Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
J Neurophysiol. 2012 Jun;107(11):3155-67. doi: 10.1152/jn.00785.2011. Epub 2012 Mar 21.
Blood-depressing substance I (BDS-I), a 43 amino-acid peptide from sea anemone venom, is used as a specific inhibitor of Kv3-family potassium channels. We found that BDS-I acts with even higher potency to modulate specific types of voltage-dependent sodium channels. In rat dorsal root ganglion (DRG) neurons, 3 μM BDS-I strongly enhanced tetrodotoxin (TTX)-sensitive sodium current but weakly inhibited TTX-resistant sodium current. In rat superior cervical ganglion (SCG) neurons, which express only TTX-sensitive sodium current, BDS-I enhanced current elicited by small depolarizations and slowed decay of currents at all voltages (EC(50) ∼ 300 nM). BDS-I acted with exceptionally high potency and efficacy on cloned human Nav1.7 channels, slowing inactivation by 6-fold, with an EC(50) of approximately 3 nM. BDS-I also slowed inactivation of sodium currents in N1E-115 neuroblastoma cells (mainly from Nav1.3 channels), with an EC(50) ∼ 600 nM. In hippocampal CA3 pyramidal neurons (mouse) and cerebellar Purkinje neurons (mouse and rat), BDS-I had only small effects on current decay (slowing inactivation by 20-50%), suggesting relatively weak sensitivity of Nav1.1 and Nav1.6 channels. The biggest effect of BDS-I in central neurons was to enhance resurgent current in Purkinje neurons, an effect reflected in enhancement of sodium current during the repolarization phase of Purkinje neuron action potentials. Overall, these results show that BDS-I acts to modulate sodium channel gating in a manner similar to previously known neurotoxin receptor site 3 anemone toxins but with different isoform sensitivity. Most notably, BDS-I acts with very high potency on human Nav1.7 channels.
降压物质 I（BDS-I）是一种来自海葵毒液的 43 个氨基酸肽，用作 Kv3 家族钾通道的特异性抑制剂。我们发现 BDS-I 对调节特定类型的电压依赖性钠通道具有更高的效力。在大鼠背根神经节（DRG）神经元中，3 μM 的 BDS-I 强烈增强了河豚毒素（TTX）敏感的钠电流，但微弱抑制了 TTX 抗性的钠电流。在大鼠颈上神经节（SCG）神经元中，BDS-I 增强了由小去极化引起的电流，并减缓了所有电压下的电流衰减（EC50∼300 nM），而这些神经元只表达 TTX 敏感的钠电流。BDS-I 对克隆的人 Nav1.7 通道表现出异常高的效力和效能，使失活速度减慢 6 倍，EC50 约为 3 nM。BDS-I 还减慢了 N1E-115 神经母细胞瘤细胞（主要来自 Nav1.3 通道）中钠电流的失活，EC50∼600 nM。在海马 CA3 锥体神经元（小鼠）和小脑浦肯野神经元（小鼠和大鼠）中，BDS-I 对电流衰减的影响较小（失活速度减慢 20-50%），表明 Nav1.1 和 Nav1.6 通道的敏感性相对较弱。BDS-I 在中枢神经元中的最大作用是增强浦肯野神经元中的再生电流，这一作用反映在浦肯野神经元动作电位复极化阶段增强了钠电流。总的来说，这些结果表明，BDS-I 通过类似于先前已知的神经毒素受体部位 3 海葵毒素的方式调节钠通道门控，但对不同的亚型具有不同的敏感性。值得注意的是，BDS-I 对人 Nav1.7 通道具有非常高的效力。
