API

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Relationship: 2625

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Altered kinetics of sodium channel leads to Disruption in action potential generation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Altered kinetics of sodium channel
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Disruption in action potential generation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of voltage gate sodium channels leading to impairment in learning and memory during development adjacent Arthur Author (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates High NCBI
Invertebrates Invertebrates High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male
Female

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Long lasting modification of VGSC increases the channel opening time. The direct consequence is a more hyperpolarised potential. This underlies the disruption of neuronal activity with changes in the ions intracellular concentrations and neuronal excitability. Depending on the time the channel is left open, the disruption of the action potential is getting qualitative different and this difference is measurable in electrophysiological recording of the action potential. Limited opening will lead to repetitive firing while following prolonged opening the membrane potential ultimately becomes depolarised to the point at which generation of an action potential is not possible (depolarisation-dependent block) (Shafer et al., 2005).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The mechanistic understanding of the generation of membrane potentials, based on Na, K, Cl and Ca ions is broadly accepted and extensive documentation is also available. However, some uncertainties can be detected. The uncertainties and inconsistencies detected in the Meyer et al., 2008 are also applicable for this KER.

The events investigated by Cao et al. (2011) e.g. depolarisation and calcium entry, glutamate release, activation of NMDA receptors and additional calcium entry, were not directly measured in the study. Moreover, as reported also for VGSCs, the action of pyrethroids on calcium channel is temperature dependent and may have an impact on the deltamethrin-induced calcium influx in neocortical neurons. in the study from Cao et al. (2011) the temperature at which the experiment was carried out is not reported. 9 out of 11 pyrethroids tested were able to produce a concentration-dependent elevation in intracellular calcium concentration in neocortical neurons which occurred secondary to activation of VGSCs. The nine pyrethroids that stimulated calcium influx displayed distinct efficacies. The rank order of efficacy for calcium influx was similar to that for sodium influx (Cao et al., 2009) with the exception of S-bioallethrin, which is the least efficacious compound on calcium influx. Deltamethrin, the prototype stressor for this AOP, is in position 6 (out of 9) in terms of potency.

It should be further noted that other ionic channels may have an impact on the action potential generation and in this regard the knowledge is limited.

Also, in this case, some inconsistencies can be observed in experimental studies. They can be associated with the electrophysiological technique used to study ionic currents in individual isolated living cells, tissue sections or patches of cells. The solution used in the bath can be similar to cytoplasm composition or completely different, they can be changed by adding ions or drugs to study the ion channels under different conditions.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help