Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies
Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies
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DOI：
10.1124/mol.62.1.48
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发表时间：
2002-07-01
影响因子：
3.6
通讯作者：
Lazdunski, M
中科院分区：
文献类型：
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作者：
Escoubas, P;Diochot, S;Lazdunski, M
从非洲狼蛛Stromatopelma calceata （ScTx1）和Heteroscodra maculata （HmTx1, HmTx2）的毒液中鉴定出3个具有抑制电压依赖性钾通道的shab （Kv2）和shal （Kv4）亚科的新肽。这三种毒素是34- 38个氨基酸的肽，属于抑制剂胱氨酸结蜘蛛肽的结构家族，由三个二硫桥网状。COS细胞的电生理记录表明，这些毒素作为电压依赖性K+通道的门控调节剂。ScTx1是第一个高亲和力的Kv2.2通道亚型抑制剂（IC50, 21.4 nM）。ScTx1也抑制Kv2.1通道，IC50为12.7 nM，并且Kv2.1/Kv9.3异聚体被认为参与肺动脉肌细胞的O-2感应。此外，它是迄今为止描述的最有效的Kv4.2通道抑制剂，IC50为1.2 nM。HmTx毒素与钾通道阻滞剂毒素（HmTx1）和钙通道阻滞剂毒素omega-GsTx SIA （HmTx2）具有序列相似性。它们在100 ~ 300 nM浓度范围内抑制与Kv2亚型相关的钾电流。HmTx2似乎是Kv2通道的特异性抑制剂，而HmTx1也以相同的效力抑制Kv4通道，包括Kv4.1。HmTx1是第一个被描述的Kv4.1亚型的肽效应。这些新毒素为研究不同钾通道亚基在细胞生理中的生理作用提供了新的工具。
Three novel peptides with the ability to inhibit voltage-dependent potassium channels in the shab (Kv2) and shal (Kv4) subfamilies were identified from the venom of the African tarantulas Stromatopelma calceata (ScTx1) and Heteroscodra maculata (HmTx1, HmTx2). The three toxins are 34- to 38-amino acid peptides that belong to the structural family of inhibitor cystine knot spider peptides reticulated by three disulfide bridges. Electrophysiological recordings in COS cells show that these toxins act as gating modifier of voltage-dependent K+ channels. ScTx1 is the first high-affinity inhibitor of the Kv2.2 channel subtype (IC50, 21.4 nM) to be described. ScTx1 also inhibits the Kv2.1 channels, with an IC50 of 12.7 nM, and Kv2.1/Kv9.3 heteromultimers that have been proposed to be involved in O-2 sensing in pulmonary artery myocytes. In addition, it is the most effective inhibitor of Kv4.2 channels described thus far, with an IC50 of 1.2 nM. HmTx toxins share sequence similarities with both the potassium channel blocker toxins (HmTx1) and the calcium channel blocker toxin omega-GsTx SIA (HmTx2). They inhibit potassium current associated with Kv2 subtypes in the 100 to 300 nM concentration range. HmTx2 seems to be a specific inhibitor of Kv2 channels, whereas HmTx1 also inhibits Kv4 channels, including Kv4.1, with the same potency. HmTx1 is the first described peptide effector of the Kv4.1 subtype. Those novel toxins are new tools for the investigation of the physiological role of the different potassium channel subunits in cellular physiology.