Dual Effect of Phosphatidyl (4,5)-Bisphosphate PIP2 on Shaker K+ Channels
Dual Effect of Phosphatidyl (4,5)-Bisphosphate PIP2 on Shaker K+ Channels
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DOI：
10.1074/jbc.m112.382085
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发表时间：
2012-10-19
影响因子：
4.8
通讯作者：
Loussouarn, Gildas
中科院分区：
文献类型：
--
作者：
Abderemane-Ali, Fayal;Es-Salah-Lamoureux, Zeineb;Loussouarn, Gildas
磷脂酰肌醇(4,5)-二磷酸（PIP2）是一种质膜磷脂，已被证明是几种离子通道的关键调节剂。Kir通道的功能研究和最近的结构研究揭示了PIP2对开放状态稳定的主要影响。已经提出PIP2对延迟整流器Kv7.1和Kv11.1（两个电压门控K+通道）的类似作用，但分子机制仍然难以理解，对于PIP2对其他Kv（如Shaker家族的Kv）的作用一无所知。通过结合os -7细胞中的巨片离子和门控电流记录，以及非洲爪蟾卵母细胞中的电压钳荧光法，我们发现PIP2对最大电流振幅产生了功能增益效应，与开放状态的稳定一致；2)通过正向移动激活电压依赖性产生了功能损失效应，很可能是通过直接影响电压传感器的运动。如分子动力学模拟所示。
Phosphatidylinositol (4,5)-bisphosphate (PIP2) is a phospholipid of the plasma membrane that has been shown to be a key regulator of several ion channels. Functional studies and more recently structural studies of Kir channels have revealed the major impact of PIP2 on the open state stabilization. A similar effect of PIP2 on the delayed rectifiers Kv7.1 and Kv11.1, two voltage-gated K+ channels, has been suggested, but the molecular mechanism remains elusive and nothing is known on PIP2 effect on other Kv such as those of the Shaker family. By combining giant-patch ionic and gating current recordings in COS-7 cells, and voltage-clamp fluorimetry in Xenopus oocytes, both heterologously expressing the voltage-dependent Shaker channel, we show that PIP2 exerts 1) a gain-of-function effect on the maximal current amplitude, consistent with a stabilization of the open state and 2) a loss-of-function effect by positive-shifting the activation voltage dependence, most likely through a direct effect on the voltage sensor movement, as illustrated by molecular dynamics simulations.