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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
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Binding to voltage gate sodium channels during development leads to cognitive impairment adjacent Iris Mangas (send email) Under development: Not open for comment. Do not cite Under Review

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 High
Female High

Life Stage Applicability

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

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

Modification of VGSC kinetics may be represented by an alteration in the channel opening or closing. Some modifications, such as blocking by TTX, directly prevent the generation of an action potential. Other VGSC kinetic kinetics may shift the membrane potential required to trigger an action potential. Modification of VGSC kinetics may also be represented by slowing down the activation and inactivation of the channel. This slowing of the timeline increases the channel opening time producing a population of channels that remain open when unmodified channels have closed. A direct consequence of persistent channel opening is depolarization of the membrane to action potential threshold and the induction of repetitive firing of the cell.

However, if the channel is held open for a sufficiently long period, the membrane potential eventually becomes depolarized to the point that generation of action potentials is not possible (depolarization-dependent block). Thus, the effects of disruption VGSC kinetics on the action potential are qualitatively different based on the time the channel remains open and this can be measured electrophysiologically. A limited chemically-induced increase in channel opening will lead to repetitive firing while a prolonged opening blocks action potential generation (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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plausibility of KER2 (Altered kinetics of sodium channel leads to Disruption in action potential generation) is strong. The rising phase of an action potential is caused by the opening of voltage-gated sodium channels. These ion channels are activated once the cell’s membrane potential reaches a threshold and open immediately. The electrochemical gradients drive sodium into the cell causing a strong and abrupt depolarization characteristic of an action potential. The falling phase of the action potential is caused by the inactivation of the VGSCs stopping further sodium influx, and the opening of voltage-gated potassium channels. As K+ concentrations inside the cell are very high, channels open and the current flow out serves to restore the membrane potential toward its resting state. However, the efflux of K+ ions is large leading to a hyperpolarisation (undershoot phase) of the membrane potential. Ultimately the voltage-gated K+ channels close and the membrane potential returns to its resting state. This is very well-established textbook knowledge. While it is well accepted that various combinations of channel types in a cell can give rise to differences in the shape and time course of the action potential, the underlying biological principles and relationships between VGSC and action potentials are maintained. Expression of VGSCs is spatially and temporally dependent and have differential expression during CNS development. As in the adult, binding to VGSC isoforms will also disrupt the channel gating kinetics and action potential generation in the developing brain (see reviews by Shafer et al., 2005; Soderlund et al., 2002).

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

Evidence supporting this KER is derived nearly entirely from in vitro experiments, as it is not possible to measure directly sodium channel function in vivo, only proxies of it. However, in vivo recordings of action potentials demonstrate repeated firing in both mammalian and non-mammalian species, supporting that the KER relationship exists across species and in intact nervous systems. Additional uncertainty exists due to the diversity of different sodium channel subunits and understanding their role in the action potential. Thus, the exact compositions of sensitive channels are not characterized. With respect to temporal relationships, different pyrethroid compounds exhibit differing levels of use dependence (Soderlund, 2010), which can be influenced by channel type. However, the level of evidence supporting this KER in the peer-reviewed literature is abundant and the confidence in this KER is high.

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

As noted above, the composition of different VGSC channel subunits, as well as compositions of voltage-gated potassium and calcium channels in the cell, can influence the overall shape and timing of the action potential. This includes changes that might be the result of developmentally specific expression of channels and subunits.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

The relationship between alteration of VGSC kinetics and action potential generation has been modeled in neuroblastoma cells for tetramethrin (Mohan et al., 2006; Molnar and Hickman, 2014). However, the extent to which this model has been extended to other pyrethroids is not clear.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The KE channel opening lasts micro-seconds and modification by compounds occurs quickly, but in the case of state dependence, can be exacerbated with repeated depolarization. Action potential typically last less than a millisecond under normal biological conditions. Modification of the VGSC by pyrethroids can result in repeated firing of action potentials that occur for hundreds of milliseconds (e.g., Song and Narahashi, 1996). Thus, KER happens within milliseconds to microsecond time-scale.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

As described above, the state-dependent interaction of pyrethroids can result in exacerbation of effects with repeated depolarizations. When VGSC inactivation occurs at for short intervals, action potentials are fired repetitively. Such is the case for permethrin and other Type I pyrethroids. By contrast, pyrethroids (type II) prolonged VGSC inactivation for a longer period, depolarizing the membrane potential to the point that action potentials can no longer be generated - depolarization-dependent block (Shafer et al., 2005).

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

The relationship between activity of VGSC and action potential generation is well described in the literature and highly conserved from low-level phyla (e.g. planarians) to humans, is present in both sexes and throughout development (Smith and Walsh, 2020).

References

List of the literature that was cited for this KER description. More help

Bloomquist JR. Ion channels as targets for insecticides. Annu Rev Entomol. 1996; 41:163-90.

Cao Z, Shafer TJ and Murray TF, 2011. Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons, Journal of Pharmacology and Experimental Therapeutics, 336 (1), 197–205. American Society for Pharmacology and Experimental Therapeutics. doi: https://doi.org/10.1124/jpet.110.171850

Hwang, K.S., Kan, H., Kim, S.S., Chae, J.S., Yang, J.Y., Shin, D.S., Ahn, S.H., Ahn, J.H., Cho, J.H., Jang, I.S., Shin, J., Joo, J., Kim, C.H., Bae, M.A. (2020) Efficacy and pharmacokinetics evaluation of 4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as an anti-seizure agent. Neurochemistry international. 141:104870.

Lee KH, Lee H, Yang CH, Ko JS, Park CH, Woo RS, Kim JY, Sun W, Kim JH, Ho WK, Lee SH. Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergic Synapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus. J Neurosci. 2015 Dec 16;35(50):16479-93. 

Meyer DA, Carter JM, Johnstone AF and Shafer TJ, 2008. Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture. Neurotoxicology, 29(2), 213–225. doi: 10.1016/j.neuro.2007.11.005.

Mohan DK, Molnar P, Hickman J. Toxin detection based on action potential shape analysis using a realistic mathematical model of differentiated NG108-15 cells. J.Biosens Bioelectron. 2006 Mar 15;21(9):1804-11. doi: 10.1016/j.bios.2005.09.008. Epub 2006 Feb 3.PMID: 16460924 Morgan and Soltesz, 2008

Molnar P, Hickman J Modeling of action potential generation in NG108-15 cells. J.Methods Mol Biol. 2014;1183:253-61. doi: 10.1007/978-1-4939-1096-0_16.PMID: 25023314

Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14.

Narahashi T, Aistrup GL, Lindstrom JM, Marszalec W, Nagata K, Wang F, Yeh JZ. Ion channel modulation as the basis for general anesthesia. Toxicol Lett. 1998 Nov 23;100-101:185-91. doi: 10.1016/s0378-4274(98)00184-2. PMID: 10049141.

Santhakumar V, Aradi I, Soltesz I. (2005). Role of mossy fiber sprouting and mossy cell loss in hyperexcitability: a network model of the dentate gyrus incorporating cell types and axonal topography. Journal of neurophysiology. 93

Shafer TJ, Meyer DA and Crofton KM, 2005. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environmental Health Perspectives, 113(2), 123–136. https://doi.org/10.1289/ehp.7254

Smith RS, Walsh CA. Ion Channel Functions in Early Brain Development. Trends Neurosci. 2020 Feb;43(2):103-114. doi: 10.1016/j.tins.2019.12.004. Epub 2020 Jan 17. PMID: 31959360; PMCID: PMC7092371.

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D,and Weiner ML, 2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59.

Soderlund DM. State-Dependent Modification of Voltage-Gated Sodium Channels by Pyrethroids. Pestic Biochem Physiol. 2010 Jun 1;97(2):78-86. doi: 10.1016/j.pestbp.2009.06.010.PMID: 20652092

Song JH, Narahashi T. Modulation of sodium channels of rat cerebellar Purkinje neurons by the pyrethroid tetramethrin. J Pharmacol Exp Ther. 1996 Apr;277(1):445-53.PMID: 8613953

Song JH, Narahashi T. Selective block of tetramethrin-modified sodium channels by (+/-)-alpha-tocopherol (vitamin E). J Pharmacol Exp Ther. 1995 Dec;275(3):1402-11.