title: Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Xu
authors.forename: Sujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Zi
authors.initials: Z
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhou
authors.forename: Wenxing
authors.initials: W
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Han
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002104:Cadmium / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D002104:Cadmium; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases