Latrophilin-3 (LPHN3), also known as ADGRL3, is a member of the adhesion G-protein-coupled receptor (aGPCR) family. This family is characterized by the presence of a GPCR autoproteolysis-inducing (GAIN) domain that facilitates receptor cleavage and activation, along with seven transmembrane domains^1,3. LPHN3 is primarily localized to the cell membrane and is prominently expressed in neurons, with high levels observed in brain regions such as the hippocampus and prefrontal cortex^1,5.

LPHN3 plays critical roles in neuronal development and synapse formation. It mediates its effects through dual mechanisms: coupling with intracellular G-proteins, particularly Gαs and Gα12/13, and recruiting phase-separated postsynaptic protein scaffolds. Activation of LPHN3 is triggered by interactions with its ligands, such as teneurins and FLRTs, which enhance synaptic clustering by promoting scaffold protein condensates. Alternative splicing of Lphn3, studied in mouse models, modulates these pathways, influencing synaptic connectivity and neuronal activity^3,4.

Biologically, LPHN3 is involved in attention regulation and motor control, with its dysregulation linked to attention deficit hyperactivity disorder (ADHD). Genetic variants in LPHN3 are associated with altered dopaminergic signaling and increased susceptibility to ADHD, as demonstrated in human studies^1,2. Furthermore, LPHN3 dysfunction has been implicated in substance use disorders and learning deficits, underscoring its importance in neuropsychiatric and cognitive processes^2,5.