title: S-nitrosylation and S-palmitoylation reciprocally regulate synaptic targeting of PSD-95.
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.
authors: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Gary P H
authors: GP
authors: Ho
authors: Balakrishnan
authors: B
authors: Selvakumar
authors: Jun
authors: J
authors: Mukai
authors: Lynda D
authors: LD
authors: Hester
authors: Yuxuan
authors: Y
authors: Wang
authors: Joseph A
authors: JA
authors: Gogos
authors: Solomon H
authors: SH
authors: Snyder
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D054878:Lipoylation / Q000187:drug effects / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D010168:Palmitates; C022776:2-bromopalmitate; D009569:Nitric Oxide; D016202:N-Methylaspartate; D000217:Acyltransferases; D051528:Guanylate Kinases