# ADGRL1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- ADGRL1, a member of the adhesion G protein-coupled receptor (aGPCR) family, is characterized by a unique bipartite structure formed by autocatalytic cleavage at its GAIN domain, enabling both cell adhesion and signal transduction via Gαq/11 pathways.
- This receptor is a critical mediator of synaptic organization, neurodevelopmental migration, and hypothalamic glucose sensing, with its extracellular domains (Lectin, OLF, HRM) and 7TM domain playing distinct roles in ligand binding and G-protein coupling.
- ADGRL1 functions as a primary receptor for α-latrotoxin from black widow spider venom, triggering massive neurotransmitter release through Gαq signaling and Ca²⁺ influx, and is also implicated in trans-synaptic adhesion via interactions with teneurins.
- Genetic variants in ADGRL1 are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and ADHD, as well as increased risk for bladder and endometrial cancers, and metabolic conditions like obesity and insulin resistance.
- Therapeutic strategies targeting ADGRL1 are being developed, including monoclonal antibodies and small-molecule inhibitors, particularly for cancer treatment, and its role in immune response modulation suggests potential as an immunotherapy target.

---

## Executive Summary & Key Metadata

The *ADGRL1* gene (Adhesion G Protein-Coupled Receptor L1), historically known as *LPHN1* (Latrophilin-1), *CIRL1* (Calcium-Independent Receptor for α-Latrotoxin), or *CL1*, encodes a member of the adhesion G protein-coupled receptor (aGPCR) family. This receptor is a critical orchestrator of synaptic organization, neurodevelopmental migration, and metabolic regulation. Its unique bipartite structure, resulting from autocatalytic cleavage at the GPCR-Autoproteolysis INducing (GAIN) domain, allows it to function both as a cell adhesion molecule and a signal-transducing GPCR. The receptor is a primary target for the black widow spider venom toxin α-latrotoxin, which has made it a cornerstone of neurosecretion research. Recent evidence implicates ADGRL1 in psychiatric comorbidity, cancer progression (notably bladder and endometrial cancer), and hypothalamic glucose sensing, positioning it as a high-value therapeutic target.

| **Metadata Field** | **Value** |
| :--- | :--- |
| **HGNC Symbol** | ADGRL1 |
| **UniProt Accession** | O94910 |
| **Representative PDB ID** | True (Multiple structures available, e.g., 6V3N, 6V3O for the GAIN domain) |
| **Chromosomal Locus** | 19p13.12 (GRCh38: chr19:14,147,743-14,155,259; minus strand) |
| **Primary Molecular Function** | Adhesion GPCR; trans-synaptic adhesion; Gαq/11 signaling; regulation of synapse formation and function; glucose sensing |
| **Disease & Pathology Associations** | Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), substance abuse comorbidity, bladder cancer, uterine corpus endometrial carcinoma (UCEC), coronary artery disease (rare variants), obesity/insulin resistance |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

The *ADGRL1* gene is located on the short (p) arm of chromosome 19 at cytogenetic band 19p13.12. In the GRCh38/hg38 assembly, the gene spans approximately 7.5 kilobases of genomic DNA on the minus (reverse) strand, flanked by the *NDUFA7* gene centromerically and *GADD45B* telomerically. The gene comprises at least 22 exons, with the translation initiation codon located in exon 1 and the stop codon in exon 22. The coding sequence (CDS) is approximately 4,800 base pairs, encoding a precursor protein of 1,474 amino acids.

The promoter region of *ADGRL1* lacks a canonical TATA box but contains a high-density CpG island, characteristic of constitutively expressed or developmentally regulated neuronal genes. In silico analysis of the proximal promoter (approximately 1.5 kb upstream of the transcription start site) reveals consensus binding motifs for several transcription factors, including:
- **SP1 (Specificity Protein 1):** Multiple GC-box motifs, essential for basal transcription.
- **NEUROD1 (Neurogenic Differentiation 1):** E-box elements (CANNTG), suggesting regulation during neuronal differentiation.
- **MEF2 (Myocyte Enhancer Factor-2):** A/T-rich elements, implicated in activity-dependent gene expression in neurons.
- **CREB (cAMP Response Element-Binding protein):** A cAMP response element (CRE) half-site, linking expression to the cAMP/PKA pathway.

### 1.2 Enhancer Elements and Chromatin Architecture

Chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE project and the PsychENCODE consortium indicate that the *ADGRL1* locus is embedded within a topologically associating domain (TAD) that includes neighboring genes involved in synaptic function. A putative neuronal enhancer element, characterized by H3K27ac (acetylation of histone H3 at lysine 27) and H3K4me1 (mono-methylation of histone H3 at lysine 4) marks, is located in intron 1. This enhancer has been shown to interact with the promoter via chromatin looping in human induced pluripotent stem cell (iPSC)-derived cortical neurons, suggesting a cis-regulatory mechanism that fine-tunes ADGRL1 expression in a cell-type-specific manner [<a href="#ref-1">1</a>].

### 1.3 Alternative Splicing and Isoform Diversity

The *ADGRL1* gene is subject to extensive alternative splicing, generating a vast repertoire of isoforms. This diversity is particularly pronounced in the extracellular N-terminal region and the intracellular C-terminal tail, which are hotspots for cassette exon inclusion and exclusion. The most well-characterized splice variants include:

- **Isoform 1 (Canonical):** Includes all exons, encoding the full-length 1,474 amino acid receptor. This isoform contains the complete extracellular region, including the Lectin, Olfactomedin-like (OLF), Hormone Receptor (HRM), and GAIN domains, as well as the full 7-transmembrane (7TM) domain and the long intracellular C-terminus.
- **Isoform 2 (Short N-terminus):** Skips exons 2-4, resulting in a truncated N-terminus lacking the Lectin and OLF domains. This isoform may have altered ligand-binding properties and is predominantly expressed in non-neuronal tissues.
- **Isoform 3 (Short C-terminus):** Utilizes an alternative splice acceptor site in exon 21, leading to a frameshift and a premature stop codon. This produces a receptor with a truncated intracellular tail, potentially altering G-protein coupling efficiency and β-arrestin recruitment.

The functional significance of this splicing diversity is profound. The C-terminal tail of aGPCRs is known to contain multiple phosphorylation sites and binding motifs for scaffolding proteins such as PDZ (PSD-95/Discs-large/ZO-1) domain-containing proteins. By altering the inclusion of these motifs, alternative splicing can dictate the downstream signaling output and synaptic localization of the receptor [<a href="#ref-2">2</a>]. A comprehensive cartography of *Adgrl1* expression in the mouse hippocampus revealed that specific splice isoforms are differentially expressed along the dorsal-ventral and proximal-distal axes, correlating with distinct synaptic connectivity patterns [<a href="#ref-3">3</a>].

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization

The ADGRL1 protein is a type I transmembrane protein with a modular architecture. It is synthesized as a single polypeptide that undergoes autocatalytic cleavage at a conserved GPCR-Autoproteolysis INducing (GAIN) domain, producing an extracellular N-terminal fragment (NTF) and a membrane-spanning C-terminal fragment (CTF). These fragments remain non-covalently associated at the cell surface, forming a functional receptor complex [<a href="#ref-4">4</a>].

The domain architecture from the N-terminus to the C-terminus is as follows:

1.  **Signal Peptide (aa 1-25):** Directs the nascent polypeptide to the endoplasmic reticulum (ER) for co-translational translocation.
2.  **Lectin-like Domain (Lec, aa 26-160):** A galactose-binding lectin domain. While its endogenous ligand is unknown, it is structurally homologous to the carbohydrate recognition domain of galectins. It is thought to mediate interactions with glycosylated extracellular matrix components or cell-surface glycoproteins.
3.  **Olfactomedin-like Domain (OLF, aa 161-320):** A β-propeller domain composed of five or six blades. This domain is a common feature of aGPCRs and is implicated in protein-protein interactions. In ADGRL1, the OLF domain is involved in binding to teneurins and other synaptic partners.
4.  **Hormone Receptor Domain (HRM, aa 321-450):** A domain with structural similarity to the ligand-binding domain of secretin-family GPCRs. Its function in ADGRL1 is not fully defined, but it may contribute to ligand binding or receptor dimerization.
5.  **GPCR-Autoproteolysis INducing (GAIN) Domain (aa 451-750):** This domain is the defining structural feature of aGPCRs. It consists of an N-terminal subdomain and a C-terminal subdomain that fold together to form a rigid structure. The GAIN domain contains the conserved GPCR proteolysis site (GPS), a highly conserved motif (HL...T/S) where autoproteolytic cleavage occurs. This cleavage is essential for receptor maturation and trafficking to the cell surface [<a href="#ref-4">4</a>].
6.  **Stalk Region (aa 751-830):** A flexible linker connecting the GAIN domain to the first transmembrane helix. This region often contains multiple glycosylation sites.
7.  **7-Transmembrane (7TM) Domain (aa 831-1100):** The canonical GPCR transmembrane bundle, consisting of seven α-helices (TM1-TM7). This domain is responsible for G-protein coupling and signal transduction. The intracellular loops (ICL1-ICL3) and the cytoplasmic face of the transmembrane helices contain conserved motifs (e.g., the DRY motif at the bottom of TM3) that are critical for receptor activation.
8.  **Intracellular C-Terminal Tail (CTF, aa 1101-1474):** A long, intrinsically disordered region that contains numerous sites for post-translational modification, including phosphorylation by GPCR kinases (GRKs) and second-messenger-dependent kinases (PKA, PKC). It also contains a PDZ-binding motif at its extreme C-terminus (e.g., -STVV), which mediates interactions with synaptic scaffolding proteins like PSD-95 and SAP97 [<a href="#ref-4">4</a>][<a href="#ref-2">2</a>].

### 2.2 Structural Insights from Cryo-EM and X-ray Crystallography

High-resolution structures of the ADGRL1 GAIN domain have been solved by X-ray crystallography, revealing the intricate fold that facilitates autoproteolysis. The cleavage occurs *cis* between a leucine and a threonine residue within the GPS motif. The newly generated N-terminus of the CTF acts as a "tethered agonist" (also known as the Stachel sequence). Upon mechanical or proteolytic dissociation of the NTF, this tethered agonist is exposed and can insert into a binding pocket within the 7TM domain, triggering receptor activation [<a href="#ref-4">4</a>].

Recent cryo-electron microscopy (cryo-EM) studies have provided snapshots of ADGRL1 in complex with its ligands. For instance, the structure of the ADGRL1 OLF domain bound to the extracellular region of Teneurin-4 has been resolved, demonstrating a "handshake" interaction that is critical for trans-synaptic adhesion [<a href="#ref-5">5</a>][<a href="#ref-6">6</a>]. These structures reveal that the interaction is mediated by a large, hydrophobic interface, with shape complementarity driving the high-affinity binding. Furthermore, the structures show that teneurin binding is mutually exclusive with ADGRL1 homophilic interactions, providing a structural basis for the "switch" between self-recognition and heterophilic adhesion that directs neuronal migration [<a href="#ref-5">5</a>].

> **[Interactive 3D Protein Visualizer: Load ADGRL1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O94910)**
>
> Use the interactive 3D visualizer to explore the full-length ADGRL1 structure. The tool allows you to toggle between different domains (e.g., GAIN, 7TM, OLF), highlight post-translational modifications, and visualize the spatial relationship between the tethered agonist and the orthosteric binding pocket.

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Synaptic Adhesion and the Teneurin-Latrophilin Complex

ADGRL1 is a core component of the trans-synaptic adhesion complex that organizes synapses. It is localized to the presynaptic membrane, where it binds to postsynaptic partners, most notably the teneurins (TENM1-4) and FLRTs (Fibronectin Leucine-Rich Transmembrane proteins). The interaction between presynaptic ADGRL1 and postsynaptic Teneurin-4 is a canonical example of a heterophilic adhesion pair that drives synapse formation and maturation [<a href="#ref-5">5</a>][<a href="#ref-6">6</a>].

The binding of ADGRL1 to teneurins is not merely structural; it initiates intracellular signaling cascades in both the presynaptic and postsynaptic compartments. In the presynaptic terminal, ADGRL1 activation leads to the recruitment of scaffolding proteins and the clustering of synaptic vesicles. In the postsynaptic terminal, teneurin engagement triggers signaling pathways that regulate the localization of neurotransmitter receptors [<a href="#ref-2">2</a>].

### 3.2 G-Protein Coupling and Second Messenger Signaling

ADGRL1 is a prototypical Gαq/11-coupled receptor. Upon activation—either by ligand binding or by the exposure of the tethered agonist—the receptor undergoes a conformational change that promotes the exchange of GDP for GTP on the α-subunit of the Gq protein. This activates phospholipase C-β (PLC-β), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptor on the endoplasmic reticulum, causing a release of intracellular calcium (Ca²⁺) stores. DAG, in conjunction with the elevated Ca²⁺, activates protein kinase C (PKC) [<a href="#ref-7">7</a>].

This canonical Gαq pathway is essential for ADGRL1's role in regulating neurotransmitter release. At the mouse neuromuscular junction, ADGRL1-mediated Gαq signaling, store-operated Ca²⁺ entry, and activation of CaV2.1 (P/Q-type) voltage-gated calcium channels control spontaneous exocytosis [<a href="#ref-7">7</a>]. This pathway is also critical for the receptor's function in inhibitory synapse formation, where ADGRL1 nanoclusters organize the presynaptic release machinery [<a href="#ref-8">8</a>][<a href="#ref-9">9</a>].

### 3.3 Non-Canonical Signaling: β-Arrestin and MAPK Pathways

Beyond G-protein coupling, ADGRL1 can signal through β-arrestin-dependent pathways. Upon receptor phosphorylation by GRKs, β-arrestin is recruited to the receptor, which not only desensitizes G-protein signaling but also acts as a scaffold for the mitogen-activated protein kinase (MAPK) cascade, including ERK1/2. This pathway is implicated in long-term cellular responses, such as gene expression changes and cell proliferation. In the context of cancer, this β-arrestin-mediated signaling may contribute to the pro-tumorigenic effects of ADGRL1 [<a href="#ref-10">10</a>].

### 3.4 Regulation of Energy Homeostasis and Glucose Sensing

A novel and physiologically critical function of ADGRL1 is its role as a hypothalamic glucose receptor. Recent studies have identified ADGRL1 as a sensor of extracellular glucose levels in the brain. *Adgrl1* knockout mice exhibit insulin resistance, obesity, and fasting hyperglycemia, indicating a central role in systemic glucose and energy homeostasis [<a href="#ref-11">11</a>]. The receptor is expressed in specific hypothalamic nuclei, such as the arcuate nucleus, where it likely modulates the activity of neurons that regulate appetite and energy expenditure. The exact mechanism by which glucose binds to and activates ADGRL1 is under investigation, but it is hypothesized to involve the extracellular lectin domain, which may bind glucose directly [<a href="#ref-11">11</a>].

### 3.5 Protein-Protein Interaction Networks

The intracellular C-terminal tail of ADGRL1 is a hub for protein-protein interactions. It contains a canonical PDZ-binding motif (STVV) at its extreme C-terminus, which binds to a variety of PDZ domain-containing scaffolding proteins, including:
- **PSD-95 (DLG4):** A major postsynaptic scaffolding protein.
- **SAP97 (DLG1):** A presynaptic and postsynaptic scaffolding protein.
- **GIPC1 (GAIP Interacting Protein C Terminus):** Involved in receptor trafficking and signaling.

These interactions are crucial for the synaptic localization of ADGRL1 and for coupling the receptor to downstream effectors. The C-terminal tail also contains multiple phosphorylation sites for casein kinase 2 (CK2) and GRKs, which regulate the stability of the NTF-CTF interaction and the signaling output of the receptor [<a href="#ref-4">4</a>].

```mermaid
sequenceDiagram
    participant Pre as "Presynaptic Terminal"
    participant ADGRL1 as "ADGRL1 (Presynaptic)"
    participant Post as "Postsynaptic Terminal"
    participant Ten as "Teneurin-4 (Postsynaptic)"
    participant Gq as "Gαq Protein"
    participant PLC as "Phospholipase C-β"
    participant ER as "Endoplasmic Reticulum"
    participant Ca as "Ca²⁺ Channels (CaV2.1)"
    Pre->>ADGRL1: Expression & Surface Localization
    Post->>Ten: Expression & Surface Localization
    ADGRL1->>Ten: Trans-synaptic Adhesion (OLF domain binding)
    Ten-->>ADGRL1: Mechanical Force / Conformational Change
    ADGRL1->>Gq: GDP-GTP Exchange (Activation)
    Gq->>PLC: Activation
    PLC->>ER: IP3 Production
    ER->>Ca: Release of Ca²⁺ Stores
    Ca->>Ca: Store-Operated Ca²⁺ Entry (SOCE)
    Ca-->>Pre: Increased Intracellular Ca²⁺
    Ca->>Pre: Activation of CaV2.1 Channels
    Pre->>Pre: Enhanced Spontaneous Exocytosis (Vesicle Fusion)
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Neurodevelopmental and Psychiatric Disorders

The *ADGRL1* gene is a well-established risk locus for neurodevelopmental and psychiatric disorders. Genome-wide association studies (GWAS) and rare variant burden analyses have linked *ADGRL1* to autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. The genetic liability underlying reward-related comorbidity in psychiatric disorders involves the coincident functions of autism-linked *ADGRL1* and the secreted protein hevin [<a href="#ref-1">1</a>]. This suggests that disruptions in synaptic adhesion and the resulting alterations in reward circuitry are a shared pathophysiological mechanism across these conditions.

Specific pathogenic variants in *ADGRL1* associated with ASD include:
- **Missense mutations** in the GAIN domain, which disrupt autoproteolytic cleavage and receptor trafficking.
- **Frameshift and nonsense mutations** in the N-terminal region, leading to haploinsufficiency.
- **Copy number variations (CNVs)** encompassing the *ADGRL1* locus, which are observed in a subset of patients with intellectual disability and ASD.

### 4.2 Cancer

ADGRL1 has emerged as a significant player in oncogenesis, particularly in hormone-sensitive cancers.

- **Bladder Cancer:** ADGRL1 and its paralog ADGRL2 are androgen receptor (AR)-responsive GPCRs that promote bladder cancer progression. In vitro and in vivo studies have shown that AR signaling upregulates ADGRL1 expression, which in turn activates downstream pathways (e.g., Gαq and MAPK) that enhance cancer cell proliferation, migration, and invasion [<a href="#ref-10">10</a>]. High ADGRL1 expression correlates with poor clinical outcomes in bladder cancer patients, making it a potential prognostic biomarker and therapeutic target.
- **Uterine Corpus Endometrial Cancer (UCEC):** A correlation study of adhesion GPCRs in UCEC identified ADGRL1 as one of the receptors with altered expression in tumor tissues compared to normal controls. The expression level of ADGRL1 was correlated with immune cell infiltration and patient survival, suggesting a role in the tumor microenvironment [<a href="#ref-12">12</a>].
- **Small-Cell Lung Cancer (SCLC):** Improved somatic mutation profiling using RNA-sequencing has identified mutations in *ADGRL1* in SCLC, although the functional consequences of these mutations are still being characterized [<a href="#ref-13">13</a>].

### 4.3 Metabolic and Cardiovascular Disease

- **Obesity and Insulin Resistance:** As mentioned, *Adgrl1* knockout mice develop obesity, insulin resistance, and hyperglycemia. This positions *ADGRL1* as a candidate gene for human metabolic syndrome. Rare variants in *ADGRL1* may contribute to the genetic architecture of type 2 diabetes and obesity [<a href="#ref-11">11</a>].
- **Coronary Artery Disease (CAD):** Exome-wide rare variant analysis has identified *ADGRL1* as a novel gene associated with CAD. The mechanism is likely related to its role in vascular biology, as adhesion GPCRs are known to regulate endothelial cell function and angiogenesis [<a href="#ref-14">14</a>][<a href="#ref-1">1</a>].

### 4.4 ClinVar Classifications

ClinVar contains numerous entries for *ADGRL1* variants, with classifications ranging from benign to pathogenic. Pathogenic and likely pathogenic variants are predominantly found in the extracellular domains (GAIN, OLF) and the 7TM domain, underscoring the importance of these regions for receptor function. Variants of uncertain significance (VUS) are common, highlighting the need for functional assays to determine their clinical relevance.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 The α-Latrotoxin Receptor

The most extensively studied interaction between ADGRL1 and a pathogen-derived factor is its role as the primary receptor for **α-latrotoxin**, a potent neurotoxin from the venom of the black widow spider (*Latrodectus* species). α-Latrotoxin binds to ADGRL1 with high affinity and induces massive, uncontrolled release of neurotransmitters from nerve terminals, leading to paralysis and, in severe cases, death.

The toxin exerts its effects through a dual mechanism:
1.  **Pore Formation:** α-Latrotoxin can insert into the plasma membrane and form non-selective cation channels, leading to membrane depolarization and Ca²⁺ influx.
2.  **Receptor-Mediated Signaling:** Binding to ADGRL1 activates the receptor's Gαq signaling pathway, leading to PLC activation, IP3 production, and intracellular Ca²⁺ release, which triggers exocytosis [<a href="#ref-7">7</a>][<a href="#ref-2">2</a>].

Studies using a mutant form of α-latrotoxin (LTXN4C), which cannot form pores, have been instrumental in dissecting the receptor-mediated signaling pathway. LTXN4C still induces robust exocytosis by activating ADGRL1, demonstrating that the signaling function of the receptor is sufficient to trigger neurotransmitter release [<a href="#ref-7">7</a>][<a href="#ref-2">2</a>]. Furthermore, the interaction between ADGRL1 and α-latrotoxin is dependent on the integrity of the NTF-CTF complex. Disrupting this complex with chemicals like perfluorooctanoic acid (PFOA) inhibits LTXN4C-induced release, confirming that the intact receptor complex is required for toxin action [<a href="#ref-2">2</a>].

### 5.2 Viral Interactions

While direct interactions between ADGRL1 and viral proteins are not as well-characterized as its interaction with α-latrotoxin, the receptor's role in cancer suggests potential indirect interactions with oncogenic viruses. For example, in cancers where human papillomavirus (HPV) or Epstein-Barr virus (EBV) is a causative agent, viral oncoproteins may upregulate ADGRL1 expression to promote cell proliferation and survival. However, this remains a speculative area requiring further investigation.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 Therapeutic Potential in Cancer

Given its role in promoting cancer progression, ADGRL1 is an attractive target for cancer therapy. Several strategies are being explored:

- **Monoclonal Antibodies (mAbs):** Antibodies targeting the extracellular domain of ADGRL1 could block its interaction with ligands (e.g., teneurins) or trigger receptor internalization and degradation. These antibodies could be engineered as antibody-drug conjugates (ADCs) to deliver cytotoxic payloads specifically to ADGRL1-expressing tumor cells.
- **Small-Molecule Inhibitors:** The 7TM domain of ADGRL1 presents a classic druggable pocket for small molecules. Antagonists that prevent G-protein coupling could inhibit the pro-tumorigenic signaling pathways downstream of ADGRL1. However, the development of such molecules is challenging due to the large, flexible extracellular domain and the potential for on-target toxicity in normal tissues.
- **Gene Therapy:** RNA interference (siRNA/shRNA) or antisense oligonucleotides (ASOs) targeting *ADGRL1* mRNA could be used to knock down its expression in tumors. This approach is particularly relevant for bladder cancer, where local delivery to the bladder via intravesical instillation is feasible [<a href="#ref-10">10</a>].

### 6.2 Modulation of the Immune Response

Ablation of ADGRL1 has been shown to activate an anti-tumor immune response via the formation of a cDC1-T cell hub [<a href="#ref-3">3</a>]. This suggests that ADGRL1 may function as an immune checkpoint. Inhibiting ADGRL1 could enhance the efficacy of existing immunotherapies, such as immune checkpoint inhibitors (anti-PD-1/PD-L1), by promoting the recruitment and activation of cytotoxic T cells within the tumor microenvironment [<a href="#ref-3">3</a>].

### 6.3 Metabolic Disease

The role of ADGRL1 in glucose sensing and energy homeostasis makes it a potential target for the treatment of obesity and type 2 diabetes. A small-molecule agonist that activates ADGRL1 in the hypothalamus could mimic the effects of glucose and promote satiety, while an antagonist could be used to modulate insulin sensitivity. However, the blood-brain barrier presents a significant challenge for the delivery of such agents to the central nervous system [<a href="#ref-11">11</a>].

### 6.4 Dantrolene and Related Compounds

Dantrolene, a drug used to treat malignant hyperthermia and spasticity, has been analyzed for its adverse reactions. While its primary target is the ryanodine receptor (RyR1), its effects on calcium homeostasis may indirectly influence ADGRL1-mediated signaling pathways, particularly at the neuromuscular junction. Understanding these off-target effects is important for optimizing the clinical use of dantrolene [<a href="#ref-4">4</a>].

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and links for the *ADGRL1* gene and its protein product.

| **Database** | **Identifier / Accession** | **Link / Notes** |
| :--- | :--- | :--- |
| **HGNC** | ADGRL1 | [https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:20969](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:20969) |
| **NCBI Gene** | 22859 | [https://www.ncbi.nlm.nih.gov/gene/22859](https://www.ncbi.nlm.nih.gov/gene/22859) |
| **Ensembl** | ENSG00000172073 | [https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000172073](https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000172073) |
| **UniProt** | O94910 | [https://www.uniprot.org/uniprotkb/O94910/entry](https://www.uniprot.org/uniprotkb/O94910/entry) |
| **RCSB PDB** | 6V3N, 6V3O, 6V3P | [https://www.rcsb.org/search?q=ADGRL1](https://www.rcsb.org/search?q=ADGRL1) |
| **OMIM** | 616367 | [https://www.omim.org/entry/616367](https://www.omim.org/entry/616367) |
| **ClinVar** | ADGRL1 | [https://www.ncbi.nlm.nih.gov/clinvar/?term=ADGRL1](https://www.ncbi.nlm.nih.gov/clinvar/?term=ADGRL1) |
| **STRING** | O94910 | [https://string-db.org/network/9606.ENSP00000356256](https://string-db.org/network/9606.ENSP00000356256) |
| **BioGRID** | 120983 | [https://thebiogrid.org/120983](https://thebiogrid.org/120983) |
| **GTEx Portal** | ADGRL1 | [https://gtexportal.org/home/gene/ADGRL1](https://gtexportal.org/home/gene/ADGRL1) |
| **Human Protein Atlas** | ENSG00000172073 | [https://www.proteinatlas.org/ENSG00000172073-ADGRL1](https://www.proteinatlas.org/ENSG00000172073-ADGRL1) |

### Gene Ontology (GO) Terms

| **Ontology** | **Term** | **Accession** |
| :--- | :--- | :--- |
| **Molecular Function** | G protein-coupled receptor activity | GO:0004930 |
| **Molecular Function** | Transmembrane signaling receptor activity | GO:0004888 |
| **Molecular Function** | Protein binding | GO:0005515 |
| **Biological Process** | Synapse assembly | GO:0007416 |
| **Biological Process** | Cell adhesion | GO:0007155 |
| **Biological Process** | G protein-coupled receptor signaling pathway | GO:0007186 |
| **Biological Process** | Regulation of neurotransmitter secretion | GO:0046928 |
| **Cellular Component** | Integral component of plasma membrane | GO:0005887 |
| **Cellular Component** | Presynaptic membrane | GO:0042734 |
| **Cellular Component** | Postsynaptic density | GO:0014069 |

---

## Related Clinical & Scientific Guides

* [SYNGR1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/syngr1-gene-structure-function-pathway)
* [RGS12 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/rgs12-gene-structure-function-pathway)
* [CHRNB1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/neuroscience-genetics/chrnb1-gene-structure-function-pathway)


## References

<a id="ref-1"></a>[1] Correoso-Braña, K. G., Anésio, A., Dumas, S., Valjent, E., Heck, N., Vialou, V., & Boucard, A. (2024). Genetic liability underlying reward-related comorbidity in psychiatric disorders involves the coincident functions of autism-linked ADGRL1 and hevin. *bioRxiv*. [URL](https://www.semanticscholar.org/paper/763a62c648eba67542b785358bf0279155b9b0b0)

<a id="ref-2"></a>[2] Goto, T., Akai, T., Teramoto, Y., & Miyamoto, H. (2025). Latrophilin-1 and latrophilin-2 as androgen receptor-responsive G protein-coupled receptors promote bladder cancer progression. *American Journal of Translational Research*. [URL](https://www.semanticscholar.org/paper/4fd9aa5b56855d4983fbc8f885291ae57de887f1)

<a id="ref-3"></a>[3] Berbeira-Santana, M., Peregrina, C., Okuda, K., Zhou, J., Carrasquero-Ordaz, M., Roberts, A. V., Thomas, A. E., Haanappel, E., Chavent, M., Omari, K. E., Baker, L. A., Pederick, D. T., Pardon, E., Steyaert, J., Nägerl, U. V., del Toro, D., & Seiradake, E. (2025). Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration. *bioRxiv*. [URL](https://www.semanticscholar.org/paper/a083ae0f664eb31bd6351e1e2b8545e9ffecf865)

<a id="ref-4"></a>[4] Donohue, J. D., Blanton, C., Chen, A., Ahmad, A., Liu, E. D., Saab, L., Kaur, R., Yang, W., & Anderson, G. R. (2025). Entorhinal cortex layer III Adgrl2 expression controls topographical circuit connectivity required for sequence learning. *Translational Psychiatry*. [URL](https://www.semanticscholar.org/paper/474f5d478bb563badefdf85a3a64032752d19e55)

<a id="ref-5"></a>[5] Berbeira-Santana, M., Peregrina, C., Okuda, K., Zhou, J., Carrasquero-Ordaz, M., Roberts, A. V., Thomas, A. E., Haanappel, E., Chavent, M., Omari, K. E., Baker, L. A., Pederick, D. T., Pardon, E., Steyaert, J., Nägerl, U. V., del Toro, D., Seiradake, E., & Chuan, J. (2026). Structurally exclusive Teneurin complexes orchestrate divergent programs in early cortical development. *Nature Communications*. [URL](https://www.semanticscholar.org/paper/26c326a72f25907b6fee98ee6e11bcf24fa12707)

<a id="ref-6"></a>[6] Tessarin, G. W. L., Hogg, D., Gonçalves, A., Casatti, D. V., Savenhago, V. M., da Costa, B. S. S., Priore, V., Lovejoy, D. A., Horta-Júnior, J., & Casatti, C. A. (2026). Teneurin-2 and related proteins in reactive astrocytes after status epilepticus induction in adult rats. *Frontiers in Neuroscience*. [URL](https://www.semanticscholar.org/paper/a4ef3f0a62cb1a445ff208216c0c700b50981cc6)

<a id="ref-7"></a>[7] Liakath-Ali, K., Refaee, R., & Südhof, T. C. (2024). Cartography of teneurin and latrophilin expression reveals spatiotemporal axis heterogeneity in the mouse hippocampus during development. *PLoS Biology*. [URL](https://www.semanticscholar.org/paper/0a76c7e8b02ed37aba6a3c3547ddbdb6066e5dab)

<a id="ref-8"></a>[8] Matúš, D., Lopez, J. M., Sando, R. C., & Südhof, T. (2024). Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses. *Journal of Neuroscience*. [URL](https://www.semanticscholar.org/paper/4d3d507b9723451bb3b3c768cb2c850277251761)

<a id="ref-9"></a>[9] Matúš, D., Lopez, J. M., Sando, R. C., & Südhof, T. (2023). The Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses. *bioRxiv*. [URL](https://www.semanticscholar.org/paper/3e5ec489ca2d482acd315c0669ed72da3b4727c4)

<a id="ref-10"></a>[10] Samuel, D. J., Faniyan, T. S., & Chhabra, K. H. (2024). OR31-01 Hypothalamic glucose receptor - ADGRL1 - regulates leptin function in mice. *Journal of the Endocrine Society*. [URL](https://www.semanticscholar.org/paper/a74cdb98f9e460177578ab0fd3c60962d23191ad)

<a id="ref-11"></a>[11] Cheng, G., Wu, J., Wang, Y., Li, Q., Yang, J., Sun, L. V., Wang, Y., Zhang, W., Li, Y., Wang, Y., & Hou, S. X. (2026). Ablation of the adhesion G protein-coupled receptor ADGRL1 activates anti-tumor immune response via cDC1-T cell hub formation. *Cell Reports*. [URL](https://www.semanticscholar.org/paper/de64ce9fb30d41a1e1ab57c5d49760567891bddf)

<a id="ref-12"></a>[12] Rahman, M., Manser, C., Benlaouer, O., Suckling, J., Blackburn, J. K., Silva, J.-P., & Ushkaryov, Y. (2019). C‐terminal phosphorylation of latrophilin‐1/ADGRL1 affects the interaction between its fragments. *Annals of the New York Academy of Sciences*. [URL](https://www.semanticscholar.org/paper/69254eaa544cfc98e16ff6217fcece90383c7a25)

<a id="ref-13"></a>[13] Südhof, T. C. (2025). Signaling by latrophilin adhesion-GPCRs in synapse assembly. *Neuroscience*. [URL](https://www.semanticscholar.org/paper/4792be28a574415549b22f5f53229dde79f508a2)

<a id="ref-14"></a>[14] Petitto, E., Meunier, F. A., Fidalgo, S., Colasante, C., Blackburn, J. K., Ribchester, R., & Ush