Atomic basis for therapeutic activation of neuronal potassium channels.
Atomic basis for therapeutic activation of neuronal potassium channels.
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DOI：
10.1038/ncomms9116
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发表时间：
2015-09-03
影响因子：
16.6
通讯作者：
Kurata HT
中科院分区：
文献类型：
--
作者：
Kim RY;Yau MC;Galpin JD;Seebohm G;Ahern CA;Pless SA;Kurata HT
雷替加宾是最近被批准的一种抗惊厥药物，它通过增强KCNQ2-5通道产生的神经元M电流，与通道孔域中保守的Trp残基相互作用而发挥作用。利用非自然的氨基酸突变，我们巧妙地改变了这种色氨酸的性质，以揭示雷替加宾作用所需的特定化学相互作用。引入非天然等位氢键缺陷色氨酸类似物可消除通道增强作用，表明雷替加宾效应强烈依赖于与保守的孔道色氨酸形成氢键。支持这一模式，用氟化的色氨酸类似物取代，随着氢键倾向的增加，增强了雷替加宾的效力。此外，许多雷替加宾类似物的效力与大多数KCNQ激活剂中存在的羰基/氨基甲酸酯氧原子的负静电表面电位相关。这些发现从功能上精确地指出了原子尺度的相互作用对于瑞替加宾的作用是必不可少的，并提供了严格的限制条件，可能指导合理改进新兴药物类别的KCNQ通道激活剂。抗癫痫药物雷替加宾增强神经元KCNQ钾通道。在这里，作者使用非天然氨基酸突变和电生理学的组合来证明雷替加宾通过与通道孔中色氨酸吲哚氮的氢键起作用。
Retigabine is a recently approved anticonvulsant that acts by potentiating neuronal M-current generated by KCNQ2–5 channels, interacting with a conserved Trp residue in the channel pore domain. Using unnatural amino-acid mutagenesis, we subtly altered the properties of this Trp to reveal specific chemical interactions required for retigabine action. Introduction of a non-natural isosteric H-bond-deficient Trp analogue abolishes channel potentiation, indicating that retigabine effects rely strongly on formation of a H-bond with the conserved pore Trp. Supporting this model, substitution with fluorinated Trp analogues, with increased H-bonding propensity, strengthens retigabine potency. In addition, potency of numerous retigabine analogues correlates with the negative electrostatic surface potential of a carbonyl/carbamate oxygen atom present in most KCNQ activators. These findings functionally pinpoint an atomic-scale interaction essential for effects of retigabine and provide stringent constraints that may guide rational improvement of the emerging drug class of KCNQ channel activators. The antiepileptic drug retigabine potentiates neuronal KCNQ potassium channels. Here, the authors use a combination of unnatural amino acid mutagenesis and electrophysiology to show that retigabine acts by hydrogen bonding with a tryptophan indole nitrogen in the channel pore.