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

• Published in: Protein & cell 2017-06, Vol.8 (6), p.401-438
• Main Authors: Huang, Weiyun, Liu, Minhao, Yan, S. Frank, Yan, Nieng
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Calcium Channels, L-Type - chemistry; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cell Biology; Channelopathies - genetics; Channelopathies - metabolism; channelopathy; Developmental Biology; Drug discovery; Human Genetics; Humans; Life Sciences; Mutation; Nav channels; NAV1.1 Voltage-Gated Sodium Channel - chemistry; NAV1.1 Voltage-Gated Sodium Channel - genetics; NAV1.1 Voltage-Gated Sodium Channel - metabolism; NAV1.5 Voltage-Gated Sodium Channel - chemistry; NAV1.5 Voltage-Gated Sodium Channel - genetics; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Nav1.7; NAV1.7 Voltage-Gated Sodium Channel - chemistry; NAV1.7 Voltage-Gated Sodium Channel - genetics; NAV1.7 Voltage-Gated Sodium Channel - metabolism; pain; Protein Domains; Protein Science; Rabbits; Resource; Stem Cells; structure modeling; Structure-Activity Relationship; 动作电位; 原子结构; 基因突变; 电压门控钠通道; 疾病; 离子通道; 药物发现; 评估
• ISSN: 1674-800X; 1674-8018
• DOI: 10.1007/s13238-017-0372-z

Voltage-gated sodium （Nav） channels are essential for the rapid upstroke of action potentials and the propa- gation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related muta- tions have been identified in Nay channels, with Nay1.1 and Nay1.5 each harboring more than 400 mutations. Nay channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav chan- nels are required to understand their function and dis- ease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium （Car） channel Carl.1 provides a template for homology-based structural modeling of the evolutionarily related Nay channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nay1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nay channels, the analysis presented here serves as the base framework for mechanistic investi- gation of Nav channelopathies and for potential struc- ture-based drug discovery.