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Event: 1353

Key Event Title

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Inhibit, voltage-gated sodium channel

Short name
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Inhibit, voltage-gated sodium channel
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Biological Context

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Level of Biological Organization
Molecular

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

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Molecular events lead to epilepsy KeyEvent Lyle Burgoon (send email) Open for adoption
presynaptic neuron 1 activation to epilepsy KeyEvent Lyle Burgoon (send email) Open for adoption
Inhibition of voltage gate during development is leading to cognitive disorders MolecularInitiatingEvent 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

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All life stages

Sex Applicability

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Male
Female

Key Event Description

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Ion channels are integral membrane proteins that are critical for neuronal function. They form pores in the plasma membrane that allow certain ions to travel with their concentration gradient across the membrane. Those that open in response to a change in membrane voltage potential are called voltage-gated ion channels. Channels that open in response to binding using a chemical signal or molecule are ligand-gated ion channels. 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. Voltage-gated sodium channels are therefore responsible for action potential initiation and propagation in excitable cells, including nerve, muscle and neuroendocrine cell types. They are also expressed at low levels in non-excitable cells. It is important to note is that functional VGSC are present in both grey and white matter in the brain and approximately 50% of white matter oligodendrocyte precursor cells producing trains of action potentials and receiving synaptic input (Fields, 2008). VGSC are also present on microglia cells and contribute to release of major pro-inflammatory cytokines (Hossain et al., 2017).

Mammalian VGSC are composed of one α and two β subunits. Ten separate α subunits (Ogata and Ohishi, 2002) and four different β subunits (Isom, 2002) have been identified and are expressed in a tissue, region and time specific manner. The diverse functional roles of VGSCs depend on the numerous potential combinations of α and β subunits (Ogata and Ohishi, 2002). The type of VGSCs expressed in different cell types and regions, and their sensitivity and their functional role, may all contribute to the manifestation of toxicity and age dependent sensitivity, including the effects caused by pyrethroids.

At resting membrane potentials the channel is closed. During the rising phase of an action potential the channel activates or opens. Channel inactivation contributes to the falling phase. During the undershoot phase the channel deactivates before returning to the closed phase once resting membrane resting potential has been restored. Source: adapted from Motifolio Biomedical PowerPoint Toolkit Suite.

How It Is Measured or Detected

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The sodium channel protein has been discovered and characterised in biochemical and molecular detail, even to atomic resolution. The initial works performed to measure and detect the electrical signals in nerves were initiated by Hodgkin and Huxley in 1952, showing a voltage‐dependent activation of sodium current that carries Na+ inward. The structure of VGSCs is nowadays known in detail and some seminal papers are available (Catterall, 2012).

Intracellular microelectrode recording using voltage or patch clamp are the common methods used for electrophysiological studies of VGSC. Channels and locations can also be measured using immunohistochemical methods, transcriptomics and at protein levels.

Expression of different sodium channel isoforms can be measured using a panel of sodium channel subunit-specific antibodies. Quantification of immunocytochemical staining is difficult due to differences in equipment, tissue preparation, inter-assay variability and analysis methods. However, using a quantitative approach, it is possible to determine the localisation and relative levels of sodium channel subunit protein expression (Westenbroek et al., 2013). PCR amplification and competitive PCR approach, real-time PCR, are used to isolate the mRNA levels of VGSC isoforms (Haufe et al., 2005).

Domain of Applicability

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Every cell within living organisms actively maintains an intracellular Na+ concentration that is 10–12 times lower than the extracellular concentration. The cells then utilise this transmembrane Na+ concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising VGSC (Navs) is essential for such signalling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another. VGSC were first predicted in squid and were later identified through molecular biology in the electric eel. Since then, these proteins have been discovered in organisms ranging from bacteria to humans (Chaihne, 2018).

Sodium channels consist of a highly processed α subunit, which is approximately 260 kDa, associated with auxiliary β subunits of 33–39 kDa. Sodium channels in the adult central nervous system (CNS) and heart contain a mixture of β1–β4 subunits, while sodium channels in adult skeletal muscle have only the β1 subunit. Nine different sodium channels have been identified using electrophysiological recording, biochemical purification, and cloning (Catterall, 2012).

Nomenclature of the different sodium channels utilises a numerical system to define subfamilies and subtypes based on similarities between the amino acid sequences of the channels. In this nomenclature system, the name of an individual channel consists of the chemical symbol of the principal permeating ion (Na) with the principal physiological regulator (voltage) indicated as a subscript (Nav). The number following the subscript indicates the gene subfamily (currently only Nav 1), and the number following the full point identifies the specific channel isoform (e.g. Na­v 1.1). This last number has been assigned according to the approximate order in which each gene was identified. Splice variants of each family member are identified by lower-case letters following the numbers (e.g. Nav 1.1a). Nine mammalian sodium channel isoforms have been identified and functionally expressed with all greater than 50% identical in amino acid sequence in the transmembrane and extracellular domains, where the amino acid sequence is similar enough for clear alignment (Catterall, 2012). In addition to these nine sodium channels that have been functionally expressed, closely related sodium channel-like proteins (Nax) have been cloned from mouse, rat and human. They are approximately 50% identical to the Nav 1 subfamily of channels but more than 80% identical to each other (Catterall, 2012).

In mammals, neuronal VGSC are expressed in the adult and developing brain. Evidence from mutation and knockout animal models demonstrates that perturbation of VGSC function during development impair nervous system structure and function, including muscle function, pain reception and cardia arrythmias (Chahine, 2018). VGSC show complex regional and temporal ontogeny in mammals (see Table 1, from Shafer et al., 2005). In general, embryonically expressed forms of VGSCs are replaced by expression of adult forms as neurodevelopment proceeds.

This complex ontogeny of VGSCs confounds any simple linkage of VGSCs to adverse outcomes and is an uncertainty in the development of this AOP. Since brain development in both humans and rodents extends from early gestation through lactation, it is not currently possible to state which VGSC subtype, or subtypes, may be responsible for the AOs.

Ion channels, including VGSCs, are also expressed in oligodendrocytes, Schwann cells (Baker, 2002) and microglia (Hossain et al., 2017). The expression and function of VGSS in cells of the oligodendrocyte lineage follow a time and regional ontogeny. While present and active in the early stages of oligodendrocyte maturation, VGSC function decreases over developmental time and is absent in mature oligodendrocytes (Paez et al., 2009; Berret et al., 2017). Knockdown of VGSC in rat oligodendrocyte precursor cells (OPCs) leads to reduced myelination suggesting a function of VGSC for axon myelination (Berret et al., 2017).

The physiological and anatomical ontogeny of Schwann cells is well known (Jessen and Mirsky, 2005). VGSCs are present in Schwann cells including the tetrodotoxin sensitive and Nav 1.7 types (Ritche, 1992; Chiu, 1991; Baker, 2002) less is known about their developmental profile.

Microglia cells express several ion channels, including Cl-, K+, H+ and Ca2+ and VGSC that are involved in several cellular functions such as maintaining the membrane potential, cellular volume and intracellular ion concentrations. VGSCs are demonstrated, to be present both in rodents and human microglia. Different isoforms are present in primary microglia (Nav 1.1, 1.2, 1.3, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.1 isoforms) compared to immortalised BV2 cells (Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 isoforms) (Jung et al., 2013; Black and Waxman, 2012; reviewed by Hossain et al., 2017). Presence of sodium channel isoforms in immortalised BV2 cells and primary microglia were detected by mRNA expression with standard PCR. BV2 cells express some sodium channel isoforms including Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 whereas primary microglia from 1–2-day-old mice express channel isoforms Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 1.8, 1.9, and 2.1. Primary microglia expressed higher levels of Nav 1.1. 1.2, 1.3, 1.6, 1.9, and 2.1 compared with BV2 cells.

References

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

Baker MD, 2002. Electrophysiology of mammalian Schwann cells. Progress in Biophysics and Molecular Biology, 78(2–3), 83–103. https://doi.org/10.1016/S0079–6107(02)00007-X

Berret E, Barron T, Xu J, Debner E, Kim EJ and Kim JH, 2017. Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation. Nature Communications, 8(1), 1–15. https://doi.org/10.1038/s41467–017–00688–0

Black JA and Waxman SG, 2012. Sodium channels and microglial function. Experimental Neurology, 234(2), 302–315. https://doi.org/10.1016/j.expneurol.2011.09.030

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

Catterall WA, 2012. Voltage‐gated sodium channels at 60: structure, function and pathophysiology. Journal of Physiology, 590(11), 2577–2589. https://doi.org/10.1113/jphysiol.2011.224204

Catterall WA, Cestèle S, Yarov-Yarovoy V, Frank HY, Konoki K and Scheuer T, 2007. Voltage-gated ion channels and gating modifier toxins. Toxicon, 49(2), 124–141. doi: 10.1016/j.toxicon.2006.09.022

Chahine M (ed.), 2018. Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Vol. 246. Springer.

Chiu SY, 1991. Functions and distribution of voltage‐gated sodium and potassium channels in mammalian Schwann cells. Glia, 4(6), 541–558. https://doi.org/10.1002/glia.440040602

Fields RD, 2008. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. The Neuroscientist, 14(6), 540–543.

Haufe V, Camacho JA, Dumaine R, Günther B, Bollensdorff C, Von Banchet GS, and Zimmer, T, 2005. Expression pattern of neuronal and skeletal muscle voltage‐gated Na+ channels in the developing mouse heart. Journal of Physiology, 564(3), 683–696. https://doi.org/10.1113/jphysiol.2004.079681

Hossain MM, Liu J and Richardson JR, 2017. Pyrethroid insecticides directly activate microglia through interaction with voltage-gated sodium channels. Toxicological Sciences, 155(1), 112–123. Oxford Academic, https://doi.org/10.1093/toxsci/kfw187

Isom LL, 2002. β subunits: Players in neuronal hyperexcitability? Sodium Channels and Neuronal Hyperexcitability, 124, 124–138.

Jessen KR and Mirsky R, 2005. The origin and development of glial cells in peripheral nerves. Nature Reviews in Neuroscience, 6, 671–682. https://doi.org/10.1038/nrn1746

Jung GY, Lee JY, Rhim H, Oh TH and Yune TY, 2013. An increase in voltage‐gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury. Glia, 61(11), 1807–1821. https://doi.org/10.1002/glia.22559

Káradóttir R, Hamilton NB, Bakiri Y and Attwell D, 2008. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neuroscience, 11(4), 450–456. https://doi.org/10.1038/nn2060

Lee SH and Soderlund DM, 2001. The V410M mutation associated with pyrethroid resistance in Heliothis virescens reduces the pyrethroid sensitivity of house fly sodium channels expressed in Xenopus oocytes. Insect Biochemistry and Molecular Biology, 31(1), 19–29. https://doi.org/10.1016/S0965–1748(00)00089-8

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

Ogata N and Ohishi Y, 2002. Molecular diversity of structure and function of the voltage-gated Na+ channels. Japanese Journal of Pharmacology, 88(4), 365–377. https://doi.org/10.1254/jjp.88.365

Paez PM, Fulton D, Colwell CS and Campagnoni AT, 2009. Voltage‐operated Ca2+ and Na+ channels in the oligodendrocyte lineage. Journal of Neuroscience Research, 87(15), 3259–3266. https://doi.org/10.1002/jnr.21938

Ray DE, 2001. Pyrethroid insecticides: mechanisms of toxicity, systemic poisoning syndromes, paresthesia, and therapy. In: Krieger RI and Krieger WC. Handbook of Pesticide Toxicology. Academic Press, pp. 1289–1303.

Ritchie JM, 1992. Voltage-gated ion channels in Schwann cells and glia. Trends in Neurosciences, 15(9), 345–351. https://doi.org/10.1016/0166–2236(92)90052-A

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 TJ and Soderlund DM, 1998. Action of the pyrethroid insecticide cypermethrin on rat brain IIa sodium channels expressed in xenopus oocytes. Neurotoxicology, 19(6), 823–832.

Smith TJ and Soderlund DM, 2001. Potent actions of the pyrethroid insecticides cismethrin and cypermethrin on rat tetrodotoxin-resistant peripheral nerve (SNS/PN3) sodium channels expressed in Xenopus oocytes. Pesticide Biochemistry and Physiology, 70(1), 52–61. https://doi.org/10.1006/pest.2001.2538

Smith TJ, Lee SH, Ingles PJ, Knipple DC and Soderlund DM, 1997. The L1014F point mutation in the house fly Vssc1 sodium channel confers knockdown resistance to pyrethroids. Insect Biochemistry and Molecular Biology, 27(10), 807–812. https://doi.org/10.1016/S0965–1748(97)00065–9

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. https://doi.org/10.1016/S0300–483X(01)00569–8

Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D, and Catterall WA, 1997. High affinity binding of pyrethroids to the α subunit of brain sodium channels. Molecular Pharmacology, 51(4), 651–657. doi: https://doi.org/10.1124/mol.51.4.651

Vais H, Williamson MS, Devonshire AL and Usherwood PNR, 2001. The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels. Pest Management Science, 57(10), 877–888. https://doi.org/10.1002/ps.392

Vais H, Williamson MS, Goodson SJ, Devonshire AL, Warmke JW, Usherwood PN and Cohen CJ, 2000. Activation of Drosophila sodium channels promotes modification by deltamethrin: reductions in affinity caused by knock-down resistance mutations. Journal of General Physiology, 115(3), 305–318. doi: https://doi.org/10.1085/jgp.115.3.305

Volpe JJ, Kinney HC, Jensen FE and Rosenberg PA, 2011. Reprint of ‘The developing oligodendrocyte: key cellular target in brain injury in the premature infant’. International Journal of Developmental Neuroscience, 29(6), 565–582. https://doi.org/10.1016/j.ijdevneu.2011.07.008

Wakeling EN, Neal AP and Atchison WD, 2012. Pyrethroids and their effects on ion channels. Pesticides—Advances in Chemical and Botanical Pesticides. Rijeka, Croatia: InTech, 39–66. http://dx.doi.org/10.5772/5033

Wang SY, Barile M and Wang GK, 2001. A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na+ channels is critical for pyrethroid action. Molecular Pharmacology, 60(3), 620–628.

Westenbroek RE, Bischoff S, Fu Y, Maier SK, Catterall WA and Scheuer T, 2013. Localization of sodium channel subtypes in mouse ventricular myocytes using quantitative immunocytochemistry. Journal of Molecular and Cellular Cardiology, 64, 69–78. doi: 10.1016/j.yjmcc.2013.08.004