| 2012 |
The olfactomedin-like domain of CIRL1/latrophilin-1 (ADGRL1) mediates direct, high-affinity (nanomolar) binding to neurexins lacking an insert at splice site 4 (SS4); neurexins with an SS4 insert cannot bind. This interaction is trans-cellular and forms a stable intercellular adhesion complex. ADGRL1 competes with neuroligin-1 for neurexin binding. |
Saturation binding assays, deletion mapping of extracellular domains, cell adhesion assays (co-culture of neurexin- and ADGRL1-expressing cells) |
The Journal of biological chemistry |
High |
22262843
|
| 2010 |
ADGRL1/CIRL-1 undergoes constitutive autoproteolytic cleavage at its GPS domain in the endoplasmic reticulum, producing a heterodimeric two-subunit receptor complex (NTF + CTF). Protein kinase C activators (PMA and ionomycin) inhibit GPS cleavage and downregulate trafficking to the cell surface, causing accumulation of the uncleaved precursor intracellularly. A non-cleavable mutant showed that downregulation of trafficking is independent of cleavage, suggesting that GPS proteolysis is not purely autocatalytic and may require auxiliary factors. |
Transfection of wild-type and mutant CIRL-1 in cells, treatment with PKC activators PMA and ionomycin, trafficking/surface expression assays, non-cleavable soluble mutant analysis |
Biochimie |
Medium |
20100540
|
| 2018 |
Comprehensive mutagenesis of the transmembrane domain (TMD) of ADGRL1/latrophilin-1 identified specific TMD residues essential for basal constitutive activity and for agonist peptide (endogenous tethered agonist peptide) response. A cancer-associated TMD mutation showed increased basal activity and failed to rescue embryonic developmental phenotype in transgenic C. elegans, linking TMD residues to receptor activation mechanism. |
Comprehensive mutagenesis screen of TMD residues, functional assays for basal activity and agonist peptide response, transgenic C. elegans rescue experiments |
iScience |
High |
30428326
|
| 2019 |
Alternative splicing of ADGRL1/latrophilin-1 at the cytoplasmic SSB site confers dual cAMP signaling: SSB-containing variants show both constitutive Gαi/o coupling (constitutive cAMP production) and ligand-dependent Gαs activation (cAMP increase upon neurexin or FLRT binding), whereas SSB-deficient variants show only ligand-dependent cAMP decrease. Neither variant increased intracellular Ca2+ or activated MAP kinase upon ligand binding. |
cAMP competitive binding assays, pertussis toxin treatment (Gαi/o inhibition), expression of SSB-containing vs SSB-deficient LPHN1 variants, Ca2+ and MAPK assays |
Annals of the New York Academy of Sciences |
Medium |
31339586
|
| 2019 |
The C-terminal fragment (CTF) of latrophilin-1/ADGRL1 in synapses is phosphorylated on multiple sites. Phosphorylated CTF has high affinity for the N-terminal fragment (NTF) and co-purifies with it. Dephosphorylated CTF has lower affinity for NTF and can behave as a separate protein. α-Latrotoxin binding to NTF brings it together with receptor-like protein tyrosine phosphatase σ (RPTPσ), leading to CTF dephosphorylation and CTF release from the NTF–CTF complex. |
Affinity column co-purification, sucrose density gradient fractionation, phosphorylation analysis of synaptic preparations, α-latrotoxin binding experiments |
Annals of the New York Academy of Sciences |
Medium |
31553068
|
| 2022 |
ADGRL1 haploinsufficiency impairs ligand-induced regulation of intracellular Ca2+ influx (shown by in vitro expression of human variants in neuroblastoma cells). In Adgrl1 knockout mice, loss of ADGRL1 causes increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate from synaptic preparations, and Adgrl1-null neurons form synapses poorly in vitro, demonstrating that ADGRL1 regulates neurotransmitter release and synapse formation. |
In vitro Ca2+ influx assays in neuroblastoma cells expressing human ADGRL1 variants; ex vivo synaptic preparations measuring spontaneous exocytosis; in vitro synapse formation assay in Adgrl1-/- neurons; mouse knockout on two genetic backgrounds |
American journal of human genetics |
High |
35907405
|
| 2023 |
TAFA2 (a CNS-specific cytokine) directly binds to the lectin-like domain (Lec domain) of ADGRL1. This interaction activates the cAMP/PKA/CREB/BCL2 signaling pathway to suppress apoptosis. Overexpression of ADGRL1 lacking the Lec domain (ADGRL1ΔLec) failed to mediate TAFA2's anti-apoptotic effects, and ADGRL1-/- cells were unresponsive to recombinant TAFA2. |
Co-immunoprecipitation, quantitative mass spectrometry proteomics, pull-down assays, ADGRL1 knockout and Lec-deletion mutant overexpression, cAMP/p-PKA/p-CREB/BCL2 signaling measurements, apoptosis assays |
Life sciences |
High |
37944639
|
| 2023 |
ADGRL1 binds glucose and functions as a glucose receptor in hypothalamic neurons. Validated by ligand-receptor binding assays in CHO cells stably expressing human ADGRL1. Adgrl1-deficient mice showed impaired glucose sensing by VMH neurons (electrophysiology), fasting hyperinsulinemia, enhanced glucose-stimulated insulin secretion, insulin resistance, and impaired feeding responses, demonstrating a role for ADGRL1 in energy and glucose homeostasis. |
Cell-based affinity chromatography to enrich glucose-bound neurons, proteomics identification, ligand-receptor binding assays in ADGRL1-expressing CHO cells, global and hypothalamus-specific Adgrl1 knockout mice, electrophysiology of VMH neurons, metabolic phenotyping |
Diabetologia |
High |
37712955
|
| 2024 |
ADGRL1/LPHN1 deficiency in mice causes increased food consumption and severe obesity with dysregulated glucose homeostasis, and a partially inactivating human ADGRL1 mutation was identified in an obese patient, establishing ADGRL1 as a regulator of energy balance. |
Adgrl1-deficient mouse metabolic phenotyping (food intake, body weight, glucose homeostasis); human genetic variant functional characterization |
Signal transduction and targeted therapy |
Medium |
38664368
|
| 2026 |
ADGRL1 ablation activates type I interferon signaling and promotes JAK/STAT1-dependent Decorin secretion by disrupting the GSK3β/β-catenin pathway, which facilitates cDC1–CD8+ T cell hub formation and anti-tumor immunity. An ADGRL1-targeting small molecule identified by virtual screening and DARTS showed antitumor efficacy in vivo. |
RNAi screening in Drosophila tumor model, single-cell transcriptomics, genetic KO in mice, pathway analysis (IFN/JAK/STAT1, GSK3β/β-catenin), Decorin secretion assays, PD-1 blockade combination, DARTS-based compound identification, in vivo tumor models |
Cell reports |
Medium |
42172123
|
| 2026 |
ADGRL1/Latrophilin-1 recruits β-arrestins (βarr) constitutively at the plasma membrane and early endosomes. βarr recruitment is prerequisite for G-protein activation (all four G-protein families: Gs, Gi/o, Gq, G13); βarr or dynamin depletion suppressed G-protein biosensor activation, indicating endosomal priming of G-protein signaling. Splice-variant SSB determines differential trafficking kinetics and distinct βarr/G-protein complex assemblies (shared for Gs, divergent for Gq and G13) upon neurexin-1β stimulation. |
G-protein BRET biosensors, β-arrestin knockdown and knockout in HEK293 cells, dynamin inhibition, endosome-targeted biosensors, splice variant overexpression, receptor internalization imaging |
Biochimica et biophysica acta. Molecular cell research |
High |
41819453
|
| 2024 |
ADGRL1 acts as a functional receptor for hevin/SPARCL1 in nucleus accumbens neurons. Hevin interacts with membrane-expressed ADGRL1, induces its internalization, stabilizes the uncleaved receptor fraction, and alters ADGRL1/Neurexin-1-mediated intercellular adhesion contacts. Hevin stimulation selectively modulates ADGRL1 G-protein coupling with bias toward Gi3, Gs, and G13. Pan-neuronal Adgrl1 deficiency in the nucleus accumbens impairs cocaine-induced reinforcement and reward. |
Co-IP, receptor internalization assays, cell adhesion assays, G-protein coupling BRET assays, mouse Adgrl1 knockdown in NAc, cocaine conditioned place preference and self-administration |
bioRxivpreprint |
Medium |
bio_10.1101_2024.07.03.601736
|
| 2025 |
Teneurin-4 (Ten4) switches between homophilic (Ten4–Ten4) and heterophilic (Ten4–ADGRL1/Latrophilin) interactions to direct cortical neuron migration along radial glial cells: in the intermediate zone, Ten4–Latrophilin/ADGRL1 interactions promote neuron–radial glial cell association, while in the cortical plate, Ten4–Ten4 dimerization reduces radial glial cell attachment. Cryo-EM of Ten2 showed that canonical Latrophilin binding is sterically incompatible with Teneurin dimerization, making the two interactions mutually exclusive. |
Single-particle cryo-EM (Ten2 structure), engineered surface mutations disrupting Ten-Ten or Ten-Latrophilin interactions, in vivo gene editing, super-resolution microscopy, proteomics |
bioRxivpreprint |
Medium |
bio_10.1101_2025.09.09.671438
|