Mechanisms of Hair Cell Mechanotransduction Channel Gating

项目摘要 听觉机械转导通道位于毛细胞立体纤毛的顶端，在那里它们介导 将声音诱导的机械刺激转换成电信号，并将其传输到大脑。这些 通道在机械力的作用下打开，允许阳离子选择性地流入毛细胞。在.期间 选通，通道成分被认为经历了特别大的构象变化-具有 门控移动估计为~4 nm。二十多年来，人们一直在追求它们的分子身份。最近， 我们提供了强有力的证据，证明TMC1形成了听觉传导通道和熊的毛孔 与TMEM16离子通道家族的结构相似。但我们仍然不知道这个频道是如何工作的 分子水平。这是听觉的一个基本方面，因为它是声音转化为神经的基础。 机械转导复合体发出的信号。这项拟议的研究将结合蛋白质生物化学， 分子工程学和毛细胞生理学来探索TMC1的门控结构域。它将铺平一条道路 更广泛的研究将结构和功能生物化学与单细胞生理学相结合，以提供 对机械转导通道如何对力作出反应的全面分子表征。

Project Summary Auditory mechanotransduction channels reside at the tips of hair-cell stereocilia, where they mediate the conversion of sound-induced mechanical stimuli into electrical signals that are transmitted to the brain. These channels open in response to mechanical force and allow a selective influx of cations into hair cells. During gating, a channel component is thought to undergo a particularly large conformational change - with an estimated gating movement of ~ 4 nm. Their molecular identity has been pursued for over two decades. Recently, we provided strong evidence that TMC1 forms the pore of the auditory transduction channels and bears structural similarity to the TMEM16 family of ion channels. But we still don’t know how the channel works at a molecular level. This is a fundamental aspect of hearing, as it underlies the conversion of sound into neural signals by the mechanotransduction complex. The proposed research will integrate protein biochemistry, molecular engineering, and hair cell physiology to probe the gating domains of TMC1. It will pave a path to more extensive studies combining structural and functional biochemistry with single-cell physiology to provide a comprehensive molecular characterization of how mechanotransduction channels open in response to force.