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Structural Advances in Voltage-Gated Sodium Channels.
Daohua Jiang1,2, Jiangtao Zhang1,3, Zhanyi Xia1,2
1Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
Frontiers in Pharmacology
|June 20, 2022
Summary
Recent cryo-electron microscopy (cryo-EM) studies reveal the structure of voltage-gated sodium (NaV) channels. These insights into NaV channel architecture and modulation mechanisms guide the development of new therapeutics for related diseases.
Area of Science:
- Molecular and Structural Biology
- Neuroscience
- Pharmacology
Background:
- Voltage-gated sodium (NaV) channels are crucial for action potential generation in excitable cells.
- Over 1,000 mutations in NaV channels are linked to human diseases such as epilepsy, periodic paralysis, arrhythmias, and pain disorders.
- NaV channel function is modulated by natural toxins and small-molecule drugs.
Purpose of the Study:
- To review recent structural advances in eukaryotic NaV channels.
- To highlight key structural features and modulation mechanisms of NaV channels.
- To provide insights for developing subtype-selective therapeutics.
Main Methods:
- Analysis of recent cryo-electron microscopy (cryo-EM) structures of eukaryotic NaV channels.
- Integration of structural data with functional and pharmacological information.
Main Results:
- Cryo-EM structures provide detailed insights into NaV channel architecture.
- Structural analyses reveal mechanisms of activation, fast inactivation, and electromechanical coupling.
- Atomic-level templates are available for understanding ligand binding and modulation.
Conclusions:
- Recent structural studies have significantly advanced our understanding of eukaryotic NaV channels.
- Structural insights facilitate the rational design of novel therapeutics targeting NaV channelopathies.
- Understanding modulation mechanisms by diverse ligands is key for therapeutic development.
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