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

Alaa E. El-Husseini, Sarah E. Craven, Dane M. Chetkovich, Bonnie L. Firestein, Eric Schnell, Chiye Aoki, David S. Bredt

Research output: Contribution to journalArticle

Abstract

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 NH2 terminus. Mutations that disrupt dual palmitoylation of PSD-95 block both ion channel clustering by PSD-95 and its synaptic targeting. Replacing the palmitoylated NH2 terminus of PSD-95 with alternative palmitoylation motifs at either the NH2 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.

Original languageEnglish (US)
Pages (from-to)159-171
Number of pages13
JournalJournal of Cell Biology
Volume148
Issue number1
DOIs
StatePublished - Jan 10 2000

Keywords

  • Clustering
  • MAGUK
  • PSD
  • Palmitoylation
  • Trafficking

ASJC Scopus subject areas

  • Cell Biology

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    El-Husseini, A. E., Craven, S. E., Chetkovich, D. M., Firestein, B. L., Schnell, E., Aoki, C., & Bredt, D. S. (2000). Dual palmitoylation of PSD-95 mediates its vesiculotubular sorting, postsynaptic targeting, and ion channel clustering. Journal of Cell Biology, 148(1), 159-171. https://doi.org/10.1083/jcb.148.1.159