Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1
Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1
复制标题
与 C-激酶 1 相互作用的蛋白质缺陷会损害谷胱甘肽合成并通过减少表面兴奋性氨基酸载体 1 增加氧化应激
DOI：
10.1523/jneurosci.3966-14.2015
复制
发表时间：
2015
影响因子：
5.3
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Wang Ya-Nan;Zhou Liang;Wang Zhen;Li Ying-Cong;Zhang Ya-Wen;Shen Ying;Li Yun-Hong;Wang Yin;Liu Gang;Wang Zhen;Shen Y
与c -激酶1 （PICK1）相互作用的蛋白受到了相当多的关注，因为它与广泛的神经递质受体、转运体和酶相互作用，从而影响它们在中枢神经系统中的定位和功能。虽然有研究表明，PICK1的推定伴侣与精神分裂症、帕金森病、慢性疼痛和肌萎缩侧索硬化症等神经系统疾病有关，但PICK1在神经系统疾病中的功能尚不清楚。在这里，我们发现与神经系统疾病密切相关的氧化应激发生在PICK1−/−小鼠中。在PICK1−/−小鼠中，选择性地在神经元中发现氧化，并且是年龄依赖性的，导致小胶质细胞激活和炎症因子的释放。PICK1−/−小鼠的皮质和海马神经元对氧化剂的易感性增加，代谢活性氧（ROS）的能力降低；这是由谷胱甘肽含量减少和半胱氨酸运输受损引起的。谷胱甘肽的表达失调与谷氨酸表面转运体兴奋性氨基酸载体1 （EAAC1）的减少有关。过表达PICK1可以挽救EAAC1的表面表达，改善PICK1−/−神经元的谷胱甘肽缺陷。最后，表面EAAC1的减少与Rab11活性缺陷有关。转染显性阴性Rab11可有效抑制表面EAAC1，增加ROS的产生。总之，这些结果表明PICK1是谷胱甘肽稳态的关键调节因子，可能在氧化应激及其相关的神经退行性疾病中发挥重要作用。
Protein interacting with C-kinase 1 (PICK1) has received considerable attention, because it interacts with a broad range of neurotransmitter receptors, transporters, and enzymes and thereby influences their localization and function in the CNS. Although it is suggested that putative partners of PICK1 are involved in neurological diseases such as schizophrenia, Parkinson's disease, chronic pain, and amyotrophic lateral sclerosis, the functions of PICK1 in neurological disorders are not clear. Here, we show that oxidative stress, which is tightly associated with neurological diseases, occurs in PICK1−/− mice. The oxidation in PICK1−/− mice was found selectively in neurons and was age dependent, leading to microglial activation and the release of inflammatory factors. Neurons in the cortex and hippocampus from PICK1−/− mice showed increased vulnerability to oxidants and reduced capacity to metabolize reactive oxygen species (ROS); this was caused by reduced glutathione content and impaired cysteine transport. The dysregulated expression of glutathione was attributed to a decrease of the surface glutamate transporter excitatory amino acid carrier 1 (EAAC1). Overexpression of PICK1 could rescue the surface expression of EAAC1 and ameliorate the glutathione deficit in PICK1−/− neurons. Finally, reduced surface EAAC1 was associated with defective Rab11 activity. Transfection with dominant-negative Rab11 effectively suppressed surface EAAC1 and increased ROS production. Together, these results indicate that PICK1 is a crucial regulator in glutathione homeostasis and may play important roles in oxidative stress and its associated neurodegenerative diseases.