Using voltage-sensor toxins and their molecular targets to investigate NaV 1.8 gating

J Physiol. 2018 May 15;596(10):1863-1872. doi: 10.1113/JP275102. Epub 2018 Jan 6.

Abstract

Voltage-gated sodium (NaV ) channel gating is a complex phenomenon which involves a distinct contribution of four integral voltage-sensing domains (VSDI, VSDII, VSDIII and VSDIV). Utilizing accrued pharmacological and structural insights, we build on an established chimera approach to introduce animal toxin sensitivity in each VSD of an acceptor channel by transferring in portable S3b-S4 motifs from the four VSDs of a toxin-susceptible donor channel (NaV 1.2). By doing so, we observe that in NaV 1.8, a relatively unexplored channel subtype with distinctly slow gating kinetics, VSDI-III participate in channel opening whereas VSDIV can regulate opening as well as fast inactivation. These results illustrate the effectiveness of a pharmacological approach to investigate the mechanism underlying gating of a mammalian NaV channel complex.

Keywords: NaV1.8; S3b-S4 motif; gating; scorpion toxin; spider toxin; voltage-sensing domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Ion Channel Gating
  • Membrane Potentials
  • NAV1.8 Voltage-Gated Sodium Channel / drug effects
  • NAV1.8 Voltage-Gated Sodium Channel / physiology*
  • Toxins, Biological / pharmacology*
  • Voltage-Gated Sodium Channel Blockers / pharmacology

Substances

  • NAV1.8 Voltage-Gated Sodium Channel
  • Toxins, Biological
  • Voltage-Gated Sodium Channel Blockers