A novel BK channel-targeted peptide suppresses sound evoked activity in the mouse inferior colliculus.
A novel BK channel-targeted peptide suppresses sound evoked activity in the mouse inferior colliculus.
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DOI：
10.1038/srep42433
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发表时间：
2017-02-14
影响因子：
4.6
通讯作者：
Walton JP
中科院分区：
文献类型：
--
作者：
Scott LL;Brecht EJ;Philpo A;Iyer S;Wu NS;Mihic SJ;Aldrich RW;Pierce J;Walton JP
大电导钙激活（BK）通道在神经元和肌肉中广泛表达，在那里它们调节细胞活动。几十年的研究支持了对调节BK通道功能的制药应用的兴趣。在这里，我们报告了一种新的BK通道靶向肽，在体外和体内具有功能活性。这种9个氨基酸的肽，LS3，具有独特的作用，抑制通道门控而不是阻断异种表达的人类BK通道的孔。IC50在高皮摩尔范围内，表观亲和性高于已知的高亲和性BK通道毒素。在野生型或BK通道人源化秀丽隐杆线虫中，LS3通过BK通道特异性机制抑制运动活动。局部应用于小鼠听觉中脑硬脑膜表面可抑制声音诱发的神经活动，类似于一种具有良好特征的BK通道孔阻滞剂。此外，这种新的离子通道靶向肽在全身递送后迅速穿过血脑屏障来调节听觉加工。因此，一种有效的BK通道肽调节剂可用于神经学应用，例如预防起源于听觉中脑的听源性癫痫发作。
Large conductance calcium-activated (BK) channels are broadly expressed in neurons and muscle where they modulate cellular activity. Decades of research support an interest in pharmaceutical applications for modulating BK channel function. Here we report a novel BK channel-targeted peptide with functional activity in vitro and in vivo. This 9-amino acid peptide, LS3, has a unique action, suppressing channel gating rather than blocking the pore of heterologously expressed human BK channels. With an IC50 in the high picomolar range, the apparent affinity is higher than known high affinity BK channel toxins. LS3 suppresses locomotor activity via a BK channel-specific mechanism in wild-type or BK channel-humanized Caenorhabditis elegans. Topical application on the dural surface of the auditory midbrain in mouse suppresses sound evoked neural activity, similar to a well-characterized pore blocker of the BK channel. Moreover, this novel ion channel-targeted peptide rapidly crosses the BBB after systemic delivery to modulate auditory processing. Thus, a potent BK channel peptide modulator is open to neurological applications, such as preventing audiogenic seizures that originate in the auditory midbrain.