Distribution and Functional Characteristics of Voltage-Gated Sodium Channels in Immature Cochlear Hair Cells
1 Department of Otolaryngology – Head and Neck Surgery, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200125, China
2 Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai 200125, China
3 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200125, China
4 Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai 200444, China
5 Translational Institute for Cancer Pain, Xinhua Hospital Chongming Branch, Shanghai 202150, China
Abstract
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(C934). These results provide molecular and functional characteristics of VGSCs in mammalian IHCs and their contributions to spontaneous physiological activity during cochlear maturation.
Keywords
Cochlear hair cell Spontaneous action potential; Voltage-gated sodium channel; Post-transcriptional modification; Gating property
