Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier
Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier
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DOI：
10.1073/pnas.0911294107
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发表时间：
2010-08-31
影响因子：
11.1
通讯作者：
Attali, Bernard
中科院分区：
文献类型：
--
作者：
Peretz, Asher;Pell, Liat;Attali, Bernard
电压门控阳离子通道的孔区和栅区经常被药物作为通道调节剂靶向。相比之下，电压感应域（VSD）虽然是各种毒素的靶点，但实际上并没有用于治疗目的。我们最近设计了独特的二苯胺羧酸盐，它是强大的Kv7.2电压门控K+通道打开剂或阻滞剂。在这里，我们展示了一种独特的Kv7.2通道开启剂NH29，作为一种非毒素门控调节剂。NH29增加了Kv7.2电流，从而产生了激活曲线的超极化位移，减慢了激活和失活动力学。在神经元中，开瓶剂抑制诱发的尖峰放电。NH29抑制海马谷氨酸和GABA的释放，从而抑制兴奋性和抑制性突触后电流。诱变和建模数据表明，在Kv7.2中，NH29停靠在由螺旋S1、S2和S4的界面形成的外部凹槽上，以一种稳定S2和S4中两个保守带电残基之间相互作用的方式，已知在Kv通道的开放状态下进行静电相互作用。结果表明，NH29可能通过类似于蝎子和海葵毒素的电压传感器捕获机制起作用。NH29也是一种有效的TRPV1通道阻滞剂，这与狼蛛毒素的特性相似，这反映了VSD的混杂性。我们的数据为设计针对电压门控阳离子通道VSD的独特门控调节剂并用于治疗高兴奋性障碍提供了结构框架。
The pore and gate regions of voltage-gated cation channels have been often targeted with drugs acting as channel modulators. In contrast, the voltage-sensing domain (VSD) was practically not exploited for therapeutic purposes, although it is the target of various toxins. We recently designed unique diphenylamine carboxylates that are powerful Kv7.2 voltage-gated K+ channel openers or blockers. Here we show that a unique Kv7.2 channel opener, NH29, acts as a nontoxin gating modifier. NH29 increases Kv7.2 currents, thereby producing a hyperpolarizing shift of the activation curve and slowing both activation and deactivation kinetics. In neurons, the opener depresses evoked spike discharges. NH29 dampens hippocampal glutamate and GABA release, thereby inhibiting excitatory and inhibitory postsynaptic currents. Mutagenesis and modeling data suggest that in Kv7.2, NH29 docks to the external groove formed by the interface of helices S1, S2, and S4 in a way that stabilizes the interaction between two conserved charged residues in S2 and S4, known to interact electrostatically, in the open state of Kv channels. Results indicate that NH29 may operate via a voltage-sensor trapping mechanism similar to that suggested for scorpion and sea-anemone toxins. Reflecting the promiscuous nature of the VSD, NH29 is also a potent blocker of TRPV1 channels, a feature similar to that of tarantula toxins. Our data provide a structural framework for designing unique gating-modifiers targeted to the VSD of voltage-gated cation channels and used for the treatment of hyperexcitability disorders.