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Relationship: 2625
Title
Altered kinetics of sodium channel leads to Disruption in action potential generation
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | Under Review |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
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
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
Evidence Supporting this KER
Biological Plausibility
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).
Empirical Evidence
The empirical evidence of KER2 is strong. As described in KE2, natural toxins like TTX bind to VGSC and block all electrical activity including action potentials. The relationship of VGSC and action potential generation has been widely demonstrated with a variety of other stressors (e.g., local anesthetics, anticonvulsants and other pharmacological agents (Hwang et al., 2020; Lee et al., 2015). A large body of literature on pyrethroids insecticides has confirmed their ability to alter action potential firing in both insect and mammalian peripheral and central in vitro and in vivo preparations. These studies have been extensively reviewed (Soderlund et al., 2002; Narahashi et al., 1998; Bloomquist, 1996).
Dose and temporal concordance
Although it is well established that altered kinetics of VGSC lead to disruption of action potentials, due to the “all or none” firing characteristics of neuronal action potentials, it is difficult to demonstrate dose-concordance for this specific KER. However, there are examples in the literature showing dose concordance between concentration of pyrethroid insecticides and action potential generation. For deltamethrin and permethrin, changes in VGSC kinetics and disruption of the action potential are reported in vitro at concentration between 0.01 to 1 mM, in hippocampal or neocortical neurons from postnatal day 2–4 pups (Meyer et al., 2008; Cao et al., 2011). Similarly, Song and Narahashi (1995; 1996) demonstrated dose concordance for tetramethrin. As described here and in KER1, there is substantial evidence of dose-related effects of pyrethroid insecticides.
Like the temporal concordance between binding of compound to the VGSC and altered kinetics (KER1), alteration of VGSC kinetics and membrane excitability/action potential generation also occur very quickly. Thus, temporal concordance is difficult to demonstrate directly using experimental approaches. As mentioned, pyrethroid effects have been described as “use-dependent”. As such, increased modification of the channel with repeated depolarizations results in further disruption of action potentials.
Uncertainties and Inconsistencies
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
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.
Quantitative Understanding of the Linkage
Generation of action potentials and the roles of different ion channels in action potential generation and propagation are well understood, and described by the Hodgkin-Huxley model, so theoretically, a quantitative model could be constructed that incorporates alterations in VGSC kinetics and links to action potential generation. It has been estimated than an increased in opening time of a small percentage of VGSCs (< 1% of the VGSCs in a neuron) is all that is required to trigger repetitive firing of that neuron, and an accelerated cycling of the naïve VGSC to cycle through their resting/open/inactivation stages (Narahashi, 1996). Computational models of VGSC conductance and action potential generation have been published (Santha-Kumar et al., 2005). These models exemplify both dose and temporal concordance between these two KEs.
Response-response Relationship
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
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
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
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
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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
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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
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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.
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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
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