Department of Otolaryngology - Head and Neck Surgery, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200125, China.
Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, 200125, China.
Neurosci Bull. 2020 Jan;36(1):49-65. doi: 10.1007/s12264-019-00415-3. Epub 2019 Aug 6.
Voltage-gated sodium channels (VGSCs) are transiently expressed in cochlear hair cells before hearing onset and play an indispensable role in shaping spontaneous activity. In this study, we showed that Na currents shaped the spontaneous action potentials in developing mouse inner hair cells (IHCs) by decreasing the time required for the membrane potential to reach the action-potential threshold. In immature IHCs, we identified 9 known VGSC subtypes (Nav1.1α-1.9α), among which Nav1.7α was the most highly expressed subtype and the main contributor to Na currents in developing hair cells. Electrophysiological recordings of two cochlea-specific Nav1.7 variants (CbmNav1.7a and CbmNav1.7b) revealed a novel loss-of-function mutation (C934R) at the extracellular linker between segments 5 and 6 of domain II. In addition, post-transcriptional modification events, such as alternative splicing and RNA editing, amended the gating properties and kinetic features of CbmNav1.7a These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.
电压门控钠离子通道（VGSCs）在听觉起始前短暂表达于耳蜗毛细胞中，在塑造自发性活动方面发挥不可或缺的作用。在本研究中，我们表明，钠电流通过减少膜电位达到动作电位阈值所需的时间来塑造发育中的小鼠内耳毛细胞（IHC）的自发性动作电位。在未成熟的 IHC 中，我们鉴定了 9 种已知的 VGSC 亚型（Nav1.1α-1.9α），其中 Nav1.7α是表达丰度最高的亚型，也是发育中毛细胞钠电流的主要贡献者。对两个耳蜗特异性 Nav1.7 变体（CbmNav1.7a 和 CbmNav1.7b）的电生理记录揭示了位于 II 域 5 和 6 节段之间的细胞外环中的一个新的失活突变（C934R）。此外，转录后修饰事件，如选择性剪接和 RNA 编辑，改变了 CbmNav1.7a 的门控特性和动力学特征。这些结果提供了哺乳动物 IHC 中 VGSCs 的分子和功能特征及其对耳蜗成熟过程中自发性生理活动的贡献。
