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Title 

PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release

Authors 

S Y LeeD Y HwangY K KimJ W LeeI C ShinK W OhM K LeeJ S LimDo Young YoonS J HwangJ T Hong

Publisher 

Federation of American Society of Experimental Biology (FASEB)

Issue Date 

2006

Citation 

FASEB Journal, vol. 20, no. 1, pp. 151-153

Keywords 

caspase 3protein pS2ryanodine receptoranimal cellcalcium cell levelcalcium homeostasiscalcium transportcell strainnerve cellcalcium

Abstract 

Increase of neuronal cell vulnerability by presenilin-2 (PS2) mutation by increase of caspase-3 activity through ryanodine receptor-mediated perturbation of calcium homeostasis was investigated. Stably transfected PC12 cells and cortical neurons from transgenic mice expressing mutant PS2 (N141I) showed a significantly enhanced sensitivity to L-glutamate, Aβ25.35, and Aβ1.42 (ADDLs form) compared with cells expressing wild-type PS2. Consistent with this result, much greater intracellular calcium levels and caspase-3 activity were found in PC12 cells and cortical neurons expressing mutant PS2 after treatment with L-glutamate, Aβ25.35, and Aβ1.42. Double-labeling confocal micrographic and coimmunoprecipitation analyses showed that ryanodine receptor type 3 (RyR) and PS2 colocalize in the endoplasmic reticulum (ER) in PC12 cells and in the brain of transgenic mice. The expression of RyR was much higher in the neurons of cells expressing mutant PS2. Moreover, pretreatment with dantrolene, an agent that blocks calcium release from RyR, protected against the mutant PS2-enhanced neuronal cell death and caspase-3 activity. The present data indicate that activation of caspase-3 by RyR-mediated increase of intracellular calcium levels may be an important neurotoxic mechanism in the neuronal cells expressing mutant PS2.

ISSN 

0892-6638

Link 

http://dx.doi.org/10.1096/fj.05-4017fje;1

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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