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Ann Geriatr Med Res > Volume 14(4); 2010 > Article
Journal of the Korean Geriatrics Society 2010;14(4):242-252.
DOI: https://doi.org/10.4235/jkgs.2010.14.4.242    Published online December 31, 2010.
Glutamate Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Primary Rat Astrocytes
Sung Ho Kim, Yong Jae Han, Jae Hwang Park, Su Jin Yoo
Department of Emergency Medicine, Wonkwang University College of Medicine, Iksan, Korea. ysoojin@wmc.wonkwang.ac.kr
글루타메이트에 의한 소포체 스트레스 유도성 성상세포 자멸사
김성호.한용재.박재황.유수진
원광대학교 의과대학 응급의학교실
Abstract
BACKGROUND
Glutamate is a well-known central nervous system (CNS) excitatory neurotransmitter that plays a role in memory and learning. However, in excess, it leads to a process called excitotoxicity resulting in cell death. To investigate the mechanism of glutamate cytotoxicity, the apoptosis signaling pathway of primary rat astrocytes was explored in vitro. With this study, we hope to improve the prevention and treatment of ischaemic strokes and various central nervous system disorders.
METHODS
To produce a model of cell injury, primary rat astrocytes were treated with glutamate.
RESULTS
Treatment with glutamate induced death by apoptosis in primary rat astrocytes. This was evidenced by an increase in sub-G0/G1 fraction of the cell cycle with a loss of cell viability. Glutamate also increased the intracellular accumulation of Ca2+ ions, the expression levels of glucose-regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP) protein, and the phosphorylation of protein kinase r-like endoplasmic reticulum kianse (PERK). However, the expression pattern of activating transcription factor (ATF)4 protein did not change and the 90 kDa ATF6 was cleaved to 50 kDa along with a reduced amount of Bcl-2 protein in a time-dependent manner. Interestingly, pre-treatment with glutathione markedly suppressed the reactive oxygen species (ROS) generation and the sub-G0/G1 fraction. However, the intracellular concentration of Ca2+ did not change.
CONCLUSION
Our findings suggest that glutamate injures primary rat astrocytes through the endoplasmic reticulum (ER) stress-mediated apoptotic signaling pathway, as well as, ROS generation. More specifically, through Grp78, PERK, and CHOP, glutamate activates the ER stress-mediated signaling pathway in astrocytes and activates ATF6 to reduce the expression of the Bcl-2 proteins contributing to apoptosis. In addition, the ER stress-mediated signaling pathway is closely related to the transformation of intracellular ROS. This information should be applied to research for the prevention and treatment of strokes and other CNS conditions.
Key Words: Glutamate, Astrocyte, Endoplasmic reticulum, Apoptosis, Reactive oxygen species
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