title: Involvement of the sodium-calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity.
abstract: Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca(2+)) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca(2+) dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca(2+) homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium-calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK-WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca(2+) concentration [Ca(2+)]i induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3(-/-)) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson's disease and indicates new targets to slow down neuronal degeneration.
authors.affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA; Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Lao
authors.affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA.
authors.forename: M
authors.initials: M
authors.lastname: Katsura
authors.affiliation: Department of Neurobiology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: A
authors.initials: A
authors.lastname: Caputo
authors.affiliation: Department of Neurobiology, UCLA School of Medicine, Los Angeles, CA 90095, USA; UCLA Brain Research Institute, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Schweizer
authors.affiliation: UCLA School of Nursing, Los Angeles, CA 90095, USA; UCLA Brain Research Institute, USA; UCLA Center for the Advancement of Gerontological Nursing Sciences, USA; UCLA Clinical and Translational Science Institute, USA. Electronic address: ssokolow@sonnet.ucla.edu.
authors.forename: S
authors.initials: S
authors.lastname: Sokolow
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005659:Fungicides, Industrial / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D015039:Ziram / Q000633:toxicity*
chemical_list: D005659:Fungicides, Industrial; C491101:Slc8a3 protein, mouse; D019831:Sodium-Calcium Exchanger; D015039:Ziram; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Neurotoxicity; Parkinson's disease; Pesticide; Sodium–calcium exchanger; Ziram