ADGRL1/latrophilin-1: receptor states and context-dependent functions in neural, metabolic and cancer biology

Originally characterized as the high-affinity target of the black widow spider neurotoxin α-latrotoxin, the adhesion G protein-coupled receptor ADGRL1 (latrophilin-1) has been recognized as a multifaceted coordinator of synaptic connectivity, systemic metabolism, and oncogenesis. This functional spectrum is governed by distinct receptor states defined by modular ectodomains, autoproteolytic cleavage, alternative splicing, and contextual interactomes. These features coordinate extracellular adhesion and co-receptor organization, 7TM-dependent G-protein signaling, and intracellular scaffolding. In the central nervous system, ADGRL1 selectively maintains perisomatic inhibitory synapse stability, and its genetic disruption causes clinically heterogeneous neurodevelopmental and epileptic disorders. In systemic energy homeostasis, loss-of-function models establish essential hypothalamic and systemic metabolic roles; however, whether ADGRL1 operates as an autonomous nutrient sensor remains disputed, as glucose-triggered cAMP responses were not reproduced in independent cell-based systems. In malignant settings, functional studies distinguish androgen-responsive cell growth from secretory and scaffold-associated immune regulation, whereas lower expression in drug-resistant myeloid and myelodysplastic contexts reflects transcriptional covariation rather than validated tumor suppression. By distinguishing verified molecular mechanisms from correlative observations, this review develops a testable framework for ADGRL1 pleiotropy and delineates the principal translational challenges in targeting its distinct conformational and signaling states. ADGRL1 receptor configurations and biological functions. Extracellular binding partners and candidate chemical modulators engage ADGRL1 to regulate downstream outcomes shaped by autoproteolytic cleavage, subcellular localization, and intracellular scaffold assembly. This receptor-state framework organizes evidence and testable explanations for distinct outputs across neural architecture, metabolic control, and oncogenic signaling without requiring a uniform, sequential activation cascade. In the nervous system, endogenous ADGRL1 maintains inhibitory synapse stability, and its disruption causes pediatric neurodevelopmental syndromes. In metabolic tissues, genetic loss produces pronounced neuroendocrine phenotypes, although direct nutrient-sensing properties remain debated. In oncology, ADGRL1 coordinates secretory immune evasion in acute myeloid leukemia, supports androgen-dependent urological cancer growth, and acts as an intracellular scaffold in solid tumors to suppress anti-tumor immunity without forming direct contacts with immune cells. Panels represent distinct experimental settings; receptor models and cell densities are shown schematically.