title: A dual role of transient receptor potential melastatin 2 channel in cytotoxicity induced by silica nanoparticles.
abstract: Silica nanoparticles (NPs) have remarkable applications. However, accumulating evidence suggests NPs can cause cellular toxicity by inducing ROS production and increasing intracellular Ca(2+) ([Ca(2+)]i), but the underlying molecular mechanism is largely unknown. Transient receptor potential melastatin 2 (TRPM2) channel is known to be a cellular redox potential sensor that provides an important pathway for increasing the [Ca(2+)]i under oxidative stress. In this study, we examined the role of TRPM2 channel in silica NPs-induced oxidative stress and cell death. By quantitation of cell viability, ROS production, [Ca(2+)]i, and protein identification, we showed that TRPM2 channel is required for ROS production and Ca(2+) increase induced by silica NPs through regulating NADPH oxidase activity in HEK293 cells. Strikingly, HEK293 cells expressing low levels of TRPM2 were more susceptible to silica NPs than those expressing high levels of TRPM2. Macrophages from young mice showed significantly lower TRPM2 expression than those from senescent mice and had significantly lower viability after silica NPs exposure than those from senescent ones. Taken together, these findings demonstrate for the first time that TRPM2 channel acts as an oxidative stress sensor that plays a dual role in silica NPs-induced cytotoxicity by differentially regulating the NADPH oxidase activity and ROS generation.
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Peilin
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Zunquan
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hui
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Daishun
authors.initials: D
authors.lastname: Ling
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Lie
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.|Department of Physiology and Neurobiology and Key Laboratory of Brain Research of Henan Province, Xinxiang Medical University, Xinxiang 453003, P. R. China.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Jiang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Toxicology, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Xinqiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D019255:NADPH Oxidases / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000737:chemistry*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D012822:Silicon Dioxide; D019255:NADPH Oxidases; D002118:Calcium