Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states.
Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states.
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DOI：
10.1085/jgp.201611601
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Tucker SJ
中科院分区：
文献类型：
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作者：
McClenaghan C;Schewe M;Aryal P;Carpenter EP;Baukrowitz T;Tucker SJ
TREK 通道由多种刺激打开，至少存在两种构象，即“上”和“下”。麦克莱纳汉等人。表明通道在这两种构象中都可以打开，并且门控主要是通过通道的选择性过滤器实现的。双孔结构域 (K2P) K+ 通道的 TREK 亚家族通过广泛的物理和化学刺激表现出多模式门控。这些通道的晶体结构现在存在两种主要状态，称为“上”和“下”构象。然而，最近的研究得出了关于这两种构象的功能（即导电）状态的矛盾且相互排斥的结论。为了解决这个问题，我们使用了状态依赖性 TREK-2 抑制剂去甲氟西汀，它只能与向下状态结合，从而使我们能够在被不同刺激激活时区分这两种构象。我们的结果通过证明压力、温度、电压和 pH 值的激活产生不止一种结构上不同的开放状态来调和这些先前矛盾的门控模型，并揭示通道激活并不简单地涉及向上和向下构象之间的切换。这些结果还凸显了 K2P 通道用于集成多模门控信号的结构机制的多样性。
TREK channels, which are gated open by a wide range of stimuli, exist in at least two conformations known as “up” and “down.” McClenaghan et al. show that the channel can be open in both of these conformations and that gating is primarily achieved by the channel’s selectivity filter. The TREK subfamily of two-pore domain (K2P) K+ channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals.