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J Neurosci. 2013 Sep 25;33(39):15401-7. doi: 10.1523/JNEUROSCI.1283-13.2013.

DHHC8-dependent PICK1 palmitoylation is required for induction of cerebellar long-term synaptic depression.

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Howard Hughes Medical Institute and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, Shriners Hospitals Pediatric Research Center and Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.


The palmitoyl acyltransferase (PAT) DHHC8 is implicated in synaptic regulation but few DHHC8 substrates are known. Here we report that DHHC8 binds and palmitoylates the PDZ domain-containing protein PICK1 at a cysteine residue that is essential for long-term synaptic depression (LTD) in cultured mouse cerebellar Purkinje neurons. Cerebellar LTD is palmitoylation-dependent and induction of LTD requires DHHC8. Furthermore, PICK1 is a critical DHHC8 substrate whose palmitoylation is necessary for LTD. These results identify the first DHHC8 substrate required for a specific form of synaptic plasticity and provide new insights into synaptic roles of palmitoylation.

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