Aop:113

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/113


AOP Title

Glutamate-gated chloride channel activation leading to acute mortality
Short name: GluCl activation to mortality

Authors

Kellie Fay

Status

Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA toxCast high throughput screening data for hazard identification Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

Macrocylcic lactone (ML) antihelmintics, insecticides and acaricids (e.g. abamectin and ivermectin) target the alpha subunits of the glutamate-gated chloride channels (GluCl) present in nematodes, arthropods, crustaceans (daphnia), and mollusks. The binding of the ML may result in directly opening the ion channel, or may potentiate the effects of the endogenous agonist, glutamate, resulting in increased chloride entry into the cell. With the increased influx of chloride ions, the cell becomes hyperpolarized (neuron) or depolarized (myocyte), resulting in paralysis and death. Mammals do not possess glutamate-gated chloride channels, but the structure of the GluCl channel is similar to the glycine === Background (optional) ===

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Glutamate-gated chloride channel, Activation

Key Events

Event Support for Essentiality
Chloride conductance, Increased
neuron, hyperpolarisation
Ataxia, paralysis, or hyperactivity, N/A

Adverse Outcome

Adverse Outcome
Mortality, Increased
population, Decreased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Glutamate-gated chloride channel, Activation Directly Leads to Chloride conductance, Increased
neuron, hyperpolarisation Indirectly Leads to Ataxia, paralysis, or hyperactivity, N/A
Mortality, Increased Directly Leads to population, Decreased
Ataxia, paralysis, or hyperactivity, N/A Indirectly Leads to Mortality, Increased
Chloride conductance, Increased Directly Leads to neuron, hyperpolarisation

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
Bombus impatiens Bombus impatiens NCBI
chaetanaphothrips orchidii
Radopholus similis Radopholus similis NCBI
Daphnia magna Daphnia magna NCBI
Orius insidiosus Orius insidiosus NCBI
hymenoptera
Helicoverpa zea Helicoverpa zea NCBI
lepidoptera
Liriomyza trifolii Liriomyza trifolii NCBI
orius isidiosus
Acyrthosiphon kondoi Acyrthosiphon kondoi NCBI

Sex Applicability

Sex Evidence Links

Graphical Representation

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Overall Assessment of the AOP

Strong evidence exists for population decline in pest species (e.g., worms, ticks and mites) resulting from targeted glutamate-gated chloride channels, as well for non-target species (bees, butterflies). However, this AOP has been developed with minimal research. Given GluCl channels exist in several cell types, specific key events likely vary among species, which are not elucidated here. The review by Wolstenholme (2012) describes specific GluCl-controlled sensory inputs in worms and flies (e.g., behavioral responses to odour, temperature and light) which suggest pathways other than paralysis may be more sensitive. As such, this AOP should be considered putative with minimally-researched support.

Domain of Applicability

Glutamate-gated chloride channels are absent in vertebrates (Slimko et al., 2002). Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References

Slimko, E.M., McKinney, S., Anderson, D.J., Davisodn, N., and Lester, H.A. (2002) Selective electrical silencing of mammalian neurons in vitro by the use of invertebrate ligand-gated chloride channels. J. Neurosci. 22, 7373-7379.

Wolstenholm, A. (2012) Glutamate-gated chloride channels. J. Biological Chem. 287: 48, 40232-40238.