The membrane skeleton is constitutively remodeled in neurons by calcium signaling

• Published in: Science (American Association for the Advancement of Science) Vol. 389; no. 6760; p. eadn6712
• Main Authors: Heller, Evan, Kurup, Naina, Zhuang, Xiaowei
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.08.2025
• Subjects: Actin; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - ultrastructure; Actins - metabolism; Adducin; Animal species; Animals; Axons; Axons - metabolism; Axons - physiology; Axons - ultrastructure; Calcium; Calcium influx; Calcium ions; Calcium Signaling; Calcium signalling; Calmodulin-Binding Proteins - metabolism; Calpain; Calpain - metabolism; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cell surface receptors; Cytoskeleton; Deformation; Degeneration; Destabilization; Dismantling; Dynamics; Endocytosis; External stimuli; Filaments; G protein-coupled receptors; Image resolution; Intermediate filaments; Kinases; Membranes; Mice; Microfilament Proteins - metabolism; Microtubules; Neurons; Neurons - metabolism; Neurons - physiology; Periodic structures; Phosphorylation; Protein kinase C; Protein Kinase C - metabolism; Proteins; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors; Signal transduction; Spectrin; Spectrin - metabolism; Stimulation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adn6712

The membrane skeleton in neurons adopts a periodic lattice structure in which actin filaments, capped by adducin and tropomodulin, form ring-shaped structures connected by spectrin tetramers along neurites. This membrane-associated periodic skeleton (MPS) is important for many neuronal functions. Using live-cell super-resolution imaging, we found that the MPS is surprisingly dynamic, undergoing local disassembly and reformation constitutively in axons. MPS remodeling is driven by calcium signaling, leading to actin-ring destabilization through protein kinase C–mediated adducin phosphorylation and to spectrin degradation by calpain. Formin, an actin-nucleating and -polymerizing enzyme, plays a dual role in MPS remodeling and maintenance. MPS remodeling is enhanced by neuronal activity and functionally facilitates endocytosis. Our results highlight the importance of a dynamic membrane skeletal structure in neuronal function. The cytoskeleton provides mechanical support to the cell while also enabling cells to remodel themselves in response to their environment. The membrane-associated periodic skeleton (MPS) is a component of the neuronal cytoskeleton mostly found in axons. Heller et al . investigated the dynamics of MPS using live-cell super-resolution imaging. The authors discovered that MPS is remarkably dynamic, undergoing repeated cycles of disassembly and reformation over much of the axon’s length. Mechanistically, MPS remodeling is regulated by calcium ions and involves actin stabilization, calpain-dependent proteolysis, and protein kinase C–mediated adducin phosphorylation. These results provide valuable insights for understanding how cells carry out their most fundamental activities. —Mattia Maroso