Structural basis for severe pain caused by mutations in voltage gated sodium channels Nav1.7

Gain-of-function mutations in voltage-gated sodium channel NaV1.7 cause severe inherited pain syndromes, including Inherited Erythromelalgia (IEM). We introduced IEM mutations into the bacterial sodium channel NaVAb and confirmed the negative shift in the voltage dependence of activation that recapitulates the gain-of-function of these mutants. Unexpectedly, our structures of NaVAb IEM mutations reveal two complementary pathogenic mechanisms at the atomic level. Mutations in the voltage sensor domain facilitate the outward movement of S4 gating charges by widening the pathway for gating charge movement and modifying hydrophobic interactions with surrounding amino acid side chains or membrane phospholipids. In contrast, IEM mutations in the S4-S5 linker stabilize the activated state by forming new hydrogen bonds with residues in the pore domain, including a conserved asparagine near the activation gate. These results provide key structural insights into the dual mechanisms by which these IEM mutations cause hyperexcitability and severe pain in this debilitating disease.