Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein
Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein
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DOI：
10.1126/science.284.5421.1845
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发表时间：
1999-06-11
期刊：
影响因子：
56.9
通讯作者：
Tymianski, M
中科院分区：
文献类型：
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作者：
Sattler, R;Xiang, ZG;Tymianski, M
N-甲基-D-天冬氨酸受体(NMDAR)触发细胞内信号通路的效率控制神经元的可塑性、发育、衰老和疾病。在培养的皮质神经元中，抑制NM DAR支架蛋白PSD-95(突触后密度-95)的表达选择性地减弱由NMDAR触发的兴奋性毒性，但不能由其他谷氨酸或钙离子(Ca~(2+))通道触发。NMDAR功能未受影响，因为受体表达、NMDA电流和Ca-45(2+)负荷没有变化。抑制PSD-95选择性地阻断NMDARs产生钙激活的一氧化氮，而不影响神经元型一氧化氮合酶的表达或功能。因此，PSD-95是NMDAR活性与一氧化氮毒性有效偶联所必需的，并赋予兴奋性毒性钙信号的特异性。
The efficiency with which N-methyl-D-aspartate receptors (NMDARs) trigger intracellular signaling pathways governs neuronal plasticity, development, senescence, and disease. In cultured cortical neurons, suppressing the expression of the NM DAR scaffolding protein PSD-95 (postsynaptic density-95) selectively attenuated excitotoxicity triggered via NMDARs, but not by other glutamate or calcium ion (Ca2+) channels. NMDAR function was unaffected, because receptor expression, NMDA currents, and Ca-45(2+) loading were unchanged. Suppressing PSD-95 blocked Ca2+-activated nitric oxide production by NMDARs selectively, without affecting neuronal nitric oxide synthase expression or function. Thus, PSD-95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity, and imparts specificity to excitotoxic Ca2+ signaling.