biostudies-literatureUnknown12(7)Fei JEndocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane-associated periodic skeleton (MPS), an actin spectrin-based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways-CME, caveolin-, flotillin-, and fast endophilin-mediated endocytosis-are spatially gated by the MPS and occur exclusively within MPS-free "clearing" zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular Science advanceseaeb0803https://www.ebi.ac.uk/biostudies/studies/S-EPMC12893284biostudies-literatureMembrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.PMC12893284Zheng YTao YZhou RLaLonde CFei JfalseMembrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane-associated periodic skeleton (MPS), an actin spectrin-based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways-CME, caveolin-, flotillin-, and fast endophilin-mediated endocytosis-are spatially gated by the MPS and occur exclusively within MPS-free "clearing" zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular 2026-01-01T00:00:00Z2026 Feb2026-07-15T16:38:00.576Z2026-07-07T03:08:35.313ZS-EPMC128932844167136610.1126/sciadv.aeb0803