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

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 id...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2011-07, Vol.71 (1), p.131-141
Main Authors: Ho, Gary P.H., Selvakumar, Balakrishnan, Mukai, Jun, Hester, Lynda D., Wang, Yuxuan, Gogos, Joseph A., Snyder, Solomon H.
Format: Article
Language:English
Subjects:
Acyltransferases - genetics
Acyltransferases - metabolism
Animals
Brain
Cerebellum - drug effects
Cerebellum - metabolism
Disks Large Homolog 4 Protein
Guanylate Kinases - metabolism
HEK293 Cells
Humans
Lipoylation - drug effects
Lipoylation - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
N-Methylaspartate - pharmacology
Neurons
Nitric oxide
Nitric Oxide - metabolism
Palmitates - pharmacology
Proteins
Rodents
Synapses - metabolism
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Summary: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. ► PSD-95 is S-nitrosylated at cysteines 3 and 5 ► Nitrosylation at cysteines 3 and 5 inhibits palmitoylation at these sites ► S-nitrosylation of PSD-95 inhibits synaptic clustering ► Inhibition of PSD-95 palmitoylation increases S-nitrosylation of PSD-95
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2011.05.033