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© The Rockefeller University Press, 0021-9525/2000/1/159/ $5.00
The Journal of Cell Biology, Volume 148, Number 1, January 10, 2000 159-172

Original Article

Dual Palmitoylation of PSD-95 Mediates Its Vesiculotubular Sorting, Postsynaptic Targeting, and Ion Channel Clustering

Alaa E. El-Husseinia, Sarah E. Cravena, Dane M. Chetkovicha,b, Bonnie L. Firesteina, Eric Schnella, Chiye Aokic, and David S. Bredta
a Department of Physiology, University of California at San Francisco, San Francisco, California 94143
b Department of Neurology, University of California at San Francisco, San Francisco, California 94143
c Center for Neural Science, New York University, New York 10003

Correspondence to: David S. Bredt, University of California at San Francisco School of Medicine, 513 Parnassus Ave., San Francisco, CA 94143-0444. Tel:(415) 476-6310 Fax:(415) 476-4929 E-mail:bredt{at}itsa.ucsf.edu.

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.

Key Words: PSD, palmitoylation, trafficking, MAGUK, clustering


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