title: Signaling cascades mediate astrocyte death induced by zinc.
abstract: Zinc overload is known to cause the death of neural cells. Although the activation of extracellular signal-regulated kinase (ERK) and cytosolic phospholipase A(2) (cPLA(2)) have been implicated in zinc-induced astrocyte death, the detailed mechanisms of their activation and upstream regulatory cascades are incompletely understood. Here, we report that protein kinase C (PKC)- and Src-related Ras/Raf/ERK cascades and ERK-associated cPLA(2) participate in astrocyte death caused by ZnCl(2). Sustained exposure to ZnCl(2) caused damage to astrocytes in a time- and concentration-dependent manner. The cell death caused by ZnCl(2) was accompanied by increased reactive oxygen species (ROS) generation, PKC-α membrane association, Src phosphorylation, Ras membrane association, Raf phosphorylation, ERK phosphorylation, and cPLA(2) activation, and decreased protein phosphatase activity. Pharmacological studies revealed that these activations/inactivations all contributed to ZnCl(2)-induced astrocyte death. ROS, such as superoxide, appear to be a key trigger in response to ZnCl(2) treatment in astrocytes because of the attenuations in protein phosphatase inhibition, signaling activation, and cell death by antioxidant treatments. Mechanistic studies had suggested that ROS/PKC-α/Ras/Raf/ERK and ROS/Src/Ras/Raf/ERK were potential signals linking zinc and cPLA(2). These observations indicated that ROS/PKC-α/Ras/Raf/ERK and ROS/Src/Ras/Raf/ERK signaling and cPLA(2) were actively involved in zinc-induced astrocyte damage.
authors.affiliation: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Su-Lan
authors.initials: SL
authors.lastname: Liao
authors.forename: Yen-Chuan
authors.initials: YC
authors.lastname: Ou
authors.forename: Shih-Yi
authors.initials: SY
authors.lastname: Lin
authors.forename: Tsung-Kuei
authors.initials: TK
authors.lastname: Kao
authors.forename: Hung-Chuan
authors.initials: HC
authors.lastname: Pan
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Lai
authors.forename: Hsi-Chi
authors.initials: HC
authors.lastname: Lu
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Wang
authors.forename: Chun-Jung
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D016923:Cell Death; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D017967:Zinc Compounds / Q000633:toxicity*; D048490:raf Kinases / Q000502:physiology; D018631:ras Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D002712:Chlorides; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C016837:zinc chloride; D019061:src-Family Kinases; D048490:raf Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins