Electric field-induced pore constriction in the human Kv2.1 channel

• 成果类型: Article
• 署名作者: Mandala, Venkata Shiva; MacKinnon, Roderick
• 署名单位: Rockefeller University; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13571
• DOI: 10.1073/pnas.2426744122
• 发表日期: 2025-05-20
• 关键词: dependent k+ channel; gating charge; activation gate; voltage sensor; intracellular gate; skeletal-muscle; shaker; inactivation; MOVEMENT; sensitivity

摘要

Gating in voltage-dependent ion channels is regulated by the transmembrane voltage. This form of regulation is enabled by voltage-sensing domains (VSDs) that respond to transmembrane voltage differences by changing their conformation and exerting force on the pore to open or close it. Here, we use cryogenic electron microscopy to study the neuronal K(v)2.1 channel in lipid vesicles with and without a voltage difference across the membrane. Hyperpolarizing voltage differences displace the positively charged S4 helix in the voltage sensor by one helical turn (similar to 5 angstrom). When this displacement occurs, the S4 helix changes its contact with the pore at two different interfaces. When these changes are observed in fewer than four voltage sensors, the pore remains open, but when they are observed in all four voltage sensors, the pore constricts. The constriction occurs because the S4 helix, as it displaces inward, squeezes the right-handed helical bundle of pore-lining S6 helices. A similar conformational change occurs upon hyperpolarization of the EAG1 channel but with two helical turns displaced instead of one. Therefore, while K(v)2.1 and EAG1 are from distinct architectural classes of voltage-dependent ion channels, called domain-swapped and non-domain-swapped, the way the voltage sensors gate their pores is very similar.