S-Nitrosylation and S-Palmitoylation Reciprocally Regulate Synaptic Targeting of PSD-95

Gary P.H. Ho, Balakrishnan Selvakumar, Jun Mukai, Lynda D. Hester, Yuxuan Wang, Joseph A. Gogos, Solomon H. Snyder

Research output: Contribution to journalArticle

Abstract

PSD-95, a principal scaffolding component of the postsynaptic density, is targeted to synapses by palmitoylation, where it couples NMDA receptor stimulation to production of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS). Here, we show that PSD-95 is physiologically S-nitrosylated. We identify cysteines 3 and 5, which are palmitoylated, as sites of nitrosylation, suggesting a competition between these two modifications. In support of this hypothesis, physiologically produced NO inhibits PSD-95 palmitoylation in granule cells of the cerebellum, decreasing the number of PSD-95 clusters at synaptic sites. Further, decreased palmitoylation, as seen in heterologous cells treated with 2-bromopalmitate or in ZDHHC8 knockout mice deficient in a PSD-95 palmitoyltransferase, results in increased PSD-95 nitrosylation. These data support a model in which NMDA-mediated production of NO regulates targeting of PSD-95 to synapses via mutually competitive cysteine modifications. Thus, differential modification of cysteines may represent a general paradigm in signal transduction.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalNeuron
Volume71
Issue number1
DOIs
StatePublished - Jul 14 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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