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.

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2024-11-06 DOI:10.1016/j.jbc.2024.107970
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
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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 STREX-2 (stress axis regulated exon) variant and an alternative splice of exon9 (alt9), which significantly shift the voltage dependence of the BK channels when co-expressed 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 co-expression 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.

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小鼠内毛细胞中独立于 Ca2+ 的 BKCa 通道激活机制以及 BK 通道在听觉感知中的关键作用。
BK 通道在小鼠耳蜗内毛细胞(IHC)中表达,并在负电位时表现出不依赖 Ca2+ 的激活。然而,小鼠耳蜗内毛细胞中 BK 通道不依赖 Ca2+ 激活的机制仍不清楚。在这项研究中,我们发现在 IHCs 中表达的 BK 通道含有 STREX-2(应力轴调控外显子)变体和外显子 9 的替代剪接(alt9),当它们与 LRRC52 共同表达于 0 [Ca2+]i 时,会显著改变 BK 通道的电压依赖性。此外,我们还发现机械力也会诱导 IHC 表达的 BK 通道的电压依赖性发生负移。因此,我们认为机械力、特殊同工酶和 LRRC52 共同表达对电压依赖性转变的叠加效应可能是 IHC 中 BK 通道不依赖 Ca2+ 激活的原因。此外,我们还发现,IHC 特异性地缺失 BK 通道会导致小鼠听力受损。我们的研究提出了 IHC 中 Ca2+ 非依赖性激活的机制,并强调了 BK 通道在听觉感知中的关键作用。
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Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
发文量
1233
期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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