Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells?
Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells?
复制标题
DOI：
10.1523/jneurosci.1148-16.2016
复制
发表时间：
2016-10-26
影响因子：
5.3
通讯作者：
Holt, Jeffrey R.
中科院分区：
文献类型：
--
作者：
Corey, David P.;Holt, Jeffrey R.
脊椎动物毛细胞中的感觉传导和调节它的分子长期以来一直引起人们的极大兴趣。机械转导装置的一些组件已经被鉴定，大多数是耳聋基因产物。尽管之前已经提出了机械转导通道的候选方案，但每一个都随着新的证据而逐渐消失。现在，在人类和小鼠中发现了耳聋基因，出现了两个强有力的候选基因，TMC1和TMC2(跨膜通道样)。它们在发育过程中的正确时间表达：恰好在机械敏感性开始时表达。它们在正确的地方表达：在毛细胞中，而不是在周围的细胞中。荧光标记的TMC定位于立体纤毛的尖端，也就是转导通道的位置。TMCs结合了机械感觉所必需的其他蛋白质，这意味着一个更大的转导复合体。尽管TMC1和TMC2可以相互替代，但两者的基因缺失会使小鼠毛细胞机械地变得不敏感。最后，转导通道的电导和钙离子选择性取决于TMC蛋白，在毛细胞表达一种或另一种TMC时不同，如果TMC1含有点突变也不同。已经出现了一些相反的证据：在TMC基因敲除中，毛细胞中由负压激活的电流与转导电流有一些相似之处。但目前还不清楚这种异常电流是否由相同的蛋白质携带。还需要进一步的证据，例如纯TMC产生机械门控电导。但绝大多数证据与这些TMCs作为长期寻找的毛细胞转导通道的孔形成亚单位是一致的。
Sensory transduction in vertebrate hair cells and the molecules that mediate it have long been of great interest. Some components of the mechanotransduction apparatus have been identified, most as deafness gene products. Although prior candidates for the mechanotransduction channel have been proposed, each has faded with new evidence. Now, two strong candidates, TMC1 and TMC2 (transmembrane channel-like), have emerged from discovery of deafness genes in humans and mice. They are expressed at the right time during development: exactly at the onset of mechanosensitivity. They are expressed in the right place: in hair cells but not surrounding cells. Fluorescently tagged TMCs localize to the tips of stereocilia, the site of the transduction channels. TMCs bind other proteins essential for mechanosensation, suggesting a larger transduction complex. Although TMC1 and TMC2 can substitute for each other, genetic deletion of both renders mouse hair cells mechanically insensitive. Finally, the conductance and Ca2+ selectivity of the transduction channels depend on the TMC proteins, differing when hair cells express one or the other TMC, and differing if TMC1 harbors a point mutation. Some contrary evidence has emerged: a current activated in hair cells by negative pressure, with some similarity to the transduction current, persists in TMC knock-outs. But it is not clear that this anomalous current is carried by the same proteins. Further evidence is desired, such as production of a mechanically gated conductance by pure TMCs. But the great majority of evidence is consistent with these TMCs as pore-forming subunits of the long-sought hair-cell transduction channel.