Consequences of acute Nav1.1 exposure to deltamethrin

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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.

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