Integration of Semaphorin/Plexin activation and amplification by a Neuropilin-like coreceptor ensures robust homeostatic plasticity.

Robust homeostatic plasticity is essential for survival, enabling neuronal circuits to withstand destabilizing forces and restore function during critical challenges such as predator evasion or toxin exposure. Semaphorin/Plexin signaling is central to presynaptic homeostatic potentiation at central synapses and at neuromuscular junctions across species. However, our understanding of this pathway has remained incomplete, as secreted Semaphorins bind weakly to their Plexin receptors and require additional coreceptors for efficient signaling. Here, we identify Neuropilin and Tolloid-like protein (Neto-α), an auxiliary subunit for ionotropic glutamate receptors (iGluRs), and the tyrosine kinase Abelson (Abl) as essential components of the Sema2b/PlexB signaling pathway that drives rapid homeostatic potentiation and stabilizes synaptic strength at the Drosophila neuromuscular junction. Neto-α functions as a Neuropilin-like coreceptor that cooperates with Sema2b to relieve PlexB autoinhibition and initiate signaling. In parallel, Neto-α recruits Abl, which functions as a cytosolic amplifier to enhance pathway output. We demonstrate that both pathway activation and amplification are required for a rapid and effective homeostatic response. By integrating these two functions within a single molecular assembly, Neto-α ensures fast and efficient compensatory responses to perturbations. This evolutionarily conserved signaling module, Neto (or Neuropilin)/Sema/Plex/Abl, likely operates in cellular contexts beyond neural function, including in tumorigenesis.