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Inhibit, voltage-gated sodium channel leads to Altered kinetic of sodium channel
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of voltage gate sodium channels leading to impairment in learning and memory during development||adjacent||Andrea Terron (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages|
Key Event Relationship Description
VGSCs are critical in generation and conduction of electrical signals in multiple excitable tissues. Natural and synthetic toxins are known to interact with VGSC by altering the gate kinetic of the channel by slowing the activation and deactivation rate of the VGSC and shift to a more hyperpolarised potentials the membrane potential at which the VGSC activate.
The detailed mechanism of voltage sensing and voltage-dependent activation of the voltage sensor of sodium channels through a series of resting and activated states is known at the atomic level.
There is evidence supporting that the binding of pyrethroids to VGSC (Trainer et al., 1997; O’Reilly et al., 2006) induces disruption of the sodium channel gate kinetics (Meyer et al., 2008; Soderlund et al., 2002).
Evidence Supporting this KER
It is well known that ion channels are integral membrane proteins that are critical for the execution of action potential and therefore for neuronal function and activation. Action potentials are the electrical impulses that travel along the axons of neurons and result from the movement of Na+ and potassium (K+) ions across the membrane. Binding of excitatory neurotransmitters to their receptors opens cation-permeable ion channels causing the membrane to depolarise or become more positive. This depolarisation activates (opens) VGSCs allowing Na+ to enter the neuron further depolarising the membrane. This increase in membrane permeability to Na+ is responsible for the rising phase of the action potential, eventually causing the membrane polarity to reverse (overshoot phase). The falling phase of the action potential is caused by the inactivation of the VGSCs and the opening of voltage-gated potassium channels allowing K+ to leave the cell. The efflux of K+ ions results in hyperpolarisation (undershoot phase) of the membrane. Ultimately the voltage-gated K+ channels close and the membrane potential returns to its resting state. Type I and II pyrethroids cause stimulus dependent membrane depolarisation and conduction block.
It is therefore biologically plausible that binding of a chemical substance to a VGSC leads sodium channels to open at more hyperpolarised potentials and kept open longer (disruption of channel kinetic), allowing more sodium ions to cross and depolarise the neuronal membrane (Shafer et al., 2005)
Expression of VGSC are spatially and temporally dependent; however, it is biologically plausible that also in developing brain pyrethroids would bind to VGSC isoforms and disrupt the channel gating kinetic (Shafer et al., 2005; Soderlund et al., 2002).
Uncertainties and Inconsistencies
The fact that binding of pyrethroids to VGSCs results in altered sodium channel gate kinetics is well accepted and supported by some evidence. However, some minor uncertainties can be detected as reported below.
Uncertainties in the overall knowledge remain as the sodium channels’ ontogeny is a complex process. Since brain development in both humans and rodents extends from early gestation through lactation it is not possible to state with certainty which isoform of the sodium channels’ α subunits is preferentially affected by deltamethrin.
For in vitro methodologies, there is still a lack of knowledge on stability of deltamethrin in the medium and the partitioning of this compound with plastic, lipid and protein. Indeed, the high lipophilicity of pyrethroids is still a limitation for the sensitivity of the assays and for the identification of a single binding site on any given sodium channel and its mediated action this may affect the sensitivity of the assays (Ruigt et al., 1987). Also, the metabolic competence of the test systems used in various assays is unknown.
Moreover, the study from Meyer et al. (2008) is an indirect measurement of the interaction between the prototype stressor, deltamethrin and VGSCs. Also, the exact temperature at which the patch clamp recording was made is uncertain (in the publication it is stated at room temperature) and it is well documented that pyrethroids effects on VGSCs are negatively temperature dependent (reviewed in Narahashi, 2000). Finally, Meyer and colleagues used hippocampal cell culture from rats PND 2–4 which were not characterised and did not contain microglia or oligodendrocyte precursors cells, therefore there are still uncertainties in the knowledge of the interaction between pyrethroids and microglia or oligodendrocytes precursor VGSC.
Some inconsistencies can be observed in experimental studies. They are associated with the electrophysiological technique used to study ionic currents in individual isolated living cells, tissue sections or patches of cells. The solution used in the bath can be similar to cytoplasm composition or completely different, they can be changed by adding ions or drugs to study the ion channels under different conditions. In the study of Meyer et al. (2008) different effects, i.e. burst duration, were observed for permethrin (type I) and deltamethrin (type II) and it was not clear if this represents a true difference in the mode of action between type I and type II pyrethroids or simply a difference between the two compounds. This could only be determined by the examination of additional chemicals.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Chahine M (ed.), 2018. Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Vol. 246. Springer.
Meisler MH, Kearney J, Ottman R and Escayg A, 2001. Identification of epilepsy genes in human and mouse. Annual Review of Genetics, 35(1), 567–588.
Meyer DA and Shafer TJ, 2006. Permethrin, but not deltamethrin, increases spontaneous glutamate release from hippocampal neurons in culture. Neurotoxicology, 27, 594–603.
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.
Narahashi T, 2000. Neuroreceptors and ion channels as the basis for drug action: past, present, and future. J Pharmacol Exp Ther, 294, 1–26.
O'Reilly AO, Khambay BP, Williamson MS, Field LM, Wallace BA and Davies TG, 2006. Modelling insecticide-binding sites in the voltage-gated sodium channel. Biochemical Journal, 396(2), 255–263.
Planells-Cases R, Caprini M, Zhang J, Rockenstein EM, Rivera RR, Murre C, … and Montal M, 2000. Neuronal death and perinatal lethality in voltage-gated sodium channel αII-deficient mice. Biophysical Journal, 78(6), 2878–2891.
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.
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
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, pp. 39–66. http://dx.doi.org/10.5772/50330