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

Thull, S, Neacsu, C, O'Reilly, AO, Bothe, S, Hausmann, R, Huth, T, Meents, J and Lampert, A (2020) Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5. Toxicology and Applied Pharmacology, 397. ISSN 0041-008X

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Abstract

Voltage-gated sodium channels are responsible not only for the fast upstroke of the action potential, but they also modify cellular excitability via persistent and resurgent currents. Insecticides act via permanently opening sodium channels to immobilize the animals. Cellular recordings performed decades ago revealed distinctly hooked tail currents induced by these compounds. Here, we applied the classical type-II pyrethroid deltamethrin on human cardiac Nav1.5 and observed resurgent-like currents at very negative potentials in the absence of any pore-blocker, which resemble those hooked tail currents. We show that deltamethrin dramatically slows both fast inactivation and deactivation of Nav1.5 and thereby induces large persistent currents. Using the sea anemone toxin ATx-II as a tool to prevent all inactivation-related processes, resurgent-like currents were eliminated while persistent currents were preserved. Our experiments suggest that, in deltamethrin-modified channels, recovery from inactivation occurs faster than delayed deactivation, opening a brief window for sodium influx and leading to hooked, resurgent-like currents, in the absence of an open channel blocker. Thus, we now explain with pharmacological methods the biophysical gating changes underlying the deltamethrin induced hooked tail currents. SUMMARY: The pyrethroid deltamethrin induces hooked resurgent-like tail currents in human cardiac voltage-gated Nav1.5 channels. Using deltamethrin and ATx-II, we identify additional conducting channel states caused by a faster recovery from inactivation compared to the deltamethrin-induced delayed deactivation.

Item Type: Article
Uncontrolled Keywords: 1115 Pharmacology and Pharmaceutical Sciences
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Biological & Environmental Sciences (new Sep 19)
Publisher: Elsevier
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Date Deposited: 03 Jun 2020 12:15
Last Modified: 03 Jun 2020 12:15
DOI or Identification number: 10.1016/j.taap.2020.115010
URI: http://researchonline.ljmu.ac.uk/id/eprint/13045

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