This study elucidates the specific roles of voltage-sensing domains in the gating and fast inactivation of the NaV1.8 channel using a pharmacological chimera approach.
Enables VSD-specific NaV gating studies; leaves open translation to cardiac isoforms or therapeutics.
Voltage‐gated sodium (Na V ) 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 (Na V 1.2). By doing so, we observe that in Na V 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 Na V channel complex.
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Gilchrist et al. (2017) studied this question.
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