Differential state-dependent modification of inactivation-deficient Nav1.6 sodium channels by the pyrethroid insecticides S-bioallethrin, tefluthrin and deltamethrin

Abstract

Pyrethroid insecticides disrupt nerve function by modifying the gating kinetics of transitions between the conducting and nonconducting states of voltage-gated sodium channels. Pyrethroids modify rat Nav1.6 + β1 + β2 channels expressed in Xenopus oocytes in both the resting state and in one or more states that require channel activation by repeated depolarization. The state dependence of modification depends on the pyrethroid examined: deltamethrin modification requires repeated channel activation, tefluthrin modification is significantly enhanced by repeated channel activation, and S-bioallethrin modification is unaffected by repeated activation. Use-dependent modification by deltamethrin and tefluthrin implies that these compounds bind preferentially to open channels. We constructed the rat Nav1.6Q3 cDNA, which contained the IFM/QQQ mutation in the inactivation gate domain that prevents fast inactivation and results in a persistently open channel. We expressed Nav1.6Q3 + β1 + β2 sodium channels in Xenopus oocytes and assessed the modification of open channels by pyrethroids by determining the effect of depolarizing pulse length on the normalized conductance of the pyrethroid-induced sodium tail current. Deltamethrin caused little modification of Nav1.6Q3 following short (10 ms) depolarizations, but prolonged depolarizations (up to 150 ms) caused a progressive increase in channel modification measured as an increase in the conductance of the pyrethroid-induced sodium tail current. Modification by tefluthrin was clearly detectable following short depolarizations and was increased by long depolarizations. By contrast modification by S-bioallethrin following short depolarizations was not altered by prolonged depolarization. These studies provide direct evidence for the preferential binding of deltamethrin and tefluthrin (but not S-bioallethrin) to Nav1.6Q3 channels in the open state and imply that the pyrethroid receptor of resting and open channels occupies different conformations that exhibit distinct structure–activity relationships.

Consequences of acute Na v 1.1 exposure to deltamethrin

“…Previous research has established that deltamethrin has high affinity for the open (active) state of Na v channels (He and Soderlund, 2011; McCavera and Soderlund, 2012; Dong and Priestley, 2003), and we therefore tested this aspect of function as well. Use-dependent activity of deltamethrin was assessed with two separate test pulses to −10 mV prior to or after a train of sub-threshold depolarizations to −30 mV at a rate of 10 or 5 Hz, and representative traces of the protocols and their results are shown in Fig.…”

“…Na v channels are similarly the target of neurotoxic effects in mammals but are accompanied with a wider array of responses due to Na v isoform diversity in mammals (Tan and Soderlund, 2010, 2009; He and Soderlund, 2011; McCavera and Soderlund, 2012). Na v channels in the mammalian brain are comprised of a functional, pore-forming α subunit with accessory β subunits (Goldin, 2001; Catterall, 2000).…”

“…Type I pyrethroid acute exposures are correlated with a T syndrome characterized by tremors while type II pyrethroid acute exposures correlate with a CS syndrome characterized by choreoathetosis with salivation (Breckenridge et al, 2009; Romero et al, 2015). Furthermore, type I pyrethroids have a higher propensity for resting-state modification of Na v channels whereas type II pyrethroids have a higher affinity for the open state of a Na v channel (Tan and Soderlund, 2010; Breckenridge et al, 2009; He and Soderlund, 2011; McCavera and Soderlund, 2012). These correlations are strong but not absolute, as some pyrethroids demonstrate activity associated with both categories of pyrethroid action (Tan and Soderlund, 2010; Breckenridge et al, 2009; He and Soderlund, 2011).…”

“…Previous studies have demonstrated that Na v 1.6 is sensitive to pyrethroid activity while other isoforms like Na v 1.2 are more resistant but not impervious (Tan and Soderlund, 2010; He and Soderlund, 2011; McCavera and Soderlund, 2012; O’Reilly et al, 2006; Oliveira et al, 2013; Tan et al, 2005). The V409 residue in cockroach sodium channel is involved on conferring natural sensitivity to pyrethroid activity, and when this residue is mutated to an isoleucine, pyrethroid resistance occurs (Oliveira et al, 2013).…”

Synergistic Actions of Pyridostigmine Bromide and Insecticides on Muscle and Vascular Nociceptors

“…As TTX was unable to reduce permethrin-induced spontaneous discharges or excitability shifts in muscle nociceptors (figure 2), the activity was necessarily dependent upon permethrin modified TTXr channel proteins, such as Na v 1.8, rather than the many other mammalian TTXs proteins that are modified by pyrethroids (including Na v 1.2, Na v 1.3 and Na v 1.6; Song et al, 1996;Smith and Soderlund, 1998;Meacham et al, 2008;Tan and Soderlund, 2009;Tan and Soderlund, 2010;McCavera and Soderlund, 2012). Nociceptors also widely express the TTXr Na v 1.9 (Fang et al, 2002;.…”