The membrane-tethered cis-ligand Belly roll elicits GPCR signaling thereby enabling adaptive avoidance behaviors

Animals adapt their behavioral responses to sensory stimuli through neuromodulatory circuits. Increasing fluid osmolality drives water-seeking behaviors via neuromodulation. However, the neural circuits and molecular mechanisms linking internal osmotic state to behavioral adaptation remain unclear. Here, we show that desiccation stress increases hemolymph osmolality and enhances avoidance of dry substrates in Drosophila larvae, enabling larvae to seek humid environments. We identify the abdominal leucokinin-producing (ABLK) neurons as a key circuit node that mediates this adaptive response. We further show that the GPI-anchored protein Belly roll (Bero), a member of the lymphocyte antigen-6/urokinase-type plasminogen activator receptor (LU) superfamily, acts as a non-canonical endogenous cis-ligand for the neuropeptide G protein-coupled receptor Allatostatin C receptor 2 (AstC-R2). Genetic, biochemical, and imaging analyses revealed that Bero activates AstC-R2 to induce phospholipase C {beta} (PLC{beta})-dependent signaling, thereby suppressing sensory transmission in ABLK neurons. Desiccation-induced increase in hemolymph osmolality activates VMA-AstC+ neurons to trigger Allatostatin C (AstC) release, which antagonizes Bero-mediated AstC-R2 signaling and promotes dry substrate avoidance. Together, our findings uncover a neural circuit and a molecular mechanism by which changes in internal physiological state dynamically switch GPCR signaling through the opposing actions of membrane-tethered and secreted ligands, thereby reshaping adaptive behavioral responses.