时间: 14:00-15:30 on Tues.,Feb.25, 2025

地点：生物医学馆E109会议室

主讲人: Dr.Zhiqiang Yan

主持人: Dr. Wei Zhang

题目: Hearing Sound with TMC Proteins

摘要：

Mechanotransduction within the specialized hair cells of the cochlea allows us to perceive mechanical stimuli initiated by sound. Despite significant advancements in genetic research related to hereditary hearing loss revealing several components of the mechanotransduction (MET) complex, the specific pore-forming subunits and their underlying mechanisms remain a subject of debate. In 2020, we expressed TMC1 from the green sea turtle (CmTMC1) and TMC2 from the budgerigar (MuTMC2) in insect cells, purified and reconstituted the proteins, and showed that liposome-reconstituted CmTMC1 and MuTMC2 proteins possess ion channel activity, and can indeed respond to mechanical stimuli. Our results showed that the CmTMC1 and MuTMC2 proteins are pore forming subunits of mechanosensitive ion channels, supporting TMC1 and TMC2 as hair cell transduction channels. This work was published in Neuron in 2020. However, controversy persists because the heterogeneously expressed TMC1/2 in cultured cells lack evidence of mechanical gating, primarily due to their absence from the plasma membrane. Our recent work published in Neuron in 2025 overcame this hurdle. By employing domain swapping with OSCA1.1 and subsequent point mutations, we successfully identified membrane-localized mouse TMC1/2 mutants, demonstrating that they are mechanically gated in heterologous cells. Further, whole genome CRISPRi screening enabled wild-type human TMC1/2 localization in the plasma membrane, where they responded robustly to poking stimuli. In addition, wild-type human TMC1/2 showed stretch-activated currents and clear single-channel current activities. Deafness-related TMC1 mutations altered the reversal potential of TMC1, indicating that TMC1/2 are pore-forming mechanotransduction channels. In summary, our study provides evidence that human TMC1/2 are pore-forming mechanically activated ion channels, supporting their roles as the mechanotransduction channels in hair cells.

简介：

闫致强，首都医科大学基础医学院教授、院长，首都医学创新中心医学生理学研究所资深研究员、所长。2004年获复旦大学学士学位， 2004-2009年分别于中国科学院神经科学研究所、北京生命科学研究所以及中科院生物物理研究所进行博士研究并获得博士学位。2009-2013加州大学旧金山分校及霍华德•休斯医学研究所师从著美国科学院院士詹裕农，叶公杼 (Yuh-Nung Jan，Lily Jan)进行博士后研究。2013-2020年任复旦大学生命科学学院研究员、 博士生导师，2020-2024年任深圳湾实验室分子生理所资深研究员、副所长。长期致力于感觉神经生物学，尤其是听觉、触觉、渴觉等感觉受体的鉴定和门控机理研究，感觉系统神经回路，以及感觉系统疾病的机理和治疗。以通讯作者在Neuron、PNAS、Nature Structural & Molecular Biology 和Cell Reports 等国际高水平杂志发表多篇论文。