Mechanisms of Hair Cell Mechanotransduction Channel Gating

项目摘要 听觉机械传导通道位于毛细胞静纤毛的顶端，在那里它们介导听觉传导。 将声音引起的机械刺激转换为传输到大脑的电信号。这些 通道响应于机械力而打开并允许阳离子选择性流入毛细胞。期间 门控时，通道组分被认为经历特别大的构象变化， 估计门控移动约4 nm。二十多年来，人们一直在追求它们的分子身份。最近， 我们提供了有力的证据，证明TMC 1形成了听觉传导通道的孔， 与离子通道的TMEM16家族结构相似。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，因为它是声音转换成神经信号的基础。 机械传导复合物的信号。拟议的研究将整合蛋白质生物化学， 分子工程和毛细胞生理学来探测TMC 1的门控结构域。它将为我们 更广泛的研究结合结构和功能生物化学与单细胞生理学， 一个全面的分子表征如何mechanotransduction通道开放，以回应力。

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.