Using voltage‐sensor toxins and their molecular targets to investigate NaV1.8 gating

摘要

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 (NaV1.2). By doing so, we observe that in NaV1.8, 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.