Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices.
Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices.
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DOI：
10.1126/sciadv.abo1126
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发表时间：
2022-07-15
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
跨膜 (TM) 通道样 1 (TMC1) 和 TMC2 蛋白在听觉转导中发挥核心作用，形成将声音转换为电信号的离子通道。然而，它们门控的分子机制仍然未知。在这里，使用预测的结构模型作为指导，我们探讨了 12 个突变对表达病毒引入的 TMC1 变体的 Tmc1/2 缺失小鼠的天然毛细胞中转导电流的机械门控的影响。全细胞电生理记录显示，孔衬 TM4 和 TM6 螺旋内的突变改变了门控，降低了力敏感性或改变了通道的开放概率，或两者兼而有之。对于一些突变体，这些变化伴随着单通道电导的变化。我们的观察结果与模型一致，其中 TM4 和 TM6 螺旋的构象变化参与转导通道的机械门控。结构建模、诱变和毛细胞生理学阐明了内耳机械感觉通道门控的各个方面。
The transmembrane (TM) channel-like 1 (TMC1) and TMC2 proteins play a central role in auditory transduction, forming ion channels that convert sound into electrical signals. However, the molecular mechanism of their gating remains unknown. Here, using predicted structural models as a guide, we probed the effects of 12 mutations on the mechanical gating of the transduction currents in native hair cells of Tmc1/2-null mice expressing virally introduced TMC1 variants. Whole-cell electrophysiological recordings revealed that mutations within the pore-lining TM4 and TM6 helices modified gating, reducing the force sensitivity or shifting the open probability of the channels, or both. For some of the mutants, these changes were accompanied by a change in single-channel conductance. Our observations are in line with a model wherein conformational changes in the TM4 and TM6 helices are involved in the mechanical gating of the transduction channel. Structural modeling, mutagenesis, and hair-cell physiology elucidate aspects of inner-ear mechanosensory channel gating.
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