Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):E2399-408. doi: 10.1073/pnas.1207901109. Epub 2012 Aug 13.
Voltage-gated K(+) (Kv) channels couple the movement of a voltage sensor to the channel gate(s) via a helical intracellular region, the S4-S5 linker. A number of studies link voltage sensitivity to interactions of S4 charges with membrane phospholipids in the outer leaflet of the bilayer. Although the phospholipid phosphatidylinositol-4,5-bisphosphate (PIP(2)) in the inner membrane leaflet has emerged as a universal activator of ion channels, no such role has been established for mammalian Kv channels. Here we show that PIP(2) depletion induced two kinetically distinct effects on Kv channels: an increase in voltage sensitivity and a concomitant decrease in current amplitude. These effects are reversible, exhibiting distinct molecular determinants and sensitivities to PIP(2). Gating current measurements revealed that PIP(2) constrains the movement of the sensor through interactions with the S4-S5 linker. Thus, PIP(2) controls both the movement of the voltage sensor and the stability of the open pore through interactions with the linker that connects them.
电压门控钾 (Kv) 通道通过螺旋状的细胞内区域（S4-S5 连接子）将电压传感器的运动与通道门（s）偶联起来。许多研究将电压敏感性与 S4 电荷与双层膜外层的膜磷脂之间的相互作用联系起来。尽管内层膜叶中的磷脂酰肌醇-4,5-二磷酸 (PIP(2)) 已成为离子通道的通用激活剂，但尚未为哺乳动物 Kv 通道确立这种作用。在这里，我们表明 PIP(2)耗竭对 Kv 通道产生了两种动力学上不同的影响：电压敏感性增加和电流幅度相应降低。这些效应是可逆的，表现出不同的分子决定因素和对 PIP(2)的敏感性。门控电流测量显示，PIP(2)通过与 S4-S5 连接子的相互作用来限制传感器的运动。因此，PIP(2)通过与连接它们的连接子相互作用来控制电压传感器的运动和开放孔的稳定性。
