# ADGRL2 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- ADGRL2 is a large adhesion G protein-coupled receptor (aGPCR) critically involved in neuronal development, synapse formation, and neuronal network activity, with its gene locus spanning approximately 600 kb on chromosome 1p31.1 and featuring 35 exons.
- The protein undergoes essential autocatalytic cleavage at a conserved GPCR proteolysis site (GPS) within the GAIN domain, generating non-covalently associated N-terminal and C-terminal fragments that mediate trans-synaptic adhesion via interactions with teneurins and neurexins.
- ADGRL2 signals through multiple G protein pathways (Gαq/11, Gαs, Gα12/13), influencing calcium flux, cAMP levels, and RhoA activation, and its C-terminal tail interacts with postsynaptic density proteins like PSD-95, linking synaptic adhesion to intracellular signaling cascades.
- Germline mutations in *ADGRL2* are associated with neurodevelopmental disorders such as autism spectrum disorder and intellectual disability, while its dysregulation is implicated in glioblastoma (promoting invasion) and colorectal cancer (tumor suppression), and it serves as a host factor for SARS-CoV-2 entry.
- Therapeutic strategies targeting ADGRL2 include monoclonal antibodies and small-molecule inhibitors for cancer, and gene therapy or translational read-through agents for neurodevelopmental disorders stemming from loss-of-function mutations.

---

## Executive Summary & Key Metadata

ADGRL2 (Adhesion G Protein-Coupled Receptor L2), also historically designated as CIRL2 (Calcium-Independent Receptor of alpha-Latrotoxin 2) or LPHN2 (Latrophilin-2), encodes a member of the adhesion G protein-coupled receptor (aGPCR) family. These receptors are characterized by a large extracellular N-terminal domain that mediates cell-cell and cell-matrix interactions, coupled to a canonical seven-transmembrane (7TM) domain that transduces intracellular signals. ADGRL2 is prominently expressed in the developing and adult nervous system, where it modulates synapse formation, neuronal migration, and dendritic arborization. Beyond neurobiology, ADGRL2 has been implicated in tumor biology, particularly in glioblastoma and certain epithelial malignancies, where its expression correlates with invasive phenotypes and poor prognosis.

The following table summarizes the key metadata for ADGRL2:

| Attribute | Value |
| :--- | :--- |
| **HGNC Symbol** | ADGRL2 |
| **UniProt Accession** | O95490 |
| **Representative PDB ID** | true (see Section 2 for details) |
| **Chromosomal Locus** | 1p31.1 (GRCh38: chr1:81,215,144-81,815,592, minus strand) |
| **Primary Molecular Function** | Adhesion G protein-coupled receptor; mediates cell-cell adhesion and Gαq/11, Gαs, and Gα12/13 signaling; regulates synapse formation and neuronal network activity |
| **Disease & Pathology Associations** | Neurodevelopmental disorders (autism spectrum disorder, intellectual disability), schizophrenia, glioblastoma, colorectal cancer, and potential roles in viral entry (SARS-CoV-2) |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

The *ADGRL2* gene is located on the short arm of chromosome 1 at band p31.1. The reference genome assembly (GRCh38) places the gene between genomic coordinates 81,215,144 and 81,815,592 on the minus (reverse) strand. The gene spans approximately 600 kilobases (kb) of genomic DNA, making it one of the larger loci in the human genome. This large size is primarily due to extensive intronic sequences, which contain numerous regulatory elements and conserved non-coding regions.

The gene is composed of 35 exons, with the translation initiation codon located in exon 1 and the stop codon in exon 35. The intron-exon boundaries are highly conserved across mammals, reflecting the functional importance of the encoded protein domains. The promoter region of *ADGRL2* lacks a canonical TATA box but contains a high GC content, a hallmark of housekeeping and developmentally regulated genes. Multiple CpG islands are present in the proximal promoter and the first intron, suggesting that DNA methylation plays a role in the tissue-specific regulation of *ADGRL2* expression.

### 1.2 Promoter Architecture and Transcriptional Regulation

The core promoter of *ADGRL2* spans approximately 1,000 base pairs upstream of the transcription start site (TSS). In silico analysis and chromatin immunoprecipitation (ChIP) experiments have identified several conserved transcription factor binding motifs within this region. Key regulators include:

- **SP1 (Specificity Protein 1):** Binds to GC-rich motifs and is essential for basal transcriptional activity.
- **NEUROD1 (Neurogenic Differentiation 1):** A basic helix-loop-helix (bHLH) transcription factor that drives neuronal differentiation and directly activates *ADGRL2* expression in post-mitotic neurons.
- **REST (RE1-Silencing Transcription Factor):** Binds to a conserved RE1 motif in the first intron and represses *ADGRL2* transcription in non-neuronal tissues. This dual regulation (activation by NEUROD1, repression by REST) ensures tight neuronal-specific expression.
- **TCF/LEF (T-Cell Factor/Lymphoid Enhancer Factor):** Mediates Wnt/β-catenin signaling, which has been shown to upregulate *ADGRL2* in neural progenitor cells during cortical development.

Enhancer elements are distributed across the large introns. Notably, an enhancer located in intron 5 has been shown to interact with the promoter via chromatin looping in human brain tissue, as demonstrated by Hi-C and 3C-seq data. This enhancer contains binding sites for the transcription factors FOXG1 and TBR1, both of which are critical for forebrain development. Single nucleotide polymorphisms (SNPs) within this enhancer region have been associated with altered *ADGRL2* expression in the prefrontal cortex, linking them to schizophrenia susceptibility.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing is a major source of functional diversity for ADGRL2. At least five distinct transcript variants have been experimentally validated, encoding protein isoforms that differ primarily in their extracellular domains.

- **Isoform 1 (Canonical, 1,471 amino acids):** This is the longest isoform and contains all functional domains: the N-terminal signal peptide, the olfactomedin-like (OLF) domain, a lectin-like domain, an autoproteolysis-inducing (GAIN) domain, and the 7TM region. It is the predominant isoform in the adult brain.
- **Isoform 2 (1,441 amino acids):** Lacks exon 19, which encodes a portion of the GAIN domain. This isoform exhibits reduced autoproteolytic cleavage and is primarily expressed in fetal brain and certain cancer cell lines.
- **Isoform 3 (1,390 amino acids):** Contains an alternative exon 1b, which replaces the canonical signal peptide with a shorter, hydrophobic sequence. This isoform shows altered subcellular localization, with a higher proportion retained in the endoplasmic reticulum.
- **Isoform 4 (1,210 amino acids):** A truncated variant that lacks the entire 7TM domain. This soluble isoform is secreted and may act as a dominant-negative regulator by sequestering extracellular ligands.
- **Isoform 5 (1,455 amino acids):** Skipping of exon 27 results in a frameshift and a premature stop codon in the third intracellular loop. This isoform is predicted to be non-functional and is likely subject to nonsense-mediated decay (NMD).

The expression of these isoforms is tissue-specific and developmentally regulated. For instance, Isoform 4 is highly expressed in the liver and kidney, whereas Isoform 1 dominates in the cerebral cortex and hippocampus. The dynamic regulation of splicing is controlled by RNA-binding proteins such as PTBP1 (Polypyrimidine Tract-Binding Protein 1) and NOVA2 (Neuro-Oncological Ventral Antigen 2), which bind to intronic splicing enhancers and silencers flanking the alternative exons.

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

### 2.1 Domain Organization

The ADGRL2 protein is a type I transmembrane protein with a large extracellular N-terminus, a 7TM domain, and an intracellular C-terminal tail. The domain architecture, from N-terminus to 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.  **Olfactomedin-like (OLF) Domain (aa 60-220):** A globular domain composed of five-bladed β-propeller structures. This domain mediates protein-protein interactions with extracellular matrix components, including fibronectin and various collagens. In the context of ADGRL2, the OLF domain is critical for trans-synaptic adhesion by binding to postsynaptic partners such as teneurins (TENM2) and neurexins (NRXN1).
3.  **Lectin-like Domain (aa 230-310):** A small domain that adopts a C-type lectin fold. Although it lacks the canonical calcium-binding motif, it contributes to carbohydrate recognition and may modulate ligand specificity.
4.  **Hormone Receptor (HRM) Domain (aa 320-420):** Also known as the latrophilin-specific domain, this region is unique to the ADGRL family. It contains multiple glycosylation sites and is involved in the binding of the spider venom toxin α-latrotoxin.
5.  **Autoproteolysis-Inducing (GAIN) Domain (aa 430-650):** This domain is the defining feature of the adhesion GPCR family. It contains a conserved GPCR proteolysis site (GPS) motif, which undergoes autocatalytic cleavage during maturation in the ER. The cleavage occurs between a leucine and a threonine residue (L-T) within the GPS, generating an N-terminal fragment (NTF) and a C-terminal fragment (CTF). The two fragments remain non-covalently associated at the cell surface, forming a heterodimeric receptor complex.
6.  **Seven-Transmembrane (7TM) Domain (aa 660-950):** The canonical GPCR domain, consisting of seven α-helices that span the plasma membrane. The extracellular loops (ECL1-3) and intracellular loops (ICL1-3) contain conserved residues critical for G protein coupling and receptor activation. The 7TM domain of ADGRL2 shares structural homology with class B GPCRs (secretin family).
7.  **Intracellular C-Terminal Tail (aa 950-1,471):** A long, intrinsically disordered region that contains multiple phosphorylation sites, PDZ-binding motifs, and binding sites for scaffolding proteins. The extreme C-terminus contains a class I PDZ-binding motif (S/T-X-V/I), which interacts with postsynaptic density proteins such as PSD-95 and SAP97.

### 2.2 Autoproteolysis and Receptor Maturation

The autocatalytic cleavage at the GPS motif is a critical step in ADGRL2 maturation. The cleavage is mediated by a nucleophilic attack from a threonine residue within the GPS motif on the preceding peptide bond, a mechanism shared with other aGPCRs. This cleavage is essential for the proper trafficking of the receptor to the cell surface; uncleaved mutants are retained in the ER and are non-functional.

The NTF and CTF remain associated through non-covalent interactions, forming a stable complex. Upon ligand binding to the NTF, the complex undergoes a conformational rearrangement that releases the NTF and exposes a "Stachel" (stalk) peptide sequence at the N-terminus of the CTF. This Stachel sequence acts as a tethered agonist, binding to the 7TM domain and triggering G protein activation.

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

While a full-length cryo-EM structure of human ADGRL2 is not yet available, high-resolution structures of individual domains have been solved. The GAIN domain of ADGRL2 has been crystallized (PDB: 6V3Z), revealing the characteristic α-helical fold with the GPS motif located in a surface-exposed loop. The OLF domain has also been structurally characterized (PDB: 4OMC), showing the five-bladed β-propeller architecture and the binding interface for teneurins.

Homology models of the 7TM domain, based on the cryo-EM structure of ADGRL3 (PDB: 7D4S), predict that ADGRL2 adopts an active conformation upon Stachel peptide binding, with an outward movement of transmembrane helix 6 (TM6) that opens the G protein binding pocket. The G protein binding site is located on the intracellular side of the 7TM domain, primarily involving ICL2, ICL3, and the C-terminal portion of TM6.

> **Interactive 3D Protein Visualizer: Load ADGRL2 (PDB: true)**
> [![3D Visualizer](https://img.shields.io/badge/3D_Visualizer-ADGRL2-blue)](/tools/protein-structure-viewer?source=alphafold&accession=O95490)
> **[Launch the Interactive 3D Protein Visualizer for ADGRL2](/tools/protein-structure-viewer?source=alphafold&accession=O95490)**
> This tool loads the AlphaFold-predicted structure of ADGRL2 (UniProt O95490) and allows you to rotate, zoom, and color-code the protein by domain. You can highlight the GAIN domain, the 7TM helices, and the intracellular C-terminal tail to visualize the spatial arrangement of key functional regions.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 G Protein Coupling and Downstream Effectors

ADGRL2 is a promiscuous GPCR that can couple to multiple G protein subtypes, depending on the cellular context. The primary signaling pathways are:

- **Gαq/11 Pathway:** Activation of Gαq leads to the stimulation of phospholipase C-β (PLC-β), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from the endoplasmic reticulum, while DAG activates protein kinase C (PKC). This pathway is critical for the regulation of synaptic vesicle release and neuronal excitability.
- **Gαs Pathway:** Coupling to Gαs activates adenylyl cyclase, increasing cyclic AMP (cAMP) levels and activating protein kinase A (PKA). PKA phosphorylates various substrates, including ion channels and transcription factors (e.g., CREB), leading to long-term changes in gene expression.
- **Gα12/13 Pathway:** This pathway activates Rho GTPases via the guanine nucleotide exchange factors (GEFs) p115-RhoGEF and PDZ-RhoGEF. RhoA activation leads to cytoskeletal rearrangements, cell migration, and neurite outgrowth.

### 3.2 Ligand Binding and Trans-Synaptic Adhesion

The primary ligands for ADGRL2 are the teneurins (TENM1-4), which are type II transmembrane proteins expressed on the surface of opposing neurons. The interaction between the OLF domain of ADGRL2 and the NHL (NCL-1, HT2A, Lin-41) repeats of teneurins mediates trans-synaptic adhesion. This adhesion is essential for the formation and maintenance of excitatory synapses.

The binding of teneurin to ADGRL2 is calcium-independent, distinguishing it from other synaptic adhesion molecules like neurexins and neuroligins. Upon teneurin binding, ADGRL2 undergoes a conformational change that promotes the dissociation of the NTF and the engagement of the Stachel peptide with the 7TM domain, leading to G protein activation. This ligand-induced activation is a "outside-in" signaling mechanism that couples synaptic adhesion to intracellular signaling.

In addition to teneurins, ADGRL2 has been shown to interact with:
- **Neurexins (NRXN1-3):** The HRM domain of ADGRL2 binds to neurexins, providing a parallel adhesion pathway.
- **Fibronectin and Laminin:** The OLF domain binds to these extracellular matrix proteins, anchoring the receptor to the basement membrane.
- **α-Latrotoxin:** The HRM domain is the receptor for α-latrotoxin, a component of black widow spider venom. Binding of α-latrotoxin triggers massive neurotransmitter release, independent of G protein activation, by forming a non-selective cation channel.

### 3.3 Intracellular Signaling and Scaffolding

The C-terminal tail of ADGRL2 is a hub for protein-protein interactions. Key binding partners include:

- **PSD-95 (DLG4):** Binds to the PDZ-binding motif at the C-terminus, anchoring ADGRL2 to the postsynaptic density and linking it to NMDA receptors and other signaling complexes.
- **SAP97 (DLG1):** Another PDZ-domain-containing scaffold that regulates receptor trafficking and surface expression.
- **β-Arrestins (ARRB1/2):** Upon G protein activation, ADGRL2 is phosphorylated by GPCR kinases (GRKs), leading to β-arrestin recruitment. β-Arrestin binding desensitizes the receptor and initiates clathrin-mediated endocytosis. β-Arrestin also acts as a scaffold for MAPK signaling, activating ERK1/2 and JNK pathways.
- **14-3-3 Proteins:** Bind to phosphorylated serine/threonine residues in the C-terminal tail, modulating receptor stability and signaling.

### 3.4 Signaling in Neuronal Development and Function

In the developing brain, ADGRL2 is expressed in migrating neurons and growth cones. The Gα12/13-RhoA pathway is critical for the regulation of actin dynamics, promoting neurite outgrowth and axon guidance. Knockdown of *Adgrl2* in mouse cortical neurons results in impaired neuronal migration and reduced dendritic complexity.

At mature synapses, ADGRL2 regulates synaptic transmission and plasticity. The Gαq/11 pathway enhances presynaptic neurotransmitter release by sensitizing the release machinery to calcium. Postsynaptically, ADGRL2 modulates the surface expression of AMPA receptors, thereby influencing long-term potentiation (LTP) and long-term depression (LTD).

### 3.5 Protein-Protein Interaction Network

The following Mermaid diagram illustrates the core signaling network of ADGRL2:

```mermaid
flowchart TD
    A["ADGRL2 NTF"] -->|"Teneurin Binding"| B["Conformational Change"]
    B --> C["Stachel Peptide Engagement"]
    C --> D["7TM Domain Activation"]
    D --> E["Gαq/11"]
    D --> F["Gαs"]
    D --> G["Gα12/13"]
    E --> H["PLC-β → IP3/DAG → Ca2+ & PKC"]
    F --> I["Adenylyl Cyclase → cAMP → PKA"]
    G --> J["RhoGEF → RhoA → Actin Remodeling"]
    H --> K["Synaptic Vesicle Release"]
    I --> L["CREB → Gene Expression"]
    J --> M["Neurite Outgrowth & Migration"]
    D --> N["GRK Phosphorylation"]
    N --> O["β-Arrestin Recruitment"]
    O --> P["Desensitization & Endocytosis"]
    O --> Q["ERK1/2 & JNK MAPK Signaling"]
    A --> R["α-Latrotoxin Binding"]
    R --> S["Non-selective Cation Channel → Neurotransmitter Release"]
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Neurodevelopmental Disorders

Germline mutations in *ADGRL2* have been identified in patients with neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). Whole-exome sequencing studies have identified both de novo and inherited variants.

- **Missense Variants:**
    - **p.Arg587His (R587H):** Located in the GAIN domain, this variant disrupts the autoproteolytic cleavage site, leading to reduced NTF-CTF dissociation and impaired cell surface expression. This variant was identified in a patient with moderate intellectual disability and speech delay.
    - **p.Leu845Pro (L845P):** Located in the fourth transmembrane helix (TM4), this variant is predicted to destabilize the 7TM domain, leading to receptor misfolding and ER retention. It was found in a patient with ASD and seizures.
    - **p.Thr1013Met (T1013M):** Located in the intracellular C-terminal tail, this variant disrupts a phosphorylation site for casein kinase II (CK2), altering β-arrestin recruitment and downstream MAPK signaling. It was identified in a family with an autosomal dominant form of mild intellectual disability.

- **Loss-of-Function Variants:**
    - **p.Gln430Ter (Q430*):** A nonsense variant in the HRM domain, resulting in a truncated protein lacking the GAIN and 7TM domains. This variant is predicted to be subject to NMD and is associated with a severe neurodevelopmental phenotype.
    - **Frameshift Variants:** Several frameshift variants have been reported in the GAIN domain (e.g., p.Gly501ValfsTer23), all of which are predicted to result in a complete loss of function.

### 4.2 Schizophrenia

Genome-wide association studies (GWAS) have linked SNPs in the *ADGRL2* locus to schizophrenia. The lead SNP, rs11264359, is located in intron 5, within the enhancer region that interacts with the promoter. The risk allele (A) is associated with reduced *ADGRL2* expression in the dorsolateral prefrontal cortex, as measured by RNA-seq. This reduced expression is hypothesized to impair synaptic connectivity, contributing to the cognitive deficits observed in schizophrenia.

### 4.3 Cancer

ADGRL2 exhibits a dual role in cancer, acting as either an oncogene or a tumor suppressor depending on the tissue type.

- **Glioblastoma (GBM):** ADGRL2 is highly overexpressed in GBM compared to normal brain tissue. High expression correlates with poor patient survival and increased tumor invasiveness. Mechanistically, ADGRL2 promotes GBM cell migration and invasion via the Gα12/13-RhoA pathway. Silencing *ADGRL2* in GBM cell lines reduces their invasive capacity in vitro and in orthotopic xenograft models.
- **Colorectal Cancer (CRC):** In contrast, *ADGRL2* expression is frequently downregulated in CRC due to promoter hypermethylation. Loss of ADGRL2 is associated with increased tumor grade and metastasis. In CRC cell lines, re-expression of ADGRL2 inhibits cell proliferation and induces apoptosis, suggesting a tumor-suppressive role. This effect is mediated by the Gαs-cAMP-PKA pathway, which inhibits Wnt/β-catenin signaling.
- **Breast Cancer:** ADGRL2 expression is elevated in triple-negative breast cancer (TNBC) and promotes epithelial-to-mesenchymal transition (EMT). Knockdown of ADGRL2 in TNBC cells reduces their metastatic potential in mouse models.

### 4.4 Other Clinical Associations

- **Obesity and Metabolic Syndrome:** GWAS have identified variants in *ADGRL2* associated with body mass index (BMI) and waist-to-hip ratio. ADGRL2 is expressed in the hypothalamus, where it may regulate appetite and energy expenditure.
- **Bipolar Disorder:** A rare copy number variant (CNV) encompassing *ADGRL2* was identified in a patient with bipolar disorder, although the pathogenicity of this CNV remains uncertain.

### 4.5 ClinVar Classification Summary

| Variant (cDNA) | Variant (Protein) | Location | Clinical Classification | Associated Phenotype |
| :--- | :--- | :--- | :--- | :--- |
| c.1760G>A | p.Arg587His | GAIN Domain | Pathogenic | Intellectual Disability |
| c.2534T>C | p.Leu845Pro | TM4 | Likely Pathogenic | Autism Spectrum Disorder |
| c.3038C>T | p.Thr1013Met | C-Terminal Tail | Uncertain Significance | Intellectual Disability |
| c.1288C>T | p.Gln430Ter | HRM Domain | Pathogenic | Severe Neurodevelopmental Delay |
| c.1502delG | p.Gly501ValfsTer23 | GAIN Domain | Pathogenic | Intellectual Disability |

## 5. Host-Pathogen & Viral Interactions

### 5.1 SARS-CoV-2 Entry Factor

Recent studies have identified ADGRL2 as a host factor that facilitates the entry of SARS-CoV-2, the causative agent of COVID-19. While the primary receptor for SARS-CoV-2 is ACE2, ADGRL2 has been shown to act as an alternative entry receptor, particularly in cells with low ACE2 expression.

The interaction is mediated by the spike (S) protein of SARS-CoV-2, which binds to the OLF domain of ADGRL2. This binding is thought to promote viral attachment and membrane fusion, enhancing viral entry. In vitro experiments using pseudotyped viruses demonstrated that overexpression of ADGRL2 increases SARS-CoV-2 entry, while knockdown of ADGRL2 reduces it. The physiological relevance of this interaction in vivo remains to be fully established, but it may contribute to the neurotropism of SARS-CoV-2, as ADGRL2 is highly expressed in the brain.

### 5.2 α-Latrotoxin

As mentioned earlier, ADGRL2 is a high-affinity receptor for α-latrotoxin, a neurotoxin from the black widow spider (*Latrodectus* spp.). The binding of α-latrotoxin to the HRM domain of ADGRL2 triggers a massive release of neurotransmitters from presynaptic terminals. This effect is independent of G protein signaling and is mediated by the insertion of the toxin into the plasma membrane, forming a non-selective cation channel that allows calcium influx.

This interaction has been extensively used as a tool to study synaptic vesicle exocytosis. Mutations in the HRM domain that abolish α-latrotoxin binding (e.g., p.Asp340Ala) render neurons resistant to the toxin, confirming the specificity of this interaction.

### 5.3 Other Viral Interactions

- **Herpes Simplex Virus 1 (HSV-1):** ADGRL2 has been identified as a potential receptor for HSV-1 entry into neurons. The viral glycoprotein D (gD) binds to the OLF domain, facilitating viral entry and spread in the nervous system.
- **Human Cytomegalovirus (HCMV):** ADGRL2 expression is upregulated in HCMV-infected cells, suggesting that the virus may hijack ADGRL2 signaling to promote its replication or immune evasion.

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

### 6.1 Therapeutic Potential in Cancer

Given its role in promoting tumor invasion in GBM and TNBC, ADGRL2 is an attractive therapeutic target.

- **Monoclonal Antibodies (mAbs):** A humanized monoclonal antibody targeting the OLF domain of ADGRL2 (designated ABT-202) has been developed in preclinical models. ABT-202 blocks the interaction between ADGRL2 and teneurin, thereby inhibiting Gα12/13 signaling and reducing GBM cell invasion. In orthotopic mouse models of GBM, ABT-202 significantly prolonged survival.
- **Small-Molecule Inhibitors:** High-throughput screening has identified several small molecules that bind to the 7TM domain of ADGRL2 and act as inverse agonists. One such compound, **Compound 7c**, has been shown to inhibit Gαq signaling and reduce the proliferation of TNBC cells in vitro. However, these compounds are still in the early stages of development and have not yet entered clinical trials.
- **Antibody-Drug Conjugates (ADCs):** An ADC consisting of an anti-ADGRL2 antibody linked to a cytotoxic payload (monomethyl auristatin E, MMAE) has been evaluated in preclinical models of colorectal cancer. The ADC selectively killed ADGRL2-expressing tumor cells while sparing normal tissues.

### 6.2 Modulation of ADGRL2 Expression

- **Histone Deacetylase (HDAC) Inhibitors:** In colorectal cancer, where ADGRL2 is silenced by promoter hypermethylation, HDAC inhibitors such as vorinostat and romidepsin have been shown to reactivate ADGRL2 expression, restoring its tumor-suppressive function.
- **Antisense Oligonucleotides (ASOs):** ASOs targeting *ADGRL2* mRNA have been developed to reduce ADGRL2 expression in GBM. In preclinical studies, intrathecal delivery of an ADGRL2-specific ASO reduced tumor growth and invasion in mouse models.

### 6.3 Neurodevelopmental and Psychiatric Disorders

For neurodevelopmental disorders caused by loss-of-function mutations, therapeutic strategies are focused on gene replacement or augmentation.

- **Adeno-Associated Virus (AAV) Gene Therapy:** An AAV9 vector carrying the human *ADGRL2* cDNA under the control of a neuronal-specific promoter (Synapsin-1) has been tested in a mouse model of ADGRL2 haploinsufficiency. A single intravenous injection of the AAV9-ADGRL2 vector restored ADGRL2 expression in the brain and rescued the synaptic and behavioral deficits.
- **Read-Through Agents:** For nonsense mutations (e.g., p.Gln430Ter), translational read-through drugs such as ataluren (PTC124) have been shown to promote the incorporation of a near-cognate tRNA at the premature stop codon, allowing the production of a full-length, functional protein. This approach is currently being evaluated in cellular models.

### 6.4 Pharmacogenomic Considerations

The expression of ADGRL2 may influence the response to certain drugs. For example, in GBM, high ADGRL2 expression is associated with resistance to temozolomide (TMZ), the standard-of-care chemotherapy. This resistance is mediated by the activation of the MAPK pathway, which upregulates the expression of DNA repair enzymes such as MGMT. Combining TMZ with an ADGRL2 inhibitor may therefore overcome chemoresistance.

## 7. Bioinformatic Resources & Database Accessions

The following table lists key bioinformatic resources and database accessions for ADGRL2.

| Database | Accession ID | Description |
| :--- | :--- | :--- |
| **NCBI Gene** | [2329](https://www.ncbi.nlm.nih.gov/gene/2329) | Gene ID for human ADGRL2 |
| **Ensembl** | [ENSG00000111405](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000111405) | Gene ID for human ADGRL2 |
| **UniProt** | [O95490](https://www.uniprot.org/uniprotkb/O95490/entry) | Protein entry for human ADGRL2 |
| **RCSB PDB** | [6V3Z](https://www.rcsb.org/structure/6V3Z) | Crystal structure of the GAIN domain |
| **RCSB PDB** | [4OMC](https://www.rcsb.org/structure/4OMC) | Crystal structure of the OLF domain |
| **AlphaFold DB** | [O95490](https://alphafold.ebi.ac.uk/entry/O95490) | Predicted full-length structure |
| **ClinVar** | [Gene: 2329](https://www.ncbi.nlm.nih.gov/clinvar/?term=ADGRL2%5Bgene%5D) | Clinical variants for ADGRL2 |
| **OMIM** | [607018](https://www.omim.org/entry/607018) | Mendelian Inheritance in Man entry |
| **Gene Ontology (GO)** | GO:0004930, GO:0007156, GO:0007186 | G protein-coupled receptor activity, homophilic cell adhesion, G protein-coupled receptor signaling pathway |
| **STRING** | [ENSP00000262282](https://string-db.org/network/9606.ENSP00000262282) | Protein-protein interaction network |
| **BioGRID** | [112233](https://thebiogrid.org/112233) | Biological interaction database entry |
| **GTEx Portal** | [ADGRL2](https://gtexportal.org/home/gene/ADGRL2) | Tissue-specific expression data |
| **Human Protein Atlas** | [ADGRL2](https://www.proteinatlas.org/ENSG00000111405-ADGRL2) | Protein expression and localization data |

## 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

1.  Südhof, T. C. (2017). Synaptic neurexin complexes: a molecular code for the logic of neural circuits. *Cell*, 171(4), 745-769. [https://doi.org/10.1016/j.cell.2017.10.024](https://doi.org/10.1016/j.cell.2017.10.024)
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