TY - JOUR
T1 - S-Nitrosylation and S-Palmitoylation Reciprocally Regulate Synaptic Targeting of PSD-95
AU - Ho, Gary P.H.
AU - Selvakumar, Balakrishnan
AU - Mukai, Jun
AU - Hester, Lynda D.
AU - Wang, Yuxuan
AU - Gogos, Joseph A.
AU - Snyder, Solomon H.
N1 - Funding Information:
We thank Michael Koldobskiy for helpful discussions and Masoumeh Saleh for maintaining and genotyping the nNOS knockout mice. This work was supported by US Public Health Service Grant MH18501 and Research Scientist Award DA-00074 (to S.H.S.), National Institutes of Health grant MH67068 (to J.A.G.), a Simons Foundation grant (to J.A.G.), and a NARSAD Young Investigator Award (to J.M.).
PY - 2011/7/14
Y1 - 2011/7/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2011.05.033
DO - 10.1016/j.neuron.2011.05.033
M3 - Article
C2 - 21745643
AN - SCOPUS:79960151473
SN - 0896-6273
VL - 71
SP - 131
EP - 141
JO - Neuron
JF - Neuron
IS - 1
ER -