title: Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1.
abstract: 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.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, 75004 China.
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China, Institute of Molecular Medicine, Department of Blood Transfusion, Zhejiang Provincial People's Hospital, Hangzhou, 310014 China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China.
authors.forename: Ying-Cong
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan, 75004 China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Reproduction and Stem Cell Engineering, Xiangya Hospital, Central South University, Changsha, 410083 China, and.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058 China, yshen@zju.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002540:Cerebral Cortex / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005978:Glutathione / Q000096:biosynthesis*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050580:Excitatory Amino Acid Transporter 3; D005978:Glutathione; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C091822:Prkcabp protein, mouse; C493399:Slc1a1 protein, mouse
keywords: EAAC1; PICK1; Rab11; glutathione; oxidant; oxidative stress