PerspectiveBiochemistry

Sodium channels caught in the act

See allHide authors and affiliations

Science  22 Mar 2019:
Vol. 363, Issue 6433, pp. 1278-1279
DOI: 10.1126/science.aaw8645

You are currently viewing the summary.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Summary

Voltage-gated sodium channels (VGSCs) are primarily responsible for initiation of action potentials in many excitable cells such as nerves and muscles. Mammals have nine isoforms of VGSCs, Nav1.1 to 1.9, with largely distinct expression patterns and physiological roles. Dysfunction of these channels leads to pathophysiologies ranging from epilepsies to chronic pain (1). These proteins are targets of potent toxins found in the venoms of animals such as spiders and scorpions (2), which modulate their activity by two broad mechanisms: They either clog the permeation pathway or bind at allosteric sites in the voltage-sensing domains (VSDs) of these proteins and modulate channel opening (gating modifier toxins, GMTs). VGSCs comprise four homologous domains, each of which contribute differently to channel gating, pharmacology, and ion selectivity. For instance, the fourth domain (DIV) contributes little to channel opening but is critical for fast inactivation (3). GMTs that bind to the VSDs of different domains exhibit different functional impacts on gating. This domain specificity of GMTs offers a valuable template to develop therapeutics to treat diseases arising from mutations causing gain-of-function or loss-of-function phenotypes. On pages 1302, 1309, and 1303 of this issue, Clairfeuille et al. (4), Pan et al. (5), and Shen et al. (6), respectively, provide detailed views of different VGSCs in their activated states, bound to pore-blocking toxins and GMTs, as well as a structure of a GMT-bound deactivated state of the channel. Additionally, Xu et al. (7) report structures of toxin-bound resting and activated states of an engineered sodium channel variant. Together, these studies provide unprecedented insights into the pharmacology and gating mechanisms of VGSCs.

View Full Text

Stay Connected to Science