Consequences of acute Na v 1.1 exposure to deltamethrin

Abstract

Background Pyrethroid insecticides are the most popular class of insecticides in the world, despite their near-ubiquity, their effects of delaying the onset of inactivation of voltage-gated sodium (Nav) channels have not been well-evaluated in all the mammalian Nav isoforms. Objective Here we compare the well-studied Nav1.6 isoforms to the less-understood Nav1.1 in their responses to acute deltamethrin exposure. Methods We used patch-clamp electrophysiology to record sodium currents encoded by either Nav1.1 or Nav1.6 channels stably expressed in HEK293 cells. Protocols evaluating both resting and use-dependent modification were employed. Results We found that exposure of both isoforms to 10 μM deltamethrin significantly potentiated persistent and tail current densities without affecting peak transient current densities, and only Nav1.1 maintained these significant effects at 1 μM deltamethrin. Window currents increased for both as well, and while only Nav1.6 displayed changes in activation slope and V1/2 of steady-state inactivation for peak currents, V1/2 of persistent current activation was hyperpolarized of ~10 mV by deltamethrin in Nav1.1 cells. Evaluating use-dependence, we found that deltamethrin again potentiated persistent and tail current densities in both isoforms, but only Nav1.6 demonstrated use-dependent enhancement, indicating the primary deltamethrin-induced effects on Nav1.1 channels are not use-dependent. Conclusion Collectively, these data provide evidence that Nav1.1 is indeed vulnerable to deltamethrin modification at lower concentrations than Nav1.6, and this effect is primarily mediated during the resting state. General significance These findings identify Nav1.1 as a novel target of pyrethroid exposure, which has major implications for the etiology of neuropsychiatric disorders associated with loss of Nav1.1-expressing inhibitory neurons.

Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5

“…Pyrethroids are mainly predicted to bind to DII and DIII S6 of the insect Nav channel (Vais et al, 2003 Du et al, 2015). Thus, deltamethrin 5 mainly affects Nav channels by slowing of deactivation Narahashi, 1998, 2001;Vais et 6 al., 2000) but might also have a minor effect on fast inactivation (Chinn and Narahashi, 1986; He and 7 Soderlund, 2016;James et al, 2017). 8 Although humans are less sensitive to pyrethroids, neurotoxic symptoms of pyrethroid intoxication 9 have been described and are most likely mediated by Nav modification (Mowry et al, 2016;Field et 10 al., 2017;James et al, 2017).…”

“…Thus, deltamethrin 5 mainly affects Nav channels by slowing of deactivation Narahashi, 1998, 2001;Vais et 6 al., 2000) but might also have a minor effect on fast inactivation (Chinn and Narahashi, 1986; He and 7 Soderlund, 2016;James et al, 2017). 8 Although humans are less sensitive to pyrethroids, neurotoxic symptoms of pyrethroid intoxication 9 have been described and are most likely mediated by Nav modification (Mowry et al, 2016;Field et 10 al., 2017;James et al, 2017). They include T-syndrome (tremor) for type-I pyrethroids and CS-11 syndrome (choreoathetosis and salivation) for type-II pyrethroids, including deltamethrin.…”

Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na+ Channel 1.6 Enables Isoform-Selective Modulation

“…Having shown previously [37] and demonstrated the dose-dependency (Figure 2) of the effects of PW201 on the transient I Na of Na v 1.6 channels in heterologous cells, we next sought to characterize if these effects of PW201 were selective among CNS Na v channel isoforms. To do so, HEK293 cells stably expressing either Na v 1.1 (HEK-Na v 1.1) [24,38,42] or Na v 1.2 (HEK-Na v 1.2) [24,38,43] channels were incubated for 30 min with either 0.1% DMSO or 15 µM PW201, a concentration of the ligand selected on the basis of its IC 50 value for Na v 1.6 determined in Figure 2B. After incubation, the effects of vehicle and PW201 treatment on Na v 1.1 and Na v 1.2 channels were assessed using whole-cell voltage-clamp recordings (Figure 3).…”

“…isoforms. To do so, HEK293 cells stably expressing either Nav1.1 (HEK-Nav1.1) [24,38,42] or Nav1.2 (HEK-Nav1.2) [24,38,43] channels were incubated for 30 min with either 0.1% DMSO or 15 µM PW201, a concentration of the ligand selected on the basis of its IC50 value for Nav1.6 determined in Figure 2B. After incubation, the effects of vehicle and PW201 treatment on Nav1.1 and Nav1.2 channels were assessed using whole-cell voltage-clamp recordings (Figure 3).…”

Review: In vitro Cell Platform for Understanding Developmental Toxicity

“…Synaptic and ion channel activities, membrane potential, and action potential can be conventionally recorded using patch-clamp and multi-electrode array (MEA). These approaches have been primarily used to record changes in neural circuits of animal brain slices ( Cholanian et al, 2017 ), cultured primary cells ( Cannady et al, 2017 ; Dunn et al, 2018 ), and cell cultures ( James et al, 2017 ) responding to various environmental chemical exposures. Neurons derived from iPSCs can establish electro-physiologically mature neuronal networks that closely resemble mature primary neurons ( Gunhanlar et al, 2018 ).…”