han population: a two-stage case-control association study and gene-environment interactions. European child & adolescent psychiatry 35 30406846
2011 A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome. Translational psychiatry 35 22832519
2019 ADGRL3 (LPHN3) variants predict substance use disorder. Translational psychiatry 34 30696812
2012 Influence of a latrophilin 3 (LPHN3) risk haplotype on event-related potential measures of cognitive response control in attention-deficit hyperactivity disorder (ADHD). European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 34 23245769
2003 Lec3 Chinese hamster ovary mutants lack UDP-N-acetylglucosamine 2-epimerase activity because of mutations in the epimerase domain of the Gne gene. The Journal of biological chemistry 33 14561743
2016 ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study. Molecular genetics & genomic medicine 32 27652281
2010 Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD. Attention deficit and hyperactivity disorders 32 21432600
2015 Association of LPHN3 rs6551665 A/G polymorphism with attention deficit and hyperactivity disorder in Korean children. Gene 30 25871512
2023 The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. Cell reports 29 37224017
2020 Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility. Molecular psychiatry 27 32051549
2020 Enhanced Transient Striatal Dopamine Release and Reuptake in Lphn3 Knockout Rats. ACS chemical neuroscience 27 32203648
1999 Effects of N-butyldeoxynojirimycin and the Lec3.2.8.1 mutant phenotype on N-glycan processing in Chinese hamster ovary cells: application to glycoprotein crystallization. Protein science : a publication of the Protein Society 26 10452614
2019 Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2. Psychiatric genetics 25 30376466
2019 ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder. Neuromolecular medicine 25 30652248
2012 Quantitative real-time RT-PCR of ITGA7, SVEP1, TNS1, LPHN3, SEMA3G, KLB and MMP13 mRNA expression in breast cancer. Asian Pacific journal of cancer prevention : APJCP 24 23317273
2021 A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats. Neurobiology of disease 23 34352385
2023 Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder. Nature communications 22 36746957
2014 Association of SNAP-25, SLC6A2, and LPHN3 with OROS methylphenidate treatment response in attention-deficit/hyperactivity disorder. Clinical neuropharmacology 21 25229170
2022 Disentangling autoproteolytic cleavage from tethered agonist-dependent activation of the adhesion receptor ADGRL3. The Journal of biological chemistry 20 36244455
2021 An assessment of executive function in two different rat models of attention-deficit hyperactivity disorder: Spontaneously hypertensive versus Lphn3 knockout rats. Genes, brain, and behavior 16 34427038
2022 Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 15 36400921
2017 Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood. Progress in neuro-psychopharmacology & biological psychiatry 12 28624582
2023 adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment. Translational psychiatry 11 37783687
2022 ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP. Scientific reports 11 36151371
2020 Expression of the adult ADHD-associated gene ADGRL3 is dysregulated by risk variants and environmental risk factors. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 9 32787626
2023 Impulsive choice in two different rat models of ADHD-Spontaneously hypertensive and Lphn3 knockout rats. Frontiers in neuroscience 8 36777639
2022 Driver mutations in ADGRL3 are involved in the evolution of ependymoma. Laboratory investigation; a journal of technical methods and pathology 7 35013530
2021 ADGRL3, FGF1 and DRD4: Linkage and Association with Working Memory and Perceptual Organization Candidate Endophenotypes in ADHD. Brain sciences 7 34206913
2020 CDH13 and LPHN3 Gene Polymorphisms in Attention-Deficit/Hyperactivity Disorder: Their Relation to Clinical Characteristics. Journal of molecular neuroscience : MN 7 32691279
2023 Biased signalling is structurally encoded as an autoproteolysis event in adhesion G protein-coupled receptor Latrophilin-3/ADGRL3. Basic & clinical pharmacology & toxicology 6 37464463
2024 Social isolation intensifies adgrl3.1-related externalizing and internalizing behaviors in zebrafish. Progress in neuro-psychopharmacology & biological psychiatry 5 39542203
2023 Generation of four human induced pluripotent stem cells derived from ADHD patients carrying different genotypes for the risk SNP rs1397547 in the ADHD-associated gene ADGRL3. Stem cell research 5 36640473
2025 N-terminal fragment shedding contributes to signaling of the full-length adhesion receptor ADGRL3. The Journal of biological chemistry 4 39798870
2023 The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. bioRxiv : the preprint server for biology 4 37066404
2022 Thwarting of Lphn3 Functions in Cell Motility and Signaling by Cancer-Related GAIN Domain Somatic Mutations. Cells 4 35741042
2025 Gene × environment interaction between heterozygous deletion of the ADHD risk gene latrophilin-3 (adgrl3) and developmental deltamethrin exposure in Sprague Dawley rats. Neurotoxicology and teratology 3 39988293
2022 Case Report of a Juvenile Patient with Autism Spectrum Disorder with a Novel Combination of Copy Number Variants in ADGRL3 (LPHN3) and Two Pseudogenes. The application of clinical genetics 3 36082049
2021 Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder. Scientific reports 3 33504901
2024 Environmental enrichment reduces adgrl3.1-Related anxiety and attention deficits but not impulsivity. Behavioural brain research 2 39571939
2025 Genome sequencing reveals the Adgrl3 (ADGRL3) gene as a possible cause of cephalic hypersensitivity in the STA rat and migraine in humans. Cephalalgia : an international journal of headache 1 40635640
2019 Previously Identified Genetic Variants in ADGRL3 Are not Associated with Risk for Equine Degenerative Myeloencephalopathy across Breeds. Genes 1 31491999
2026 Gene × environment interaction between latrophilin-3 (Lphn3 or Adgrl3) and developmental permethrin exposure in Sprague Dawley rats. Neurotoxicology and teratology 0 41722825
2026 Discovery of Novel Pyrano[3,2-a]carbazole Alkaloid Derivatives against Ischemic Stroke by Targeting ADGRL3. Journal of medicinal chemistry 0 41805372
2026 Direct tensile force activates Adgrl3 in a tethered agonist-dependent manner. bioRxiv : the preprint server for biology 0 42124579
2025 Co-expression of LPHN3 and NKX3.1 as a predictive biomarker for metastasis in breast cancer. JPMA. The Journal of the Pakistan Medical Association 0 39948777
2025 adgrl3.1 knockout disrupts cortisol regulation and stress reactivity, linking externalizing and internalizing behaviors. Behavioural brain research 0 40639688
2025 Altered striatal dopamine regulation in ADGRL3 knockout mice. bioRxiv : the preprint server for biology 0 40766670
2020 Tissue Expression Of LPHN3 in Breast Cancer: An Immunohistochemistry Method. Asian Pacific journal of cancer prevention : APJCP 0 33247693

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