To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:1977
Event: 1977
Key Event Title
Disruption of sodium channel gate kinetic
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
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 | Arthur Author (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages |
Sex Applicability
Term | Evidence |
---|---|
Male | |
Female |
Key Event Description
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.
Slowed VGSC activation leads to a decrease in peak Na+ current. 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. Prolongation of the channel opening time for a short period causes repetitive firing of action potential (repetitive discharge). However, if the channel is held open for a sufficient long period, the membrane potential eventually becomes depolarised to the point at which generation of action potentials is not possible (depolarisation-dependent block). Change of a small percentage of VGSCs can increase Na+ current substantially (Narahashi, 1996).
How It Is Measured or Detected
The modifications of the sodium channel gating have been studied on voltage and patch clamp experiments in different models (Ruigt et al., 1987), 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 current 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 record transmembrane currents 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 can be measured. A single electrode serves both to measures voltage and pass current (Molleman, 2003).
Domain of Applicability
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
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