Voltage-gated sodium (Na_V) channels play a fundamental role in normal neurological function, especially via the initiation and propagation of action potentials. The Na_V1.1 subtype is found in inhibitory interneurons of the brain and it is essential for maintaining a balance between excitation and inhibition in neuronal networks. Heterozygous loss-of-function mutations of SCN1A, the gene encoding Na_V1.1, underlie Dravet syndrome (DS), a severe pediatric epilepsy. We recently demonstrated that selective inhibition of Na_V1.1 inactivation prevents seizures and premature death in a mouse model of DS. Thus, selective modulators of Na_V1.1 might be useful therapeutics for treatment of DS as they target the underlying molecular deficit. Numerous scorpion-venom peptides have been shown to modulate the activity of Na_V channels, but little is known about their activity at Na_V1.1. Here we report the isolation, sequence, three-dimensional structure, recombinant production, and functional characterization of two peptidic modulators of Na_V1.1 from venom of the buthid scorpion Hottentotta jayakari. These peptides, Hj1a and Hj2a, are potent agonists of Na_V1.1 (EC₅₀ of 17 and 32 nM, respectively), and they present dual α/β activity by modifying both the activation and inactivation properties of the channel. NMR studies of rHj1a indicate that it adopts a cystine-stabilized αβ fold similar to known scorpion toxins. Although Hj1a and Hj2a have only limited selectivity for Na_V1.1, their unusual dual mode of action provides an alternative approach to the development of selective Na_V1.1 modulators for the treatment of DS.

中文翻译：

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在电压门控钠通道Na _V 1.1上具有双重调节活性的毒肽为抗癫痫药物的开发提供了新的线索。

电压门控钠（Na _V）通道在正常的神经功能中起着基本作用，尤其是通过动作电位的启动和传播。Na _V 1.1亚型存在于大脑的抑制性神经元中，对于维持神经元网络的兴奋与抑制之间的平衡至关重要。编码Na _V 1.1的基因SCN1A的杂合功能丧失突变是严重的小儿癫痫症Dravet综合征（DS）的基础。我们最近证明，选择性抑制Na _V 1.1失活可预防DS小鼠模型中的癫痫发作和过早死亡。因此，Na _V的选择性调节剂1.1可能是治疗DS的有用疗法，因为它们靶向潜在的分子缺陷。已经显示出许多蝎毒肽可调节Na _V通道的活性，但对其在Na _V 1.1上的活性知之甚少。在这里我们报告了从蝎蝎Hottentotta jayakari的毒液中Na _V 1.1的两个肽调节剂的分离，序列，三维结构，重组生产和功能表征。这些肽Hj1a和Hj2a是Na _V 1.1（EC ₅₀分别为17 nM和32 nM），并且它们通过修改通道的激活和失活特性呈现双重α/β活性。rHj1a的NMR研究表明，它采用类似于已知蝎毒素的胱氨酸稳定化的αβ折叠。尽管Hj1a和Hj2a对Na _V 1.1的选择性只有有限的限制，但它们不寻常的双重作用方式为开发用于治疗DS的选择性Na _V 1.1调节剂提供了另一种方法。