Gain-of-function of BK channels or knockout of their β4 subunit is associated with spontaneous epilepsy. Currently, efficacy of BK (α + β4) channel modulators in preventing epilepsy was never reported. Here, we show that martentoxin selectively inhibits BK (α + β4) channels by interaction with the extracellular loop of the BK β4 subunit (hβ4-loop) at a molar ratio 4:1 (hβ4-loop vs martentoxin). Residues Glu104, Glu122, Gln124, Lys125, and Glu128 of the hβ4-loop form hydrogen bonds with residues Asp5, Glu13, Lys20, Ser24, Gln26, Lys28, and Arg35 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 (α + β4) channel is a novel therapeutic target of intractable epilepsy and martentoxin contributes to the rational drug design for epilepsy treatment.

中文翻译：

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选择性阻滞神经元BK（α+β4）通道，预防癫痫发作。

BK通道功能的获得或它们的β4亚基的敲除与自发性癫痫有关。目前，从未报道过BK（α+β4）通道调节剂在预防癫痫方面的功效。在这里，我们显示马仑托辛通过与BKβ4亚基的细胞外环（hβ4-环）以4：1的摩尔比（hβ4-环与马芬托星）相互作用来选择性抑制BK（α+β4）通道。hβ4环的残基Glu104，Glu122，Gln124，Lys125和Glu128与马芬妥辛的残基Asp5，Glu13，Lys20，Ser24，Gln26，Lys28和Arg35形成氢键，从而使马芬妥辛减少神经元突增频率并增加刺突间隔。海马海马汀注射会大大延长癫痫发作的潜伏时间，减少戊四唑诱发的致敏大鼠的癫痫发作持续时间和癫痫发作次数，抑制海马过度兴奋性和c-Fos表达，并显示对海马神经元的神经保护作用。这些结果表明，BK（α+β4）通道是顽固性癫痫的一种新型治疗靶点，而马芬妥辛有助于癫痫治疗的合理药物设计。