Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron. 2011 Jul 14;71(1):131-41. doi: 10.1016/j.neuron.2011.05.033.
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 是突触后密度的主要支架成分，通过棕榈酰化作用靶向突触，在那里它将 NMDA 受体刺激与神经元型一氧化氮合酶 (nNOS) 产生的一氧化氮 (NO) 偶联。在这里，我们表明 PSD-95 是生理性 S-亚硝基化的。我们确定了棕榈酰化的半胱氨酸 3 和 5 是亚硝基化的位点，这表明这两种修饰之间存在竞争。支持这一假设，生理产生的 NO 抑制小脑颗粒细胞中 PSD-95 的棕榈酰化，减少突触部位 PSD-95 簇的数量。此外，在异源细胞中用 2-溴棕榈酸处理或在缺乏 PSD-95 棕榈酰转移酶的 ZDHHC8 敲除小鼠中观察到的棕榈酰化减少会导致 PSD-95 亚硝基化增加。这些数据支持这样一种模型，即 NMDA 介导的 NO 产生通过相互竞争的半胱氨酸修饰调节 PSD-95 向突触的靶向。因此，半胱氨酸的差异修饰可能代表信号转导的一般范例。
