Mandala Venkata Shiva, MacKinnon Roderick
Laboratory of Molecular Neurobiology and Biophysics, HHMI, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2426744122. doi: 10.1073/pnas.2426744122. Epub 2025 May 14.
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 K2.1 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 (~5 Å). 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 K2.1 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.
电压依赖性离子通道的门控受跨膜电压调节。这种调节形式由电压感应结构域（VSD）实现，VSD通过改变其构象并对孔道施加力来打开或关闭孔道，从而响应跨膜电压差。在这里，我们使用低温电子显微镜研究脂质囊泡中的神经元K2.1通道，该脂质囊泡的膜两侧存在或不存在电压差。超极化电压差使电压传感器中带正电的S4螺旋位移一个螺旋圈（约5埃）。当发生这种位移时，S4螺旋在两个不同界面处改变其与孔道的接触。当在少于四个电压传感器中观察到这些变化时，孔道保持开放，但当在所有四个电压传感器中都观察到这些变化时，孔道收缩。收缩的发生是因为S4螺旋向内位移时挤压了构成孔道内壁的S6螺旋的右手螺旋束。EAG1通道超极化时会发生类似的构象变化，但位移是两个螺旋圈而不是一个。因此，虽然K2.1和EAG1来自不同结构类型的电压依赖性离子通道，即结构域交换型和非结构域交换型，但电压传感器控制其孔道的方式非常相似。
