Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

Voltage-gated sodium (Na_v) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Na_v channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Na_v channels, with Na_v1.1 and Na_v1.5 each harboring more than 400 mutations. Na_v channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Na_v channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Ca_v) channel Ca_v1.1 provides a template for homology-based structural modeling of the evolutionarily related Na_v channels. In this Resource article, we summarized all the reported disease-related mutations in human Na_v channels, generated a homologous model of human Na_v1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Na_v channels, the analysis presented here serves as the base framework for mechanistic investigation of Na_v channelopathies and for potential structure-based drug discovery.