Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors
Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors
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DOI：
10.1074/jbc.m607291200
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发表时间：
2007-01-12
影响因子：
4.8
通讯作者：
Zhuo, Min
中科院分区：
文献类型：
--
作者：
Wang, Hansen;Gong, Bo;Zhuo, Min
谷氨酸过度激活N-甲基-D-天冬氨酸（NMDA）受体导致神经元兴奋性毒性。cAMP是一种关键的第二信使，并有助于NMDA受体依赖性突触可塑性。腺苷酸环化酶1（AC 1）和腺苷酸环化酶8（AC 8）是中枢神经系统中两种主要的钙刺激AC。以往的研究表明，AC 1和AC 8在突触可塑性、记忆和持续性疼痛中起重要作用。然而，很少有人知道这两个AC在谷氨酸诱导的神经元兴奋性毒性的可能作用。在这里，我们报告，AC 1基因缺失显着衰减谷氨酸诱导的皮层神经元原代培养的神经元死亡，而AC 8缺失没有产生显着的效果。AC 1，而不是AC 8，有助于培养的皮层神经元中谷氨酸激活NMDA受体后细胞内cAMP的产生。AC 1参与神经元兴奋性毒性中cAMP反应元件结合蛋白活性的动态调节。为了探讨AC 1在体内细胞死亡中的可能作用，我们研究了皮层内注射NMDA诱导的神经元兴奋性毒性。在AC 1中，但在AC 8敲除小鼠中，NMDA诱导的皮质病变显著减少。我们的研究结果提供了直接的证据，AC 1在神经元兴奋性毒性中起着重要作用，并可能作为预防中风和神经退行性疾病兴奋性毒性的治疗靶点。
The excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate results in neuronal excitotoxicity. cAMP is a key second messenger and contributes to NMDA receptor-dependent synaptic plasticity. Adenylyl cyclases 1 (AC1) and 8 (AC8) are the two major calcium-stimulated ACs in the central nervous system. Previous studies demonstrate AC1 and AC8 play important roles in synaptic plasticity, memory, and persistent pain. However, little is known about the possible roles of these two ACs in glutamate-induced neuronal excitotoxicity. Here, we report that genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons, whereas AC8 deletion did not produce a significant effect. AC1, but not AC8, contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons. AC1 is involved in the dynamic modulation of cAMP-response element-binding protein activity in neuronal excitotoxicity. To explore the possible roles of AC1 in cell death in vivo, we studied neuronal excitotoxicity induced by an intracortical injection of NMDA. Cortical lesions induced by NMDA were significantly reduced in AC1 but not in AC8 knock-out mice. Our findings provide direct evidence that AC1 plays an important role in neuronal excitotoxicity and may serve as a therapeutic target for preventing excitotoxicity in stroke and neurodegenerative diseases.