1. The environmental toxicant ziram enhances neurotransmitter release and increases neuronal excitability via the EAG family of potassium channels.
- Author
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Harrigan J, Brambila DF, Meera P, Krantz DE, and Schweizer FE
- Subjects
- Animals, Drosophila melanogaster, Ether-A-Go-Go Potassium Channels metabolism, Humans, Neurons metabolism, Neurotransmitter Agents metabolism, Synaptic Vesicles metabolism, Ether-A-Go-Go Potassium Channels drug effects, Fungicides, Industrial toxicity, Neurons drug effects, Synaptic Vesicles drug effects, Ziram toxicity
- Abstract
Environmental toxicants have the potential to contribute to the pathophysiology of multiple complex diseases, but the underlying mechanisms remain obscure. One such toxicant is the widely used fungicide ziram, a dithiocarbamate known to have neurotoxic effects and to increase the risk of Parkinson's disease. We have used Drosophila melanogaster as an unbiased discovery tool to identify novel molecular pathways by which ziram may disrupt neuronal function. Consistent with previous results in mammalian cells, we find that ziram increases the probability of synaptic vesicle release by dysregulation of the ubiquitin signaling system. In addition, we find that ziram increases neuronal excitability. Using a combination of live imaging and electrophysiology, we find that ziram increases excitability in both aminergic and glutamatergic neurons. This increased excitability is phenocopied and occluded by null mutant animals of the ether a-go-go (eag) potassium channel. A pharmacological inhibitor of the temperature sensitive hERG (human ether-a-go-go related gene) phenocopies the excitability effects of ziram but only at elevated temperatures. seizure (sei), a fly ortholog of hERG, is thus another candidate target of ziram. Taken together, the eag family of potassium channels emerges as a candidate for mediating some of the toxic effects of ziram. We propose that ziram may contribute to the risk of complex human diseases by blockade of human eag and sei orthologs, such as hERG., Competing Interests: Declaration of Competing Interest No financial conflicts of interest are noted., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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