BmK AEP, an Anti-Epileptic Peptide Distinctly Affects the Gating of Brain Subtypes of Voltage-Gated Sodium Channels
BmK AEP, an Anti-Epileptic Peptide Distinctly Affects the Gating of Brain Subtypes of Voltage-Gated Sodium Channels
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BmK AEP（一种抗癫痫肽）显着影响电压门控钠通道的大脑亚型的门控
DOI：
10.3390/ijms20030729
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Cao，Zhengyu
中科院分区：
文献类型：
--
作者：
Zhang，Fan;Wu，Ying;Cao，Zhengyu
BmK AEP是一种从马氏Buthus martensii Karsch毒液中纯化的蝎肽，据报道具有抗癫痫活性。电压门控钠通道（VGSCs）负责神经元动作电位（APs）的上升阶段，因此控制神经元的兴奋性。为了阐明其抗癫痫活性的潜在分子机制，我们研究了BmK AEP对皮质神经元AP放电的影响，以及BmK AEP如何影响VGSCs的脑亚型（Nav1.1-1.3和Nav1.6）。BmK AEP浓度依赖性地抑制原代培养皮层神经元的神经元兴奋性。在不影响稳态失活的情况下，BmK AEP通过将VGSC激活的半峰值电压向超极化方向移动约7.83 mV，抑制皮层神经元Na+峰值电流，IC50值为2.12µM，与抑制AP生成的作用一致。与其对皮质神经元Na+电流的作用类似，BmK AEP对HEK-293细胞中异源表达的Nav1.1、Nav1.3和Nav1.6的Na+电流具有浓度依赖性抑制作用，IC50值分别为3.20、1.46和0.39µM，最大抑制率分别为82%、56%和93%。在Nav1.1、Nav1.3和Nav1.6中，BmK AEP分别将电压依赖性激活向超极化方向偏移~15.60 mV、~9.97 mV和~6.73 mV，对稳态失活的影响最小。相比之下，BmK AEP对Nav1.2电流的抑制最小（~15%），但延迟了通道的失活，IC50值为1.69µM。综上所述，这些数据表明BmK AEP是一种相对选择性的Nav1.6门控调节剂，可以明显影响VGSCs脑亚型的门控。
BmK AEP, a scorpion peptide purified form the venom of Buthus martensii Karsch, has been reported to display anti-epileptic activity. Voltage-gated sodium channels (VGSCs) are responsible for the rising phase of action potentials (APs) in neurons and, therefore, controlling neuronal excitability. To elucidate the potential molecular mechanisms responsible for its anti-epileptic activity, we examined the influence of BmK AEP on AP firing in cortical neurons and how BmK AEP influences brain subtypes of VGSCs (Nav1.1–1.3 and Nav1.6). BmK AEP concentration-dependently suppresses neuronal excitability (AP firing) in primary cultured cortical neurons. Consistent with its inhibitory effect on AP generation, BmK AEP inhibits Na+ peak current in cortical neurons with an IC50 value of 2.12 µM by shifting the half-maximal voltage of activation of VGSC to hyperpolarized direction by ~7.83 mV without affecting the steady-state inactivation. Similar to its action on Na+ currents in cortical neurons, BmK AEP concentration-dependently suppresses the Na+ currents of Nav1.1, Nav1.3, and Nav1.6, which were heterologously expressed in HEK-293 cells, with IC50 values of 3.20, 1.46, and 0.39 µM with maximum inhibition of 82%, 56%, and 93%, respectively. BmK AEP shifts the voltage-dependent activation in the hyperpolarized direction by ~15.60 mV, ~9.97 mV, and ~6.73 mV in Nav1.1, Nav1.3, and Nav1.6, respectively, with minimal effect on steady-state inactivation. In contrast, BmK AEP minimally suppresses Nav1.2 currents (~15%) but delays the inactivation of the channel with an IC50 value of 1.69 µM. Considered together, these data demonstrate that BmK AEP is a relatively selective Nav1.6 gating modifier which distinctly affects the gating of brain subtypes of VGSCs.