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Nat Commun. 2015 Oct 27;6:8665. doi: 10.1038/ncomms9665.

S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength.

Zhang P1,2,3, Fu WY1,2,3, Fu AK1,2,3, Ip NY1,2,3.

Author information

1
Divison of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
2
Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Hong Kong, China.
3
State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.

Abstract

Precise regulation of synaptic strength requires coordinated activity and functions of synaptic proteins, which is controlled by a variety of post-translational modification. Here we report that S-nitrosylation of p35, the activator of cyclin-dependent kinase 5 (Cdk5), by nitric oxide (NO) is important for the regulation of excitatory synaptic strength. While blockade of NO signalling results in structural and functional synaptic deficits as indicated by reduced mature dendritic spine density and surface expression of glutamate receptor subunits, phosphorylation of numerous synaptic substrates of Cdk5 and its activity are aberrantly upregulated following reduced NO production. The results show that the NO-induced reduction in Cdk5 activity is mediated by S-nitrosylation of p35, resulting in its ubiquitination and degradation by the E3 ligase PJA2. Silencing p35 protein in hippocampal neurons partially rescues the NO blockade-induced synaptic deficits. These findings collectively demonstrate that p35 S-nitrosylation by NO signalling is critical for regulating hippocampal synaptic strength.

PMID:
26503494
PMCID:
PMC4639907
DOI:
10.1038/ncomms9665
[Indexed for MEDLINE]
Free PMC Article

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