Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus
Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus
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DOI：
10.1073/pnas.1302770110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Tzounopoulos, Thanos
中科院分区：
文献类型：
--
作者：
Li, Shuang;Choi, Veronica;Tzounopoulos, Thanos
耳鸣是一种幻觉，通常是一种影响数百万人的衰弱症状。然而，人们对参与耳鸣诱发的分子知之甚少。在包含耳蜗背核的脑切片中，我们发现主要神经元自发放电率（多动症）出现耳鸣特异性增加。这种过度活跃仅在出现耳鸣的噪音暴露小鼠中以及仅在对高频声音敏感的耳蜗背核区域中观察到。我们发现 Kv7.2/3 通道活性的降低对于耳鸣诱导和耳鸣特异性多动至关重要。这种减少是由于 Kv7 通道激活的电压依赖性转变为更正的电压。我们的体内研究表明，通过药理学操作将 Kv7 的电压依赖性转变为更负的电压，可以防止耳鸣的发生。总之，我们的研究提供了 Kv7 通道的生物物理特性与耳鸣发生之间的重要联系。此外，我们的研究结果指出了以前未知的生物靶标，可用于设计可能预防人类耳鸣发展的治疗药物。
Tinnitus, the perception of phantom sound, is often a debilitating condition that affects many millions of people. Little is known, however, about the molecules that participate in the induction of tinnitus. In brain slices containing the dorsal cochlear nucleus, we reveal a tinnitus-specific increase in the spontaneous firing rate of principal neurons (hyperactivity). This hyperactivity is observed only in noise-exposed mice that develop tinnitus and only in the dorsal cochlear nucleus regions that are sensitive to high frequency sounds. We show that a reduction in Kv7.2/3 channel activity is essential for tinnitus induction and for the tinnitus-specific hyperactivity. This reduction is due to a shift in the voltage dependence of Kv7 channel activation to more positive voltages. Our in vivo studies demonstrate that a pharmacological manipulation that shifts the voltage dependence of Kv7 to more negative voltages prevents the development of tinnitus. Together, our studies provide an important link between the biophysical properties of the Kv7 channel and the generation of tinnitus. Moreover, our findings point to previously unknown biological targets for designing therapeutic drugs that may prevent the development of tinnitus in humans.