Selective Blockade of Neuronal BK (α + β4) Channels Preventing Epileptic Seizure
Selective Blockade of Neuronal BK (α + β4) Channels Preventing Epileptic Seizure
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选择性阻断神经元 BK (α β4) 通道预防癫痫发作
DOI：
10.1021/acs.jmedchem.9b01241
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发表时间：
2020-01-09
影响因子：
7.3
通讯作者：
Cao, Chunyang
中科院分区：
文献类型：
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作者：
Liu, Xinlian;Tao, Jie;Cao, Chunyang
BK通道的功能增强或其β4亚单位的敲除与自发性癫痫有关。目前，BK(α+β4)通道调节剂预防癫痫的疗效尚未见报道。在这里，我们显示马丹参毒素选择性地通过与BKβ4亚单位胞外环(hβ4环)以摩尔比4：1(hβ4环与马藤毒素)相互作用来抑制BK(α+β4)通道。H-β4环的Glu(104)、Glu(122)、Gln(124)、Lys(125)和Glu(128)残基与马藤毒素的Asp(5)、Glu(13)、Lys(20)、Ser(24)、Gln(26)、Lys(28)和Arg(35)残基形成氢键，从而降低神经元的尖峰频率，增加尖峰间隔。海马藤毒素可显著延长戊四氮致敏大鼠癫痫发作的潜伏期，缩短发作持续时间和发作次数，抑制海马神经元的兴奋性和c-Fos的表达，对海马神经元具有神经保护作用。这些结果表明，BK(β4+β4)通道是难治性癫痫治疗的新靶点，马藤毒素有助于合理设计治疗癫痫的药物。
Gain-of-function of BK channels or knockout of their beta 4 subunit is associated with spontaneous epilepsy. Currently, efficacy of BK (alpha + beta 4) channel modulators in preventing epilepsy was never reported. Here, we show that martentoxin selectively inhibits BK (alpha + beta 4) channels by interaction with the extracellular loop of the BK beta 4 subunit (h beta 4-loop) at a molar ratio 4:1 (h beta 4-loop vs martentoxin). Residues Glu(104), Glu(122), Gln(124), Lys(125), and Glu(128) of the h beta 4-loop form hydrogen bonds with residues Asp(5), Glu(13), Lys(20), Ser(24), Gln(26), Lys(28), and Arg(35) of martentoxin, by which martentoxin reduces the neuronal spiking frequency and increases interspike intervals. Intrahippocampal infusion of martentoxin significantly increases the latency time of seizure, reduces seizure duration and seizure numbers on pentylenetetrazole-induced presensitized rats, inhibits hippocampal hyperexcitability and c-Fos expression, and displays neuroprotective effects on hippocampal neurons. These results suggest that the BK (beta 4 + beta 4) channel is a novel therapeutic target of intractable epilepsy and martentoxin contributes to the rational drug design for epilepsy treatment.