Is TMC1 the Hair Cell Mechanotransducer Channel?
Is TMC1 the Hair Cell Mechanotransducer Channel?
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DOI：
10.1016/j.bpj.2016.05.032
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发表时间：
2016-07-12
影响因子：
3.4
通讯作者：
Fettiplace R
中科院分区：
文献类型：
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作者：
Fettiplace R
跨膜通道样蛋白亚型 1 (TMC1) 在过去五年中已成为内耳毛细胞中机电换能器 (MET) 通道的主要竞争者。 TMC1 被认为具有六次跨膜结构域结构，让人想起其他一些离子通道亚基，其目标是感觉毛束中静纤毛的尖端，即 MET 通道所在的位置。此外，TMC1 突变与人类耳聋相关，导致传统 MET 电流丧失、毛细胞变性和小鼠耳聋。最后，Tmc1 的突变可以改变 MET 通道的电导和 Ca2+ 选择性。但出于多种原因，目前尚不清楚TMC1确实是MET通道孔：1）在其他动物或组织中，TMC家族成员的突变不会直接影响细胞的机械敏感性； 2) Tmc1:Tmc2双敲除小鼠毛细胞中残留机械敏感性表现； 3) 迄今为止没有证据表明哺乳动物Tmc1的表达在异源细胞中表达时在质膜中产生机械敏感的离子通道； 4）还有其他蛋白质，例如TMIE和LHFPL5，其行为与TMC1类似，它们的突变也会导致MET电流丧失和耳聋。本综述将介绍这些不同的证据，并描述最近解决 TMC1 作用的工作。
Transmembrane channel-like protein isoform-1 (TMC1) has emerged over the past five years as a prime contender for the mechano-electrical transducer (MET) channel in hair cells of the inner ear. TMC1 is thought to have a six-transmembrane domain structure reminiscent of some other ion-channel subunits, and is targeted to the tips of the stereocilia in the sensory hair bundle, where the MET channel is located. Moreover, there are TMC1 mutations linked to human deafness causing loss of conventional MET currents, hair cell degeneration, and deafness in mice. Finally, mutations of Tmc1 can alter the conductance and Ca2+ selectivity of the MET channels. For several reasons though, it is unclear that TMC1 is indeed the MET channel pore: 1) in other animals or tissues, mutations of TMC family members do not directly affect cellular mechanosensitivity; 2) there are residual manifestations of mechanosensitivity in hair cells of mouse Tmc1:Tmc2 double knockouts; 3) there is so far no evidence that expression of mammalian Tmc1 generates a mechanically sensitive ion channel in the plasma membrane when expressed in heterologous cells; and 4) there are other proteins, such as TMIE and LHFPL5, which behave similarly to TMC1, their mutation also leading to loss of MET current and deafness. This review will present these disparate lines of evidence and describes recent work that addresses the role of TMC1.