Stretching out the early steps in hearing.
Stretching out the early steps in hearing.
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扩展听力的早期步骤。
DOI：
10.1073/pnas.1606666113
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发表时间：
2016
影响因子：
11.1
通讯作者：
Ashmore JF
中科院分区：
文献类型：
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作者：
Ashmore JF
机械传导的分子基础是听力和平衡的主要问题之一，可能是未解决的问题。内耳的耳蜗和前庭系统中的感觉毛细胞在一端具有一束细突起，其偏转启动最终由大脑处理的电信号。由离子孔和打开它的机制组成的转导复合物位于毛束的顶部，并且抵制了许多鉴定其分子成分的尝试。这个问题很难解决，因为每个细胞中没有多少复合物的拷贝，而且到目前为止，除了在毛细胞中，还没有人建立起检测方法来测试这些提议。然而，在细胞成熟过程中，现在似乎出现了另一组机械敏感元件，尽管是短暂的（1）。转导通道孔本身最有希望的候选者是两种蛋白质，跨膜通道样蛋白异构体1和2（TMC 1和TMC 2），其遗传学在三十多年前首次在耳聋小鼠中被描述（2），但最近才在功能上得到鉴定（3）。这些蛋白质是如何到达纤维束的顶端并与一个连接（即对任何声音干扰做出快速反应所必需的“尖端连接”）连接起来的，这一点仍然没有得到解决。毛束本身是一个细胞器，有超过200种蛋白质（4），虽然其他组件的转导复合物是已知的（5，6），他们的组织仍然是一个谜。为了打开通道，需要将束朝向最高的毛发偏转。然而，在错误或“异常”方向上移动束有时也会产生换能电流（7），但仅当束被流体射流偏转时，而不是简单地被推动。即使当TMC 1和TMC 2蛋白不存在时，电流也存在，这表明TMC是错误的候选者，或者更仁慈地说，构建功能束的步骤比甚至怀疑的更复杂（8）。由于技术原因，许多关于毛细胞如何工作的报告都是基于啮齿动物的早期耳蜗，通常不超过出生后第18天（P18）。这涵盖了耳蜗发生广泛细胞重塑的时期（人类的可比时期是妊娠24-26周）。Beurg等人(1)现在已经示出了异常（或优选地，“反向”）转导电流与
The molecular basis of mechanotransduction is one of the major problems, probably the unsolved problem, in hearing and balance. Sensory hair cells in both the cochlea and the vestibular systems of the inner ear have at one end a bundle of fine processes, the deflection of which initiates the electrical signal ultimately processed by the brain. The transduction complex, consisting of an ionic pore and the machinery to open it, lies at the top of the hair bundle and has resisted many attempts to identify its molecular components. The problem is a difficult one because there are not many copies of the complex per cell and so far no one has constructed an assay to test the proposals except in a hair cell. However, during the maturation of the cell it now seems as though another set of mechanosensitive elements makes an appearance, albeit transiently (1).The most promising candidates for the transduction channel pore itself are two proteins, transmembrane channel-like protein isoforms 1 and 2 (TMC1 and TMC2), whose genetics were first described over three decades ago in a deaf mouse (2), but only functionally identified recently (3). How these proteins get to the top of the bundle and connect up with a linkage, the “tip link,” necessary to make a fast response to any sound disturbance, remains unresolved. The hair bundle itself is an organelle with over 200 proteins (4) and, although other components of the transduction complex are known (5, 6), their organization remains a puzzle. To open the channel, the bundle needs to be deflected toward the tallest hairs. However, moving the bundle in the wrong or “anomalous” direction sometimes also produces a transduction current (7), but only when the bundle is deflected with a fluid jet, not simply pushed. The current is present even when the TMC1 and TMC2 proteins are absent, which has suggested that either the TMCs were the wrong candidates or, more charitably, that the steps to building a functional bundle are more complex than even suspected (8). For technical reasons, many of the reports on how hair cells work are based on early stage cochleas from rodents, typically no older than postnatal day 18 (P18). This covers the period when there is extensive cellular remodeling of the cochlea (the comparable period in humans is gestational weeks 24–26). Beurg et al.(1) have now shown that the anomalous (or preferably,“reverse”) transduction current is associated with channels on the