Format

Send to

Choose Destination
Neurotoxicology. 2014 Dec;45:56-66. doi: 10.1016/j.neuro.2014.09.004. Epub 2014 Oct 2.

Involvement of the sodium-calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity.

Author information

1
UCLA School of Nursing, Los Angeles, CA 90095, USA; Department of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR China.
2
UCLA School of Nursing, Los Angeles, CA 90095, USA.
3
Department of Neurobiology, UCLA School of Medicine, Los Angeles, CA 90095, USA.
4
Department of Neurobiology, UCLA School of Medicine, Los Angeles, CA 90095, USA; UCLA Brain Research Institute, USA.
5
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.

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.

KEYWORDS:

Neurotoxicity; Parkinson's disease; Pesticide; Sodium–calcium exchanger; Ziram

PMID:
25284465
PMCID:
PMC4267994
DOI:
10.1016/j.neuro.2014.09.004
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center