Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network.
Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network.
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钙信号通过诱导活性氧和激活 MAPK/mTOR 网络参与镉诱导的神经元凋亡
DOI：
10.1371/journal.pone.0019052
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发表时间：
2011-04-22
期刊：
影响因子：
3.7
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Xu B;Chen S;Luo Y;Chen Z;Liu L;Zhou H;Chen W;Shen T;Han X;Chen L;Huang S
镉(Cd)是一种有毒的环境污染物，可诱导氧化应激，导致神经退行性疾病。最近，我们发现Cd通过激活丝裂原活化蛋白激酶(MAPK)和哺乳动物靶标雷帕霉素(MTOR)途径诱导神经细胞凋亡。然而，潜在的机制仍然难以捉摸。在这里，我们发现镉能升高PC12、SH-SY5Y细胞和原代小鼠神经元内钙离子([Ca~(2+)]i)水平。细胞内Ca~(2+)螯合剂BAPTA/AM可阻断Cd诱导的细胞内[Ca~(2+)]i升高，阻断细胞外信号调节激酶1/2(ERK1/2)、c-Jun氨基末端激酶(JNK)和p38等MAKPs的CD激活，以及mTOR介导的信号转导通路和细胞死亡。细胞外Ca~(2+)螯合剂EGTA可阻止Cd诱导的[Ca~(2+)]i升高、MAPK/mTOR激活和细胞死亡，提示Cd诱导的细胞外Ca~(2+)内流在促进神经细胞凋亡中起重要作用。此外，钙调素(CaM)拮抗剂三氟拉嗪(TFP)或沉默CaM可减弱Cd对MAPK/mTOR激活和细胞死亡的影响。此外，Cd诱导的[Ca~(2+)]i升高或CaM的激活可导致细胞内产生活性氧(ROS)。BAPTA/AM、EGTA或TFP可减轻Cd诱导的神经细胞ROS和caspase-3的裂解。我们的研究结果表明，镉可升高[Ca~(2+)]i，从而诱导ROS，激活MAPK和mTOR通路，导致神经细胞凋亡。结果提示，调控镉致神经退行性疾病的[Ca~(2+)]i动态平衡可能是防治镉致神经退行性疾病的一种新策略。
Cadmium (Cd), a toxic environmental contaminant, induces oxidative stress, leading to neurodegenerative disorders. Recently we have demonstrated that Cd induces neuronal apoptosis in part by activation of the mitogen-activated protein kineses (MAPK) and mammalian target of rapamycin (mTOR) pathways. However, the underlying mechanism remains elusive. Here we show that Cd elevated intracellular calcium ion ([Ca2+]i) level in PC12, SH-SY5Y cells and primary murine neurons. BAPTA/AM, an intracellular Ca2+ chelator, abolished Cd-induced [Ca2+]i elevation, and blocked Cd activation of MAKPs including extracellular signal-regulated kinase 1/2 (Erk1/2), c-Jun N-terminal kinase (JNK) and p38, and mTOR-mediated signaling pathways, as well as cell death. Pretreatment with the extracellular Ca2+ chelator EGTA also prevented Cd-induced [Ca2+]i elevation, MAPK/mTOR activation, as well as cell death, suggesting that Cd-induced extracellular Ca2+ influx plays a critical role in contributing to neuronal apoptosis. In addition, calmodulin (CaM) antagonist trifluoperazine (TFP) or silencing CaM attenuated the effects of Cd on MAPK/mTOR activation and cell death. Furthermore, Cd-induced [Ca2+]i elevation or CaM activation resulted in induction of reactive oxygen species (ROS). Pretreatment with BAPTA/AM, EGTA or TFP attenuated Cd-induced ROS and cleavage of caspase-3 in the neuronal cells. Our findings indicate that Cd elevates [Ca2+]i, which induces ROS and activates MAPK and mTOR pathways, leading to neuronal apoptosis. The results suggest that regulation of Cd-disrupted [Ca2+]i homeostasis may be a new strategy for prevention of Cd-induced neurodegenerative diseases.
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影响因子：
7.4
作者：
Chen, Long;Xu, Baoshan;Liu, Lei;Luo, Van;Zhou, Hongyu;Chen, Wenxing;Shen, Tao;Han, Xiuzhen;Kontos, Christopher D.;Huang, Shile
通讯作者：
Huang, Shile
DOI：
10.1111/j.1749-6632.1993.tb18286.x
发表时间：
1993-05-28
影响因子：
5.2
作者：
GIBBONS, SJ;BRORSON, JR;MILLER, RJ
通讯作者：
MILLER, RJ
影响因子：
29
作者：
Gulati, Pawan;Gaspers, Lawrence D.;Thomas, George
通讯作者：
Thomas, George
影响因子：
5.6
作者：
Liu, Ying;Templeton, Douglas M.
通讯作者：
Templeton, Douglas M.
影响因子：
8
作者：
Liu, Z.-M.;Chen, G. G.;van Hasselt, C. A.
通讯作者：
van Hasselt, C. A.