The mechanism of Ca2+-independent activation of BKCa channels in mouse inner hair cells and the crucial role of the BK channels in auditory perception

Zhong-Shan Shen; Jun Gan; Bing Xu; Ya-Lin Chen; Fei-Fei Zhang; Jun-Wei Ji; Dan-Hua Chen; Yuehua Qiao; Qiong-Yao Tang; Zhe Zhang

doi:10.1016/j.jbc.2024.107970

The mechanism of Ca²⁺-independent activation of BKCa channels in mouse inner hair cells and the crucial role of the BK channels in auditory perception

J Biol Chem. 2024 Nov 7;301(1):107970. doi: 10.1016/j.jbc.2024.107970. Online ahead of print.

Authors

Zhong-Shan Shen¹, Jun Gan¹, Bing Xu², Ya-Lin Chen², Fei-Fei Zhang¹, Jun-Wei Ji¹, Dan-Hua Chen¹, Yuehua Qiao³, Qiong-Yao Tang⁴, Zhe Zhang⁵

Affiliations

¹ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Medical University, Xuzhou, Jiangsu Province, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
² Otorhinolaryngology Department, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Auditory Engineering Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
³ Otorhinolaryngology Department, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Auditory Engineering Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: [email protected].
⁴ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Medical University, Xuzhou, Jiangsu Province, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: [email protected].
⁵ Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Medical University, Xuzhou, Jiangsu Province, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. Electronic address: [email protected].

PMID: 39515584
DOI: 10.1016/j.jbc.2024.107970

Abstract

BK channels are expressed in mouse cochlear inner hair cells (IHCs) and exhibit Ca²⁺-independent activation at negative potentials. However, the mechanism underlying Ca²⁺-independent activation of the BK channels in mouse IHCs remains unknown. In this study, we found the BK channel expressed in IHCs contains both the stress-axis regulated exon 2 variant and an alternative splice of exon9 (alt9), which significantly shift the voltage dependence of the BK channels when coexpressed with LRRC52 in 0 [Ca²⁺]_i. Furthermore, we discovered that mechanical force also induces negative shifts in the voltage dependence of IHC-expressed BK channels. Thus, we propose that the additive effects of mechanical force, special isoforms, and LRRC52 coexpression on voltage dependence shifts may account for the Ca²⁺-independent activation of the BK channel in IHC. Additionally, we found that the IHCs-specific deletion of the BK channels causes hearing damage in mice. Our study suggests a mechanism for Ca²⁺-independent activation in IHCs and highlights the crucial role of the BK channel in auditory perception.

Keywords: LRRC52; hearing loss; inner hair cell; mechanical force; special isoforms; the BK channel.