Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters. Ablation of ClC‑K/barttin chloride channels causes deafness by interfering with the positive electrical potential of the endolymph, but roles of other anion channels in the inner ear have not been studied. Here we report the intracochlear distribution of all five LRRC8 subunits of VRAC, a volume-regulated anion channel that transports chloride, metabolites, and drugs such as the ototoxic anti-cancer drug cisplatin, and explore its physiological role by ablating its subunits. Sensory hair cells express all LRRC8 isoforms, whereas only LRRC8A, D and E were found in the potassium-secreting epithelium of the stria vascularis. Cochlear disruption of the essential LRRC8A subunit, or combined ablation of LRRC8D and E, resulted in cochlear degeneration and congenital deafness of mice. It was associated with a progressive degeneration of the organ of Corti and its innervating spiral ganglion. Like disruption of ClC-K/barttin, loss of VRAC severely reduced the endocochlear potential. However, the mechanism underlying this reduction seems different. Disruption of VRAC, but not ClC-K/barttin, led to an almost complete loss of Kir4.1 (KCNJ10), a strial K channel crucial for the generation of the endocochlear potential. The strong downregulation of Kir4.1 might be secondary to a loss of VRAC-mediated transport of metabolites regulating inner ear redox potential such as glutathione. Our study extends the knowledge of the role of cochlear ion transport in hearing and ototoxicity.

中文翻译：

---

LRRC8/VRAC 音量调节阴离子通道对听力至关重要


听力至关重要地取决于耳蜗离子稳态，从编码阳离子或阴离子通道和转运蛋白的各种基因突变引起的耳聋中可以明显看出这一点。 ClC-K/barttin 氯化物通道的消融通过干扰内淋巴的正电位而导致耳聋，但内耳中其他阴离子通道的作用尚未研究。在这里，我们报告了 VRAC 的所有五个 LRRC8 亚基的耳蜗内分布，VRAC 是一种容量调节的阴离子通道，可运输氯离子、代谢物和耳毒性抗癌药物顺铂等药物，并通过消除其亚基来探索其生理作用。感觉毛细胞表达所有 LRRC8 亚型，而在血管纹的钾分泌上皮中仅发现 LRRC8A、D 和 E。 LRRC8A 必需亚基的耳蜗破坏，或 LRRC8D 和 E 的联合消融，会导致小鼠耳蜗退化和先天性耳聋。它与柯蒂氏器及其支配的螺旋神经节的进行性退化有关。与 ClC-K/barttin 的破坏一样，VRAC 的丧失严重降低了耳蜗电位。然而，这种减少的机制似乎有所不同。 VRAC 的破坏（而非 ClC-K/barttin 的破坏）导致 Kir4.1 (KCNJ10) 几乎完全丧失，Kir4.1 是一种对于耳蜗内电位的产生至关重要的纹状 K 通道。 Kir4.1 的强烈下调可能是由于 VRAC 介导的调节内耳氧化还原电位的代谢物（如谷胱甘肽）运输丧失所致。我们的研究扩展了对耳蜗离子转运在听力和耳毒性中的作用的认识。