The Dorris Neuroscience Center, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell. 2012 Dec 7;151(6):1283-95. doi: 10.1016/j.cell.2012.10.041.
Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.
毛细胞是感知声音、加速度和流体运动的机械感受器。毛细胞中的机械转导通道由尖端连接蛋白控制，这些连接蛋白沿毛细胞的机械敏感方向连接纤毛。毛细胞机械转导通道的分子成分尚不清楚。在这里，我们表明，缺乏四跨膜蛋白 TMHS 的小鼠的机械转导受损。TMHS 与尖端连接蛋白成分 PCDH15 结合，并调节尖端连接蛋白的组装，而导致耳聋的 Tmhs 突变会破坏这一过程。TMHS 还调节换能器通道电导，并且是快速通道适应所必需的。因此，TMHS 类似于其他离子通道调节亚基，例如 AMPA 受体的跨膜 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体调节蛋白（TARPs），它们促进通道转运并调节孔形成通道亚基的特性。我们得出结论，TMHS 是毛细胞机械转导机制的一个组成部分，它将 PCDH15 与转导通道功能偶联。
