Maurotoxin:: A potent inhibitor of intermediate conductance Ca2+-activated potassium channels
Maurotoxin:: A potent inhibitor of intermediate conductance Ca2+-activated potassium channels
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DOI：
10.1124/mol.63.2.409
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发表时间：
2003-02-01
影响因子：
3.6
通讯作者：
Sabatier, JM
中科院分区：
文献类型：
--
作者：
Castle, NA;London, DO;Sabatier, JM
Maurotoxin是一种来自蝎毒的34-氨基酸毒素，研究了其抑制克隆的人SK（SK 1、SK 2和SK 3）、IK 1和SIo 1钙激活钾（K-Ca）通道的能力。在稳定表达IK 1的CHO细胞中，发现Maurotoxin可有效抑制Ca 2+激活的Rb-86外排（IC 50，1.4 nM）和内向整流钾电流（IC 50，1 nM）。相比之下，在生理相关的离子强度缓冲液中，高达1 μ M的maurotoxin对SK 1，SK2和SK 3小电导或SIo 1大电导K-Ca通道没有抑制作用。在低离子强度缓冲液（即，18 mM钠，250 mM蔗糖），这与之前关于抑制apamin与脑突触体结合的报道一致。在类似的低离子强度条件下，毛茛毒素抑制IK 1的效力增加了约100倍（IC 50，14 pM）。与其抑制重组IK 1钾通道的能力一致，发现毛茛毒素有效抑制人红细胞中的Gardos通道，并抑制活化的人T淋巴细胞中的K-Ca，而不影响Kv1.3编码的电压门控钾电流。Maurotoxin也不抑制Kv1.1钾通道，但有效地阻断Kv1.2（IC 50，0.1 nM）。突变分析表明，相似的氨基酸残基有助于IK 1和Kv1.2的阻断活性。这项研究的结果表明，maurotoxin是一个有效的抑制剂的IK 1亚类的K-Ca钾通道，并可能作为一个有用的工具，进一步定义该通道亚型的生理作用。
Maurotoxin, a 34-amino acid toxin from Scorpio maurus scorpion venom, was examined for its ability to inhibit cloned human SK (SK1, SK2, and SK3), IK1, and SIo1 calcium-activated potassium (K-Ca) channels. Maurotoxin was found to produce a potent inhibition of Ca2+-activated Rb-86 efflux (IC50, 1.4 nM) and inwardly rectifying potassium currents (IC50, 1 nM) in CHO cells stably expressing IK1. In contrast, maurotoxin produced no inhibition of SK1, SK2, and SK3 small-conductance or SIo1 large-conductance K-Ca channels at up to 1 muM in physiologically relevant ionic strength buffers. Maurotoxin did inhibit Rb-86 efflux (IC50, 45 nM) through, and I-125-apamin binding (K-i, 10 nM) to SK channels in low ionic strength buffers (i.e., 18 mM sodium, 250 mM sucrose), which is consistent with previous reports of inhibition of apamin binding to brain synaptosomes. Under similar low ionic strength conditions, the potency for maurotoxin inhibition of IK1 increased by similar to100-fold (IC50, 14 pM). In agreement with its ability to inhibit recombinant IK1 potassium channels, maurotoxin was found to potently inhibit the Gardos channel in human red blood cells and to inhibit the K-Ca in activated human T lymphocytes without affecting the voltage-gated potassium current encoded by Kv1.3. Maurotoxin also did not inhibit Kv1.1 potassium channels but potently blocked Kv1.2 (IC50, 0.1 nM). Mutation analysis indicates that similar amino acid residues contribute to the blocking activity of both IK1 and Kv1.2. The results from this study show that maurotoxin is a potent inhibitor of the IK1 subclass of K-Ca potassium channels and may serve as a useful tool for further defining the physiological role of this channel subtype.