ADGRL3

Summary

ADGRL3 (adhesion G protein-coupled receptor L3, HGNC:20974) is a protein-coding gene on chromosome 4q13.1, encoding Adhesion G protein-coupled receptor L3 (Q9HAR2). Orphan adhesion G-protein coupled receptor (aGPCR), which mediates synapse specificity.

This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane.

Source: NCBI Gene 23284 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 192 total — 1 pathogenic
• MANE Select transcript: NM_001387552

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20974
Approved symbol	ADGRL3
Name	adhesion G protein-coupled receptor L3
Location	4q13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0768, LEC3
Ensembl gene	ENSG00000150471
Ensembl biotype	protein_coding
OMIM	616417
Entrez	23284

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 17 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000502815, ENST00000504896, ENST00000506700, ENST00000506720, ENST00000506746, ENST00000507164, ENST00000507625, ENST00000508078, ENST00000508693, ENST00000508946, ENST00000509089, ENST00000509779, ENST00000509896, ENST00000511324, ENST00000512091, ENST00000514157, ENST00000514591, ENST00000514996, ENST00000683033, ENST00000882181

RefSeq mRNA: 37 — MANE Select: NM_001387552 NM_001322246, NM_001322402, NM_001371342, NM_001371343, NM_001371344, NM_001371345, NM_001371346, NM_001387522, NM_001387523, NM_001387524, NM_001387525, NM_001387526, NM_001387527, NM_001387528, NM_001387529, NM_001387530, NM_001387531, NM_001387532, NM_001387533, NM_001387534, NM_001387535, NM_001387536, NM_001387537, NM_001387538, NM_001387539, NM_001387540, NM_001387541, NM_001387542, NM_001387543, NM_001387544, NM_001387545, NM_001387546, NM_001387547, NM_001387548, NM_001387549, NM_001387552, NM_015236

CCDS: CCDS54768, CCDS82926, CCDS93538, CCDS93539, CCDS93541

Canonical transcript exons

ENST00000683033 — 27 exons

Exon	Start	End
ENSE00000995067	61909560	61909745
ENSE00000995068	61948100	61948276
ENSE00000995070	62037731	62037856
ENSE00000995072	61983383	61983603
ENSE00000995073	62031442	62031610
ENSE00000995074	61946914	61947122
ENSE00000995080	61998174	61998265
ENSE00000995081	61996291	61996357
ENSE00000995082	61979563	61979772
ENSE00001072407	61895731	61895834
ENSE00001072410	61676826	61676935
ENSE00001072418	61892656	61892958
ENSE00001072419	61912719	61912757
ENSE00001072423	62028855	62028881
ENSE00001154168	61732754	61733554
ENSE00001154211	61813809	61813889
ENSE00001487830	62044453	62044549
ENSE00001611428	61383124	61383189
ENSE00001682879	61730622	61730636
ENSE00002021043	61587227	61587440
ENSE00002028849	61517315	61517518
ENSE00002257205	61497121	61497348
ENSE00003504818	61935923	61936045
ENSE00003638357	61934840	61935023
ENSE00003916709	62068166	62068183
ENSE00003919403	62070109	62078335
ENSE00003920723	61200326	61201765

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 98.07.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1364 / max 176.3602, expressed in 419 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47774	1.6824	332
47775	1.2809	275
47776	0.1270	83
47779	0.0460	28

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.07	gold quality
hair follicle	UBERON:0002073	96.62	gold quality
saphenous vein	UBERON:0007318	96.46	gold quality
middle temporal gyrus	UBERON:0002771	95.60	gold quality
cortical plate	UBERON:0005343	94.62	gold quality
endothelial cell	CL:0000115	94.25	gold quality
entorhinal cortex	UBERON:0002728	93.83	gold quality
substantia nigra pars compacta	UBERON:0001965	92.83	gold quality
superior vestibular nucleus	UBERON:0007227	92.56	gold quality
orbitofrontal cortex	UBERON:0004167	92.37	gold quality
calcaneal tendon	UBERON:0003701	92.17	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.05	gold quality
corpus callosum	UBERON:0002336	91.81	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.48	gold quality
blood vessel layer	UBERON:0004797	91.46	gold quality
lateral globus pallidus	UBERON:0002476	91.29	gold quality
temporal lobe	UBERON:0001871	91.04	gold quality
parietal lobe	UBERON:0001872	90.99	gold quality
subthalamic nucleus	UBERON:0001906	90.97	gold quality
postcentral gyrus	UBERON:0002581	90.97	gold quality
superior frontal gyrus	UBERON:0002661	90.97	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.59	gold quality
medulla oblongata	UBERON:0001896	90.48	gold quality
globus pallidus	UBERON:0001875	90.39	gold quality
ventral tegmental area	UBERON:0002691	90.26	gold quality
medial globus pallidus	UBERON:0002477	90.03	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	89.86	gold quality
dorsal plus ventral thalamus	UBERON:0001897	89.84	gold quality
CA1 field of hippocampus	UBERON:0003881	89.84	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.38	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-9435	yes	1164.57
E-HCAD-35	yes	74.00
E-HCAD-25	yes	18.44
E-ANND-3	yes	6.72
E-GEOD-93593	yes	4.18
E-GEOD-124858	no	0.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

350 targeting ADGRL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197

Literature-anchored findings (GeneRIF, showing 31)

• These results further support the LPHN3 contribution to combined type ADHD, and specifically to the persistent form of the disorder (PMID:21040458)
• The mutational analysis of the entire coding region of LPHN3 in a cohort of 139 attention deficit hyperactivity disorder subjects and 52 controls, is reported. (PMID:21184580)
• LPHN3, a new gene in which variants have recently been shown to be associated with adhd. (PMID:21432600)
• single-nucleotide polymorphisms harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. (PMID:21606926)
• This study identifying loci for aADHD and led to the identification of LPHN3 as novel genes associated with ADHD across the lifespan. (PMID:22105624)
• This study demonistrated that LPHN3 and its ligand FLRT3 play an important role in glutamatergic synapse development. (PMID:22405201)
• highly significant interaction between four SNPs and maternal stress during pregnancy and development of attention-deficit/hyperactivity disorder (PMID:22486528)
• The influence of LPHN3 genotype on attention deficit-hyperactivity disorder (ADHD) and addiction is mediated through alterations in transgenic monoamine signaling. (PMID:22575564)
• A two-locus genetic interaction between LPHN3 and 11q predicts ADHD severity and long-term outcome. (PMID:22832519)
• genetic association studies in Germany: Data suggest that, within a sample of patients with attention deficit disorder hyperactivity, SNPs in LPHN3 gene impacts behavioral and neurophysiological measures of cognitive response control. (PMID:23245769)
• Increased LPHN3 mRNA expression levels correlated with axillary-node metastasis in breast cancer. (PMID:23317273)
• Study examined the association between the LPHN3 rs6551665 A/G polymorphism and Attention deficit hyperactivity disorder (ADHD) in Korea; samples used in the study consisted of 150 ADHD children and 322 controls; ADHD children appeared to have a surplus of GG genotype, studies with larger sample sizes needed. (PMID:25871512)
• LPHN3 confers ADHD susceptibility, and moderates methylphenidate treatment response in children and adolescents with ADHD. (PMID:25989180)
• Results suggest that UNC5 and LPHN3 can simultaneously bind to FLRT3, forming a trimeric complex, and that FLRT3 may form transsynaptic complexes with both LPHN3 and UNC5. (PMID:26235030)
• Associations between LPHN1 and LPHN3 polymorphisms and severity of bronchial hyper-responsiveness in asthmatics were conducted; however, no associations were found. (PMID:27325752)
• An ultraconserved brain-specific enhancer within LPHN3 is associated with ADHD susceptibility. (PMID:27692237)
• LPHN3 gene has a significant effect on the attention-deficit/hyperactivity disorder in a Chinese population. (PMID:30406846)
• ADGRL3 rs6551665 as a Common Vulnerability Factor Underlying Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder. (PMID:30652248)
• Study identified ADGRL3 as a risk gene for substance use disorder. (PMID:30696812)
• CDH13 and LPHN3 Gene Polymorphisms in Attention-Deficit/Hyperactivity Disorder: Their Relation to Clinical Characteristics. (PMID:32691279)
• G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. (PMID:32778842)
• Expression of the adult ADHD-associated gene ADGRL3 is dysregulated by risk variants and environmental risk factors. (PMID:32787626)
• Tissue Expression Of LPHN3 in Breast Cancer: An Immunohistochemistry Method. (PMID:33247693)
• Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder. (PMID:33504901)
• Adhesion G protein-coupled receptor L3 gene variants: Statistically significant association observed in the male Indo-caucasoid Attention deficit hyperactivity disorder probands. (PMID:33914279)
• Machine Learning Prediction of ADHD Severity: Association and Linkage to ADGRL3, DRD4, and SNAP25. (PMID:34009035)
• Driver mutations in ADGRL3 are involved in the evolution of ependymoma. (PMID:35013530)
• Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility. (PMID:35393556)
• Thwarting of Lphn3 Functions in Cell Motility and Signaling by Cancer-Related GAIN Domain Somatic Mutations. (PMID:35741042)
• ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP. (PMID:36151371)
• The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. (PMID:37224017)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adgrl3.1	ENSDARG00000061121
danio_rerio	adgrl3.2	ENSDARG00000090624
mus_musculus	Adgrl3	ENSMUSG00000037605
rattus_norvegicus	Adgrl3	ENSRNOG00000030149

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), CALCRL (ENSG00000064989), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Adhesion G protein-coupled receptor L3 — Q9HAR2 (reviewed: Q9HAR2)

Alternative names: Calcium-independent alpha-latrotoxin receptor 3, Latrophilin-3, Lectomedin-3

All UniProt accessions (15): Q9HAR2, A0A804HKL8, E7EMR3, E7EN28, E7ENK1, E7ES20, E7ESV6, E7ETE3, E7EUP0, E7EUW2, E7EVD6, E7EW95, E7EX52, E9PBG4, H0Y9K5

UniProt curated annotations — full annotation on UniProt →

Function. 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. 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. Coupling to G(12)/G(13) G proteins, which mediates the activation Rho small GTPases is the most efficient. Following G-protein coupled receptor activation, associates with cell adhesion molecules that are expressed at the surface of adjacent cells to direct synapse specificity. Specifically mediates the establishment of Schaffer-collateral synapses formed by CA3-region axons on CA1-region pyramidal neurons in the hippocampus. 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. Plays a role in the development of glutamatergic synapses in the cortex. Important in determining the connectivity rates between the principal neurons in the cortex. 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.

Subunit / interactions. Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked. Interacts (via olfactomedin-like domain) with FLRT1 (via extracellular domain). Interacts (via olfactomedin-like domain) with FLRT2 (via extracellular domain). Interacts (via olfactomedin-like domain) with FLRT3 (via extracellular domain); the interaction is direct. Interacts (via extracellular domain) with TENM1. Interacts (via extracellular domain) with TENM2. Interacts (via extracellular domain) with TENM3. Identified in a complex with FLRT3 and UNC5B; does not interact with UNC5B by itself. Identified in a complex with FLRT3 and UNC5D; does not interact with UNC5D by itself. Interacts (via PDZ-binding motif) with SHANK3. Interacts (via PDZ-binding motif) with DLG4.

Subcellular location. Cell membrane. Postsynaptic cell membrane. Cell projection. Axon. Cell junction.

Post-translational modifications. Autoproteolytically processed at the GPS region of the GAIN-B domain; this cleavage modulates receptor activity.

Activity regulation. Forms a heterodimer of 2 chains generated by proteolytic processing that remain associated through non-covalent interactions mediated by the GAIN-B domain. In the inactivated receptor, the Stachel sequence (also named stalk) is embedded in the GAIN-B domain, where it adopts a beta-strand conformation. On activation, the Stachel moves into the 7 transmembrane region and adopts a twisted hook-shaped configuration that forms contacts within the receptor, leading to coupling of a G-alpha protein, which activates signaling. The cleaved GAIN-B and N-terminal domains can then dissociate from the rest of the receptor.

Domain organisation. The Stachel sequence (also named stalk) in the C-terminal part of the extracellular domain (ECD) functions as a tethered agonist. In the inactivated receptor, the Stachel sequence (also named stalk) is embedded in the GAIN-B domain, where it adopts a beta-strand conformation. On activation, the Stachel moves into the 7 transmembrane region and adopts a twisted hook-shaped configuration that forms contacts within the receptor, leading to coupling of a G-alpha protein, which activates signaling. The Olfactomedin-like domain is required for the synapse-promoting function and the interaction with FLRT3. The Olfactomedin-like and the SUEL-type lectin domains are required for the interaction with TENM1.

Similarity. Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9HAR2-1	1	yes
Q9HAR2-2	2
Q9HAR2-3	3
Q9HAR2-4	4

RefSeq proteins (37): NP_001309175, NP_001309331, NP_001358271, NP_001358272, NP_001358273, NP_001358274, NP_001358275, NP_001374451, NP_001374452, NP_001374453, NP_001374454, NP_001374455, NP_001374456, NP_001374457, NP_001374458, NP_001374459, NP_001374460, NP_001374461, NP_001374462, NP_001374463, NP_001374464, NP_001374465, NP_001374466, NP_001374467, NP_001374468, NP_001374469, NP_001374470, NP_001374471, NP_001374472, NP_001374473, NP_001374474, NP_001374475, NP_001374476, NP_001374477, NP_001374478, NP_001374481, NP_056051 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000203	GPS	Conserved_site
IPR000832	GPCR_2_secretin-like	Family
IPR000922	Lectin_gal-bd_dom	Domain
IPR001879	GPCR_2_extracellular_dom	Domain
IPR003112	Olfac-like_dom	Domain
IPR003334	GPCR_2_latrophilin_rcpt_C	Domain
IPR003924	GPCR_2_latrophilin	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR032471	AGRL2-4_GAIN_subdom_A	Domain
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR043159	Lectin_gal-bd_sf	Homologous_superfamily
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF01825, PF02140, PF02191, PF02354, PF02793, PF16489

UniProt features (99 total): helix 16, strand 11, topological domain 8, glycosylation site 8, disulfide bond 8, mutagenesis site 8, transmembrane region 7, region of interest 6, splice variant 6, binding site 4, sequence variant 4, turn 4, domain 3, signal peptide 1, chain 1, short sequence motif 1, compositionally biased region 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5AFB	X-RAY DIFFRACTION	2.16
8DJG	X-RAY DIFFRACTION	2.65
7SF7	ELECTRON MICROSCOPY	2.9
6VHH	ELECTRON MICROSCOPY	2.97
8JMT	ELECTRON MICROSCOPY	3.36
5CMN	X-RAY DIFFRACTION	3.6
8VTI	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAR2-F1	69.87	0.33

Antibody-complex structures (SAbDab): 2 — 8DJG, 8VTI

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 841–842 (cleavage; by autolysis)

Ligand- & substrate-binding residues (4): 264; 312; 313; 367

Post-translational modifications (1): 1164

Disulfide bonds (8): 36–66, 45–123, 78–110, 91–97, 135–317, 805–836, 824–838, 927–999

Glycosylation sites (8): 93, 464, 549, 746, 759, 804, 830, 1076

Mutagenesis-validated functional residues (8):

Position	Phenotype
249–252	strongly reduces flrt3 binding. abolishes flrt3 binding; when associated with a-308.
308	abolishes flrt3 binding; when associated with 249-a–a-252.
844	strongly decreased g protein-coupled receptor activity.
847	strongly decreased g protein-coupled receptor activity.
914	strongly decreased g protein-coupled receptor activity.
938	strongly decreased g protein-coupled receptor activity.
1000	strongly decreased g protein-coupled receptor activity.
1068	strongly decreased g protein-coupled receptor activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, GCANCTGNY_MYOD_Q6, GTCTACC_MIR379, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEUROGENESIS, CACCAGC_MIR138, CAGCTG_AP4_Q5, ATGTTAA_MIR302C, chr4q13, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, GOBP_CELL_CELL_ADHESION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (9): neuron migration (GO:0001764), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), synapse assembly (GO:0007416), obsolete cell-cell adhesion via plasma-membrane adhesion molecules (GO:0098742), Rho-activating G protein-coupled receptor signaling pathway (GO:0160221), excitatory synapse assembly (GO:1904861), signal transduction (GO:0007165)

GO Molecular Function (8): G protein-coupled receptor activity (GO:0004930), calcium ion binding (GO:0005509), carbohydrate binding (GO:0030246), cell adhesion mediator activity (GO:0098631), molecular condensate scaffold activity (GO:0140693), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), axon (GO:0030424), postsynaptic membrane (GO:0045211), glutamatergic synapse (GO:0098978), cell projection (GO:0042995), synapse (GO:0045202), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
G protein-coupled receptor signaling pathway	2
binding	2
cellular anatomical structure	2
cell junction	2
cell migration	1
generation of neurons	1
G protein-coupled receptor activity	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
nervous system development	1
cell junction assembly	1
synapse organization	1
synapse assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
metal ion binding	1
cell adhesion	1
cell adhesion molecule binding	1
protein-macromolecule adaptor activity	1
signaling receptor activity	1
cation binding	1
membrane	1
cell periphery	1
anchoring junction	1
neuron projection	1
synaptic membrane	1
postsynapse	1
synapse	1

Protein interactions and networks

STRING

1724 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADGRL3	FLRT3	Q9NZU0	969
ADGRL3	KIR3DL2	P43630	937
ADGRL3	TENM2	Q9NT68	896
ADGRL3	TENM1	Q9UKZ4	670
ADGRL3	TENM4	Q6N022	643
ADGRL3	GRM8	O00222	640
ADGRL3	TENM3	Q9P273	611
ADGRL3	NRXN1	Q9ULB1	609
ADGRL3	UNC5D	Q6UXZ4	597
ADGRL3	NRXN2	Q9P2S2	576
ADGRL3	APLNR	P35414	573
ADGRL3	SLC38A3	Q99624	553
ADGRL3	NLGN1	Q8N2Q7	551
ADGRL3	GNAO1	P09471	529
ADGRL3	SHANK2	Q9UPX8	498

IntAct

36 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FLRT3	ADGRL3	psi-mi:“MI:0407”(direct interaction)	0.620
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
YIPF3	TMEM120B	psi-mi:“MI:0914”(association)	0.530
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
FLRT1	TCAF2	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
MMP26	SLC25A20	psi-mi:“MI:0914”(association)	0.530
CRK	ADGRL3	psi-mi:“MI:0407”(direct interaction)	0.440
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
KRTCAP3	SLC22A23	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
MPL	FAM171A2	psi-mi:“MI:0914”(association)	0.350
TMEM169	GPR89A	psi-mi:“MI:0914”(association)	0.350
MARCHF1	STXBP3	psi-mi:“MI:0914”(association)	0.350
H2AP	GNPAT	psi-mi:“MI:0914”(association)	0.350
ATP1B1	TM9SF1	psi-mi:“MI:0914”(association)	0.350
GP5	SLC19A2	psi-mi:“MI:0914”(association)	0.350
SUN3	GAS6	psi-mi:“MI:0914”(association)	0.350
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (33): LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Proximity Label-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS), LPHN3 (Affinity Capture-MS)

ESM2 similar proteins: A0A6J2ATK2, A5HUI5, A6QPT7, D3UW23, M3XFH7, O57579, O88917, O88923, O94910, O95490, O97817, O97827, O97831, P15144, P15145, P15541, P15684, P16406, P42658, P42659, P46101, P50123, P79098, P79143, P79171, P97449, P97629, Q07075, Q10737, Q22523, Q2KHK3, Q2M2H8, Q32LQ0, Q5RFP3, Q6P179, Q6Q4G3, Q7Q2T8, Q7TT41, Q80TR1, Q80TS3

Diamond homologs: A2BD09, A4IIT5, A6QLD2, B0BNI5, B5MFE9, O70624, O88917, O88923, O88998, O94910, O95490, O95897, O97817, O97827, O97831, P63056, P63057, Q0P3W2, Q0V9V5, Q0VCP3, Q25C36, Q2PT31, Q3UZZ4, Q3V1G4, Q568Y7, Q594P2, Q62609, Q66H86, Q68BL7, Q68BL8, Q6UWY5, Q6UX06, Q80TR1, Q80TS3, Q863A3, Q866N2, Q8BHP7, Q8BK62, Q8BM13, Q8JZZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

192 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	156
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2685109	GRCh37/hg19 4q12-13.3(chr4:57584845-72430996)x1	Pathogenic

SpliceAI

1725 predictions. Top by Δscore:

Variant	Effect	Δscore
4:61517313:AGGT:A	acceptor_gain	1.0000
4:61517314:GGTG:G	acceptor_gain	1.0000
4:61517516:AAGGT:A	donor_loss	1.0000
4:61517517:AGGT:A	donor_loss	1.0000
4:61517519:G:C	donor_loss	1.0000
4:61517520:T:A	donor_loss	1.0000
4:61587221:T:TA	acceptor_gain	1.0000
4:61587222:G:A	acceptor_gain	1.0000
4:61587225:A:AG	acceptor_gain	1.0000
4:61587226:G:GA	acceptor_gain	1.0000
4:61587226:GC:G	acceptor_gain	1.0000
4:61587226:GCT:G	acceptor_gain	1.0000
4:61587226:GCTT:G	acceptor_gain	1.0000
4:61587226:GCTTT:G	acceptor_gain	1.0000
4:61587436:CAAAG:C	donor_loss	1.0000
4:61587437:AAAG:A	donor_loss	1.0000
4:61587440:GGT:G	donor_loss	1.0000
4:61587441:GTAT:G	donor_loss	1.0000
4:61587442:T:G	donor_loss	1.0000
4:61590694:T:G	acceptor_gain	1.0000
4:61676817:T:A	acceptor_gain	1.0000
4:61676911:GTGCA:G	donor_gain	1.0000
4:61676916:G:GG	donor_gain	1.0000
4:61676936:G:GG	donor_gain	1.0000
4:61517303:C:CA	acceptor_gain	0.9900
4:61517310:CGCAG:C	acceptor_loss	0.9900
4:61517311:GCAGG:G	acceptor_loss	0.9900
4:61517312:CAGGT:C	acceptor_loss	0.9900
4:61517313:A:AG	acceptor_gain	0.9900
4:61517313:A:G	acceptor_loss	0.9900

AlphaMissense

10148 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001475 (4:61679454 C>G,T), RS1000003077 (4:61830433 C>A,T), RS1000007390 (4:61695360 C>T), RS1000013350 (4:61313321 C>G), RS10000153 (4:61338342 A>C), RS1000018349 (4:61653317 A>G), RS1000018418 (4:62013621 G>A), RS1000022814 (4:61556000 C>T), RS1000023428 (4:61900301 GT>G,GTT), RS1000026542 (4:61608401 C>G,T), RS1000027044 (4:61695634 A>G), RS1000028749 (4:61358620 A>T), RS1000034750 (4:62062356 A>G), RS1000040129 (4:61358849 A>G), RS1000048328 (4:61272534 G>A)

Disease associations

OMIM: gene MIM:616417 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000328_17	Biochemical measures	2.000000e-06
GCST000691_1	Partial epilepsies	3.000000e-06
GCST000883_8	Response to antipsychotic treatment in schizophrenia (working memory)	8.000000e-07
GCST002927_24	Mercury levels	5.000000e-06
GCST003075_115	Cognitive decline rate in late mild cognitive impairment	1.000000e-06
GCST003075_32	Cognitive decline rate in late mild cognitive impairment	9.000000e-07
GCST003265_280	Post bronchodilator FEV1/FVC ratio in COPD	5.000000e-06
GCST003265_441	Post bronchodilator FEV1/FVC ratio in COPD	4.000000e-06
GCST006627_79	Diastolic blood pressure	4.000000e-09
GCST007324_136	Adventurousness	1.000000e-09
GCST007880_1	Emotional lability in attention deficit hyperactivity disorder	4.000000e-06
GCST009879_8	Coronary artery disease	3.000000e-23
GCST010002_7	Refractive error	2.000000e-10
GCST010320_78	PR interval	3.000000e-09
GCST010321_210	PR interval	2.000000e-10
GCST010476_8	Myocardial infarction	1.000000e-20
GCST010478_9	Chronic kidney disease	2.000000e-07
GCST010836_5	Ischemic stroke	6.000000e-09
GCST90000047_65	Age at first sexual intercourse	4.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004335	short-term memory
EFO:0007710	cognitive decline measurement
EFO:0004713	FEV/FVC ratio
EFO:0006336	diastolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0008475	mood instability measurement
EFO:0004462	PR interval
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1355368	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs1456862	Toxicity	3	nicotine	Tobacco Use Disorder
rs1947275	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs2271339	Toxicity	3	nicotine	Tobacco Use Disorder
rs6551665	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs6813183	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity
rs734644	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

11 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs734644	ADGRL3	3	2.50	1	methylphenidate
rs1355368	ADGRL3	3	2.50	1	methylphenidate
rs1947275	ADGRL3	3	0.00	1	methylphenidate
rs6551665	ADGRL3	3	1.00	1	methylphenidate
rs6813183	ADGRL3	3	2.50	1	methylphenidate
rs1947274	ADGRL3		0.00	0
rs6858066	ADGRL3		0.00	0
rs1868790	ADGRL3		0.00	0
rs2345039	ADGRL3		0.00	0
rs2271339	ADGRL3	3	2.00	1	nicotine
rs1456862	ADGRL3	3	1.75	1	nicotine

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Adhesion Class GPCRs

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
FLRT3	Full agonist	7.8	pKd

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Nickel	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	decreases methylation	1
sotorasib	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
1,6-diaminohexane	increases abundance	1
methylselenic acid	increases expression	1
sodium arsenite	decreases expression	1
coumarin	increases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
2,6-dichloro-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	decreases methylation	1
Doxorubicin	decreases expression	1
Phthalic Acids	increases methylation	1
Silicon Dioxide	decreases expression	1
Thimerosal	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7FB	UKWi003-A	Induced pluripotent stem cell	Male
CVCL_C7FC	UKWi003-A-1	Induced pluripotent stem cell	Male
CVCL_C7FD	UKWi004-A	Induced pluripotent stem cell	Male
CVCL_C7FE	UKWi004-A-1	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.