Hg1, Novel Peptide Inhibitor Specific for Kv1.3 Channels from First Scorpion Kunitz-type Potassium Channel Toxin Family
Hg1, Novel Peptide Inhibitor Specific for Kv1.3 Channels from First Scorpion Kunitz-type Potassium Channel Toxin Family
复制标题
Hg1，针对第一个蝎子 Kunitz 型钾通道毒素家族 Kv1.3 通道的新型肽抑制剂
DOI：
10.1074/jbc.m112.343996
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发表时间：
2012-04-20
影响因子：
4.8
通讯作者：
Wu, Ying-Liang
中科院分区：
文献类型：
--
作者：
Chen, Zong-Yun;Hu, You-Tian;Wu, Ying-Liang
钾通道Kv1.3是一个有吸引力的自身免疫性疾病的药理学靶点。特异性肽抑制剂是诊断和治疗这些疾病的关键前景。在这里，我们确定了第一个蝎子Kunitz型钾通道毒素家族，有三个组和七个成员。除了作为胰蛋白酶抑制剂的功能外，重组LmKTT-1a的解离常数为140 nM，LmKTT-1b为160 nM，LmKTT-1c为124 nM，BmKTT-1为136 nM，BmKTT-2为420 nM，BmKTT-3为760 nM，Hg 1为107 nM，所有7种重组蝎Kunitz型毒素都可以阻断Kv1.3通道。电生理学实验表明，在1 μ M浓度下，7种蝎毒素中有6种对Kv1.3通道电流的抑制率为50-80%。例外的是rBm-KTT-3，其活性较弱。rBmKTT-1、rBmKTT-2和rHg 1对Kv1.3通道的IC 50值分别为129.7、371.3和6.2 nM。进一步的药理学实验表明，rHg 1是一个高度选择性的Kv1.3通道抑制剂，对其他钾通道的亲和力较弱。与经典的Kunitz型钾通道毒素不同，Hg 1的通道相互作用界面在C-末端区域。总之，这些发现描述了第一个蝎子Kunitz型钾通道毒素家族，其中一种新的抑制剂Hg 1对Kv1.3通道具有特异性。它们的结构和功能多样性强烈表明Kunitz型毒素是筛选和设计用于诊断和治疗Kv1.3介导的自身免疫性疾病的潜在肽的新来源。
The potassium channel Kv1.3 is an attractive pharmacological target for autoimmune diseases. Specific peptide inhibitors are key prospects for diagnosing and treating these diseases. Here, we identified the first scorpion Kunitz-type potassium channel toxin family with three groups and seven members. In addition to their function as trypsin inhibitors with dissociation constants of 140 nM for recombinant LmKTT-1a, 160 nM for LmKTT-1b, 124 nM for LmKTT-1c, 136 nM for BmKTT-1, 420 nM for BmKTT-2, 760 nM for BmKTT-3, and 107 nM for Hg1, all seven recombinant scorpion Kunitz-type toxins could block the Kv1.3 channel. Electrophysiological experiments showed that six of seven scorpion toxins inhibited similar to 50-80% of Kv1.3 channel currents at a concentration of 1 mu M. The exception was rBm-KTT-3, which had weak activity. The IC50 values of rBmKTT-1, rBmKTT-2, and rHg1 for Kv1.3 channels were similar to 129.7, 371.3, and 6.2 nM, respectively. Further pharmacological experiments indicated that rHg1 was a highly selective Kv1.3 channel inhibitor with weak affinity for other potassium channels. Different from classical Kunitz-type potassium channel toxins with N-terminal regions as the channel-interacting interfaces, the channel-interacting interface of Hg1 was in the C-terminal region. In conclusion, these findings describe the first scorpion Kunitz-type potassium channel toxin family, of which a novel inhibitor, Hg1, is specific for Kv1.3 channels. Their structural and functional diversity strongly suggest that Kunitz-type toxins are a new source to screen and design potential peptides for diagnosing and treating Kv1.3-mediated autoimmune diseases.