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(v)1.1 and Na(v)1.5 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(v)1.1 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(v)1.7, 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13238-017-0372-z) contains supplementary material, which is available to authorized users.