Dual palmitoylation of PSD-95 mediates its vesiculotubular sorting, postsynaptic targeting, and ion channel clustering.

El-Husseini AE, Craven SE, Chetkovich DM, Firestein BL, Schnell E, Aoki C, Bredt DS
J Cell Biol. 2000 148 (1): 159-72

PMID: 10629226 · PMCID: PMC2156213 · DOI:10.1083/jcb.148.1.159

Postsynaptic density-95 (PSD-95/SAP-90) is a palmitoylated peripheral membrane protein that scaffolds ion channels at excitatory synapses. To elucidate mechanisms for postsynaptic ion channel clustering, we analyzed the cellular trafficking of PSD-95. We find that PSD-95 transiently associates with a perinuclear membranous compartment and traffics with vesiculotubular structures, which migrate in a microtubule-dependent manner. Trafficking of PSD-95 with these vesiculotubular structures requires dual palmitoylation, which is specified by five consecutive hydrophobic residues at the NH(2) terminus. Mutations that disrupt dual palmitoylation of PSD-95 block both ion channel clustering by PSD-95 and its synaptic targeting. Replacing the palmitoylated NH(2) terminus of PSD-95 with alternative palmitoylation motifs at either the NH(2) or COOH termini restores ion channel clustering also induces postsynaptic targeting, respectively. In brain, we find that PSD-95 occurs not only at PSDs but also in association with intracellular smooth tubular structures in dendrites and spines. These data imply that PSD-95 is an itinerant vesicular protein; initial targeting of PSD-95 to an intracellular membrane compartment may participate in postsynaptic ion channel clustering by PSD-95.

MeSH Terms (29)

Animals Biological Transport Brefeldin A Cell Line Cell Nucleus Cell Polarity Cerebral Cortex Consensus Sequence Disks Large Homolog 4 Protein Dogs Epithelial Cells Green Fluorescent Proteins Guanylate Kinases Humans Intracellular Signaling Peptides and Proteins Kv1.4 Potassium Channel Luminescent Proteins Membrane Proteins Nerve Tissue Proteins Neurons Nocodazole Nucleoside-Phosphate Kinase Palmitic Acids Potassium Channels Potassium Channels, Voltage-Gated Rats Recombinant Fusion Proteins SAP90-PSD95 Associated Proteins Synapses

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