Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution

Abstract

Voltage-gated sodium (Na_v) channels are responsible for the initiation and propagation of action potentials. They are associated with a variety of channelopathies and are targeted by multiple pharmaceutical drugs and natural toxins. Here, we report the cryogenic electron microscopy structure of a putative Na_v channel from American cockroach (designated Na_vPaS) at 3.8 angstrom resolution. The voltage-sensing domains (VSDs) of the four repeats exhibit distinct conformations. The entrance to the asymmetric selectivity filter vestibule is guarded by heavily glycosylated and disulfide bond-stabilized extracellular loops. On the cytoplasmic side, a conserved amino-terminal domain is placed below VSD_I, and a carboxy-terminal domain binds to the III-IV linker. The structure of Na_vPaS establishes an important foundation for understanding function and disease mechanism of Na_v and related voltage-gated calcium channels.