Proteomic maps of synapses and synaptic vesicles across the central and enteric nervous systems.

While the synaptic proteome of the central nervous system (CNS) has been extensively characterized, its composition in the peripheral nervous system (PNS) remains unknown. There is an urgent need to delineate the precise proteomic landscape of the enteric nervous system (ENS), often referred to as the "second brain," and to systematically compare its molecular heterogeneity with that of the CNS. To address this, we developed a streamlined workflow integrating subcellular organelle isolation with PulseDIA proteomics, enabling the identification of 13,534 synaptic proteins across the CNS and ENS (including 8807 for ENS). We defined 776 synaptic vesicle-resident proteins in the CNS and 1148 in the ENS. Comparative proteomic analysis revealed a fundamental divergence-convergence relationship: while the two nervous systems exhibit distinct molecular signatures, they maintain conserved functional organization. Furthermore, energy intake restriction in mice induced extensive ENS proteome remodeling. Pharmacological inhibition of FGFR1 kinase activity suppressed thermogenesis independently of energy substrate utilization, suggesting FGFR1's potential role in ENS-mediated energy metabolism regulation. Collectively, our study provides a resource for neurobiological and neurological research and elucidates proteomic divergences and convergences between the CNS and ENS.