Structural basis of human Nav1.5 gating mechanisms

• 成果类型: Article
• 署名作者: Biswas, Rupam; Lopez-Serrano, Ana Laura; Purohit, Apoorva; Ramirez-Navarro, Angelina; Huang, Hsiang-Ling; Grandinetti, Giovanna; Cheng, Xiaolin; Heissler, Sarah M.; Deschenes, Isabelle; Chinthalapudi, Krishna
• 署名单位: University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11733
• DOI: 10.1073/pnas.2416181122
• 发表日期: 2025-05-14
• 关键词: sodium-channels; mutations; inactivation; heart

摘要

Voltage- gated Nav1.5 channels are central to the generation and propagation of cardiac action potentials. Aberrations in their function are associated with a wide spectrum of cardiac diseases including arrhythmias and heart failure. Despite decades of progress in Nav1.5 biology, the lack of structural insights into intracellular regions has hampered our understanding of its gating mechanisms. Here, we present two cryo- EM structures of human Nav1.5 in open states, revealing sequential conformational changes in gating charges of the voltage- sensing domains (VSDs) and several intracellular regions. Despite the channel being in the open state, these structures show repositioning, but no dislodging of the IFM motif in the receptor site. Molecular dynamics analyses show our structures with CTD conduct Na+ ions. Notably, our structural findings highlight a conformation of VSDs and pore opening. Electrophysiological studies confirm that disrupting this interaction alters fast inactivation of Nav1.5. Together, our structure- function studies establish a foundation for understanding the gating mechanisms of Nav1.5 and the mechanisms underlying CTD- related channelopathies.