ADGRB3 and Associated Diseases
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Overview of ADGRB3
ADGRB3, a member of the ADGRB1-3 subfamily of adhesion GPCR transmembrane proteins, is highly expressed in cerebellar and hippocampal neurons. ADGRB3, a p53 target gene, encodes a brain-specific angiogenesis inhibitor and is a member of the secretin receptor family. The ADGRB3 gene is expressed almost exclusively in the brain and encodes adhesion G protein-coupled receptor B3, or brain-specific angiogenesis inhibitor 3 (BAI3), which plays a key role in the development, maintenance, and plasticity of the central nervous system, including regulating synaptic development, axon guidance, synapse formation, myelination, with high expression in the postsynaptic density, especially in the cerebellum, and crucial roles in Purkinje cell synaptogenesis, both during development and adulthood.
Fig.1 General structure of an aGPCR. (Gad, 2020)
ADGRB3 in Disease
ADGRB3 single nucleotide polymorphisms (SNPs) have been associated with schizophrenia, bipolar disorder, and drug addiction.
- Cancer
ADGRB3 was shown to be one of the most significantly mutated genes in 13% of lung squamous and 5% of lung adenocarcinoma tumors. These mutations span the N-terminal fragment (NTF), seven-transmembrane (7TM), and the C-terminus of ADGRB3, and researchers suggested that this protein might act as a putative tumor suppressor. Adherent G protein-coupled receptor B3 (ADGRB3, also known as BAI3) is significantly mutated in many tumor entities.
- Neurological Diseases
Studies that knocked out ADGRB1-3 have identified the important role of these receptors in synaptogenesis and their potential role in neuropathology. The deletion of ADGRB3 results in perturbations to the dendritic structure in the cerebellum. SNPs in ADGRB3 have also been associated with neurodevelopmental delay and autism symptoms.
Approaches in Therapeutic Targeting of ADGRB3
The development of receptor-specific therapeutics is possible although challenging. With the great diversity of human diseases and conditions in which they have been implicated, ADGRB3 offers phenomenal opportunities for therapeutic targeting. The complex domain structure and protein interactions of aGPCRs provide a potential multimodal approach for regulating its activity, including disrupting N-terminal domain (NTD) interactions with ligands, C-terminal domain (CTD) activity modulators based on small molecules and peptides, and leveraging disease state and mutation-specific downstream signaling partners. The tethered agonist signaling mechanism of ADGRB3 additionally lends itself to peptide-based pharmacological modulation.
Owing to their diversity, specificity, and involvement in human disease, GPCRs have been a central focus of pharmaceutical drug discovery and development efforts. Creative Biolabs is offering integrated end-to-end development gene therapy services. With our extensive experience in gene therapy, we can help you answer critical questions during the project. Please feel free to contact us for more detail about your ADGRB3 target therapy research project.
Reference
- Gad, A.A.; Balenga, N. The emerging role of adhesion GPCRs in cancer. ACS pharmacology & translational science. 2020, 3(1): 29-42.
