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Event: 1977

Key Event Title

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Disruption of sodium channel gating kinetics

Short name
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Altered kinetics of sodium channel
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Biological Context

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Level of Biological Organization
Cellular

Cell term

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Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

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Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Inhibition of voltage gate during development is leading to cognitive disorders KeyEvent Andrea Terron (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

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Term Scientific Term Evidence Link
Vertebrates Vertebrates NCBI
Invertebrates Invertebrates NCBI

Life Stages

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Life stage Evidence
All life stages

Sex Applicability

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Term Evidence
Male
Female

Key Event Description

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Action potentials are a temporary shift (from negative to positive) in the neuron’s membrane potential caused by ions flowing in and out of the neuron. During the resting state, before an action potential occurs, all the gated sodium and potassium channels are closed. These gated channels only open once when an action potential has been triggered. They are called ‘voltage-gated’ because they are open and close depending on the voltage difference across the cell membrane. VGSC have two gates (gate m and gate h), while the potassium channel only has one (gate n). Gate m (the activation gate) is normally closed and opens when the cell starts to get more positive. Gate h (the deactivation gate) is normally open, and swings shut when the cells gets too positive. Gate n is normally closed, but slowly opens when the cell is depolarised (very positive). VGSC exist in one of three states: Deactivated (closed) – at rest, channels are deactivated. The m gate is closed and does not let sodium ions through. Activated (open) – when a current pass through and changes the voltage difference across a membrane, the channel will activate and the m gate will open. Inactivated (closed) – as the neuron depolarises, the h gate swings shut and blocks sodium ions from entering the cell. Voltage-gated potassium channels are either open or closed.

Typically, activation and inactivation of VGSC occur quite rapidly. However, some compounds can bind to the VGSC and disrupt the kinetics of activation and inactivation. This typically slows the kinetics of those processes. Slowed VGSC activation leads to a decrease in peak Na+ current measured throughout the cell as well as a delay in the time for the current to reach its peak. By slowing VGSC inactivation and deactivation leads to a prolonged VGSC open time. The longer channel open time results in more Na+ entering the cell and this leads to hyperexcitability, membrane depolarisation, increase in firing rate and conduction block. A short prolongation of the channel inactivation kinetics causes repetitive firing of action potentials (repetitive discharge) as a small percentage of modified channels in the membrane can cause unmodified channels to activate, or open again. However, if the channel inactivation is sufficiently period, the membrane potential eventually becomes depolarised to the point at which generation of action potentials is not possible (depolarisation-dependent block). A small percentage of modified VGSCs can increase Na+ current substantially (Narahashi, 1996), driving repetitive firing and depolarization-dependent conduction block.

How It Is Measured or Detected

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The modifications of the sodium channel gating have been studied using voltage- and patch-clamp experiments in models from many different invertebrate and vertebrate species, including mammals and even human cells (Ruigt et al., 1987; Soderlund et al., 2002), showing that the prolongation of the sodium current is mainly due to the reduced rate of closure of a fraction of sodium channels affected by pyrethroids. In neuroblastoma cell preparations, deltamethrin and other type II pyrethroids induced slow tail currents with a relatively rapid time constant. The rate at which sodium channels close during the pyrethroid-induced slow tail current depends not only on pyrethroid structure, but also on the time of exposure, temperature and membrane potential (Ruigt et al., 1987).

The voltage-clamp technique typically uses two microelectrodes, allowing control of the membrane potential and recording transmembrane currents flowing across the membrane of the entire cell that result from ion channel opening and closing (Guan et al., 2013).

Patch clamp is a highly sensitive version of the voltage-clamp technique in which currents flowing through a single ion channel, or across the entire cell membrane ("whole cell" current) of an individual can be measured, depending on the configuration of the recording. Further, pharmacological interventions can be used such that the current flowing through only a single type of channel in the memberane can be measured. For example, by blocking potassium, calcium and chloride channels, the current flowing through voltage-gated sodium channels can be isolated. A single electrode serves both to measures voltage and pass current (Molleman, 2003). This technique allows measurement of the altered kinetics of a single channel, which can then be manifested by changes in the kinetics of the whole-cell current.

Domain of Applicability

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Ion channels are essential for the initiation and propagation of action potential in excitable cells from both vertebrate and invertebrate species. In neurons, ion channels are essential for chemical communication between cells, or synaptic transmission. Ion channels also function to maintain membrane potential and initiate and propagate electrical impulses. VGSC are therefore a target of natural and synthetic chemicals and disruption of the gate kinetics has been characterised in insects and mammalian cells (Soderlund et al., 2002).

References

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

Guan B, Chen X and Zhang H, 2013. Two-electrode voltage clamp. Methods in Molecular Biology, 998, 79–89. doi: 10.1007/978-1-62703-351-0_6

Molleman A, 2003. Patch Clamping: An Introductory Guide to Patch Clamp Electrophysiology. John Wiley and Sons.

Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14. https://doi.org/10.1111/j.1600–0773.1996.tb00234.x

Ruigt GF, Neyt HC, Van der Zalm JM and Van den Bercken J, 1987. Increase of sodium current after pyrethroid insecticides in mouse neuroblastoma cells. Brain Research, 437(2), 309–322.

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargen D, … and Weiner, ML, 2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59. https://doi.org/10.1016/S0300–483X(01)00569–8