Local palmitoylation cycles define activity-regulated postsynaptic subdomains

• Published in: The Journal of cell biology Vol. 202; no. 1; pp. 145 - 161
• Main Authors: Fukata, Yuko, Dimitrov, Ariane, Boncompain, Gaelle, Vielemeyer, Ole, Perez, Franck, Fukata, Masaki
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 08.07.2013; The Rockefeller University Press
• Subjects: Animals; Cells; Cercopithecus aethiops; COS Cells; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Disks Large Homolog 4 Protein; Fluorescent Dyes - metabolism; Green Fluorescent Proteins - metabolism; Guanylate Kinases - metabolism; HEK293 Cells; Hippocampus - metabolism; Humans; Lipoylation; Membrane Proteins - metabolism; Membranes; Mice; Neuronal Plasticity; Neurons - metabolism; Palmitates - pharmacology; Plasma; Post-Synaptic Density - metabolism; Rats; Sensitivity and Specificity; Structure-Activity Relationship; Synaptic Transmission; Transfection
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201302071

Distinct PSD-95 clusters are primary landmarks of postsynaptic densities (PSDs), which are specialized membrane regions for synapses. However, the mechanism that defines the locations of PSD-95 clusters and whether or how they are reorganized inside individual dendritic spines remains controversial. Because palmitoylation regulates PSD-95 membrane targeting, we combined a conformation-specific recombinant antibody against palmitoylated PSD-95 with live-cell super-resolution imaging and discovered subsynaptic nanodomains composed of palmitoylated PSD-95 that serve as elementary units of the PSD. PSD-95 in nanodomains underwent continuous de/repalmitoylation cycles driven by local palmitoylating activity, ensuring the maintenance of compartmentalized PSD-95 clusters within individual spines. Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. Furthermore, changes in synaptic activity rapidly reorganized PSD-95 nano-architecture through plasma membrane-inserted DHHC2. Thus, the first genetically encoded antibody sensitive to palmitoylation reveals an instructive role of local palmitoylation machinery in creating activity-responsive PSD-95 nanodomains, contributing to the PSD (re)organization.