High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain.
High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain.
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DOI：
10.1371/journal.pone.0000515
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发表时间：
2007-06-13
期刊：
影响因子：
3.7
通讯作者：
Wood, John N.
中科院分区：
文献类型：
--
作者：
Drew, Liam J.;Rugiero, Francois;Cesare, Paolo;Gale, Jonathan E.;Abrahamsen, Bjarke;Bowden, Sarah;Heinzmann, Sebastian;Robinson, Michelle;Brust, Andreas;Colless, Barbara;Lewis, Richard J.;Wood, John N.
对哺乳动物躯体感觉机械传导的分子基础知之甚少。我们筛选了一个肽毒素库，用于对培养的背根神经节神经元的机械激活电流的影响。一种芋螺肽类似物，称为NMB-1，用于有害的机械感觉阻滞剂1，选择性地抑制（IC 50 1 μM）感觉神经元亚群中的持续机械激活电流。生物素化的NMB-1保留活性并选择性地结合外周蛋白阳性的伤害性感觉神经元。NMB-1的选择性通过其对电压门控钠和钙通道或配体门控通道（例如酸敏感离子通道或TRPA 1通道）没有抑制作用的事实得到证实。相反，狼蛛毒素，GsMTx-4，抑制拉伸激活离子通道，对感觉神经元中的机械激活电流没有影响。在行为测定中，NMB-1仅抑制对高强度、疼痛的机械刺激的反应，并且对低强度机械刺激或温度感觉没有影响。出乎意料的是，发现NMB-1也是耳蜗毛细胞中快速FM 1 -43加载（机械转导的量度）的抑制剂。这些数据表明，不同的通道响应不同类型的机械刺激，并建议机械激活持续电流的伤害性机械感觉。因此，NMB-1为听觉和压力诱发疼痛相关通道的分子定义提供了一种新的诊断工具。
Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC50 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain.
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