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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{"title"=>"Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network", "type"=>"journal", "authors"=>[{"first_name"=>"Baoshan", "last_name"=>"Xu", "scopus_author_id"=>"36130739900"}, {"first_name"=>"Sujuan", "last_name"=>"Chen", "scopus_author_id"=>"15828983400"}, {"first_name"=>"Yan", "last_name"=>"Luo", "scopus_author_id"=>"56539048100"}, {"first_name"=>"Zi", "last_name"=>"Chen", "scopus_author_id"=>"50661047400"}, {"first_name"=>"Lei", "last_name"=>"Liu", "scopus_author_id"=>"57193488555"}, {"first_name"=>"Hongyu", "last_name"=>"Zhou", "scopus_author_id"=>"56668978800"}, {"first_name"=>"Wenxing", "last_name"=>"Chen", "scopus_author_id"=>"55715975800"}, {"first_name"=>"Tao", "last_name"=>"Shen", "scopus_author_id"=>"55712735000"}, {"first_name"=>"Xiuzhen", "last_name"=>"Han", "scopus_author_id"=>"7402401408"}, {"first_name"=>"Long", "last_name"=>"Chen", "scopus_author_id"=>"55739243600"}, {"first_name"=>"Shile", "last_name"=>"Huang", "scopus_author_id"=>"55613245400"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-79955544309", "sgr"=>"79955544309", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0019052", "pmid"=>"21544200", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"361682362"}, "id"=>"87fc67de-c4d6-3b79-bc8a-7fc864c3c02a", "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.", "link"=>"http://www.mendeley.com/research/calcium-signaling-involved-cadmiuminduced-neuronal-apoptosis-via-induction-reactive-oxygen-species-a-1", "reader_count"=>63, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>13, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>4, "Student > Master"=>9, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>4, "Researcher"=>13, "Student > Doctoral Student"=>6, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>4, "Student > Master"=>9, "Other"=>3, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>35, "Neuroscience"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>4, "Chemistry"=>3, "Social Sciences"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Neuroscience"=>{"Neuroscience"=>4}, "Chemistry"=>{"Chemistry"=>3}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>4}}, "reader_count_by_country"=>{"Luxembourg"=>1, "Brazil"=>1, "India"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/781943"], "description"=>"<p>Indicated cells pretreated with/without TFP at indicated concentrations for 30 min (A), or infected with lentiviral shRNAs to CaM and GFP, respectively (B), were exposed to 0–20 µM Cd for 24 h, followed by ROS detection, as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. Results are presented as mean ± SE; <i>n</i> = 6. <sup>a</sup><i>P</i><0.01, difference vs. control group; <sup>b</sup><i>P</i><0.01, difference vs. 10 µM Cd group; <sup>c</sup><i>P</i><0.01, difference vs. 20 µM Cd group; <sup>d</sup><i>P</i><0.01, CaM shRNA group vs. GFP shRNA group.</p>", "links"=>[], "tags"=>["cd", "induction", "ros", "neuronal"], "article_id"=>452304, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CaM_is_essential_for_Cd_induction_of_ROS_in_neuronal_cells_/452304", "title"=>"CaM is essential for Cd induction of ROS in neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 19:02:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/781262"], "description"=>"<p>Indicated cells were pretreated with/without BAPTA/AM at indicated concentrations for 30 min, and then exposed to Cd (10 and/or 20 µM) for 24 h (A–C) or 4 h (D, E). (A) [Ca<sup>2+</sup>]<sub>i</sub> in PC12 cells was determined by measuring Fluo-3/AM-labeled fluorescent intensity, as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. (B) [Ca<sup>2+</sup>]<sub>i</sub> was stained with Fluo-4/AM and visualized by fluorescence microscopy in SH-SY5Y cells. (C) Cell viability for PC12, SH-SY5Y, and primary neurons was evaluated using one solution assay. (D and E) Indicated cell lysates were subjected to Western blotting using indicated antibodies. The blots were probed for β-tubulin as a loading control. Similar results were observed in at least three independent experiments. Results (A and C) are presented as mean ± SE; <i>n</i> = 6. <sup>b</sup><i>P</i><0.01, difference vs. control group; <sup>c</sup><i>P</i><0.01, difference vs. 10 µM Cd group; <sup>d</sup><i>P</i><0.01, difference vs. 20 µM Cd group.</p>", "links"=>[], "tags"=>["activates", "pathways", "neuronal", "apoptosis", "induction"], "article_id"=>451619, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g002", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cd_activates_MAPK_mTOR_pathways_and_neuronal_apoptosis_via_induction_of_Ca_2_i_elevation_/451619", "title"=>"Cd activates MAPK/mTOR pathways and neuronal apoptosis via induction of [Ca<sup>2<b>+</b></sup>]<sub>i</sub> elevation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 18:59:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/782063"], "description"=>"<p>PC12 cells, pretreated with/without BAPTA/AM, EGTA, and TFP at indicated concentrations for 30 min, were treated with/without 20 µM Cd for 24 h, followed by Western blot analysis using indicated antibodies. The blots were probed for β-tubulin as a loading control. Similar results were observed in at least three independent experiments.</p>", "links"=>[], "tags"=>["induces", "triggering", "apoptosis", "neuronal"], "article_id"=>452423, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g008", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cd_elevated_Ca_2_i_induces_ROS_triggering_apoptosis_of_neuronal_cells_/452423", "title"=>"Cd-elevated [Ca<sup>2<b>+</b></sup>]<sub>i</sub> induces ROS, triggering apoptosis of neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 19:03:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/781681"], "description"=>"<p>PC12 Cells infected with lentiviral shRNAs to CaM and GFP, respectively, were exposed to Cd (0–20 µM) for 4 h (A,B) or 24 h (C,D), followed by Western blotting with indicated antibodies (A, B), cell morphological analysis (C) or cell viability assay (D), as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. Note: CaM was downregulated by ∼90% by lentiviral shRNA to CaM, compared with the control (lentiviral shRNA to GFP), by densitometry using NIH Image J. Results are presented as mean ± SE; <i>n</i> = 6. <sup>a</sup><i>P</i><0.01, difference vs. control group; <sup>b</sup><i>P</i><0.01, CaM shRNA group vs. GFP shRNA group.</p>", "links"=>[], "tags"=>["cam", "attenuates", "cd", "activation", "pathways", "apoptosis", "neuronal"], "article_id"=>452039, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g005", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Downregulation_of_CaM_attenuates_Cd_activation_of_MAPK_mTOR_pathways_and_apoptosis_in_neuronal_cells_/452039", "title"=>"Downregulation of CaM attenuates Cd activation of MAPK/mTOR pathways and apoptosis in neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 19:01:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/781810"], "description"=>"<p>Indicated cells were exposed to 0–20 µM Cd for 24 h after pretreatment with/without indicated concentrations of BAPTA/AM (A) or EGTA (B) for 30 min, followed by ROS detection, as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. Results are presented as mean ± SE; <i>n</i> = 6. <sup>a</sup><i>P</i><0.05, <sup>b</sup><i>P</i><0.01, difference vs. control group; <sup>c</sup><i>P</i><0.01, difference vs. 10 µM Cd group; <sup>d</sup><i>P</i><0.01, difference vs. 20 µM Cd group.</p>", "links"=>[], "tags"=>["induces", "ros", "neuronal"], "article_id"=>452172, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cd_elevated_Ca_2_i_induces_ROS_in_neuronal_cells_/452172", "title"=>"Cd-elevated [Ca<sup>2<b>+</b></sup>]<sub>i</sub> induces ROS in neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 19:02:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/781141"], "description"=>"<p>(A and B) PC12 cells were treated with 0–20 µM Cd for 24 h, or with 0, 10 and 20 µM Cd for 0–24 h, and then loaded with 5 µM Fluo-3/AM for 30 min at 37°C in the dark, followed by measurement of [Ca<sup>2+</sup>]<sub>i</sub> fluorescence intensity, as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. (C and D) SH-SY5Y cells were exposed to 0–20 µM Cd for 24 h, or 10 µM Cd for 0–24 h, and then loaded with 2.5 µM Fluo-4/AM for 60 min at 37°C in the dark, followed by recording of the images under a fluorescence microscope. (E and F) Cell viability of PC12 cells, treated with 0–20 µM Cd for 24 h or with 20 µM Cd for 0–24 h, was evaluated by one solution assay. Results are presented as mean ± SE; <i>n</i> = 6. <sup>**</sup><i>P</i><0.01 difference vs. control group.</p>", "links"=>[], "tags"=>["neuronal", "apoptosis", "induction"], "article_id"=>451501, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cd_induced_neuronal_apoptosis_is_associated_with_induction_of_Ca_2_i_elevation_/451501", "title"=>"Cd-induced neuronal apoptosis is associated with induction of [Ca<sup>2<b>+</b></sup>]<sub>i</sub> elevation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 18:58:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/781408"], "description"=>"<p>Indicated cells were pretreated with or without 100 µM EGTA for 30 min, and then exposed to Cd (10 and/or 20 µM) for 24 h (A–D) or 4 h (E, F). (A and B) [Ca<sup>2+</sup>]<sub>i</sub> fluorescent intensities were evaluated as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019052#s2\" target=\"_blank\">Materials and Methods</a>. (C) Morphology of PC12 cells was assessed using a Nikon Eclipse TE2000-U inverted phase-contrast microscope (200×) equipped with digital camera. (D) Cell viability in SH-SY5Y cells and primary neurons was evaluated by one solution assay. (E and F) Indicated cell lysates were subjected to Western blotting using indicated antibodies. The blots were probed for β-tubulin as a loading control. Similar results were observed in at least three independent experiments. Results (A, D) are presented as mean ± SE; <i>n</i> = 6. <sup>b</sup><i>P</i><0.01, difference vs. control group; <sup>c</sup><i>P</i><0.01, difference vs. 10 µM Cd group; <sup>d</sup><i>P</i><0.01, difference vs. 20 µM Cd group.</p>", "links"=>[], "tags"=>["extracellular", "influx", "elevates", "contributing", "neuronal", "apoptosis", "activation", "mapk", "mtor"], "article_id"=>451760, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g003", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cd_induced_extracellular_Ca_2_influx_elevates_Ca_2_i_contributing_to_neuronal_apoptosis_via_activation_of_MAPK_and_mTOR_pathways_/451760", "title"=>"Cd-induced extracellular Ca<sup>2<b>+</b></sup> influx elevates [Ca<sup>2<b>+</b></sup>]<sub>i</sub> contributing to neuronal apoptosis via activation of MAPK and mTOR pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 18:59:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/781546"], "description"=>"<p>Indicated cells were pretreated with/without TFP at indicated concentrations for 30 min, and then exposed to Cd (10 and 20 µM) for 4 h (A, B) or 24 h (C). (A and B) Indicated cell lysates were subjected to Western blotting using indicated antibodies. The blots were probed for β-tubulin as a loading control. Similar results were observed in at least three independent experiments. (C) Cell viability for indicated cells was evaluated using one solution assay. Results are presented as mean ± SE; <i>n</i> = 6. <sup>a</sup><i>P</i><0.05, <sup>b</sup><i>P</i><0.01, difference vs. control group; <sup>c</sup><i>P</i><0.01, difference vs. 10 µM Cd group; <sup>d</sup><i>P</i><0.01, difference vs. 20 µM Cd group.</p>", "links"=>[], "tags"=>["cam", "tfp", "attenuates", "cd", "activation", "apoptosis", "neuronal"], "article_id"=>451899, "categories"=>["Molecular Biology", "Neuroscience", "Cell Biology"], "users"=>["Baoshan Xu", "Sujuan Chen", "Yan Luo", "Zi Chen", "Lei Liu", "Hongyu Zhou", "Wenxing Chen", "Tao Shen", "Xiuzhen Han", "Long Chen", "Shile Huang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0019052.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_CaM_by_TFP_attenuates_Cd_activation_of_MAPK_mTOR_and_apoptosis_in_neuronal_cells_/451899", "title"=>"Inhibition of CaM by TFP attenuates Cd activation of MAPK/mTOR and apoptosis in neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 19:00:34"}

PMC Usage Stats | Further Information

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