LRRC8/VRAC volume-regulated anion channels are crucial for hearing.

Autor:	Knecht DA; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany., Zeziulia M; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany; Graduate Program of the Freie Universität Berlin, Berlin, Germany., Bhavsar MB; Department of Otolaryngology, Hannover Medical School, Hannover, Germany., Puchkov D; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany., Maier H; Department of Otolaryngology, Hannover Medical School, Hannover, Germany; Cluster of Excellence 'Hearing4all', Hannover, Germany., Jentsch TJ; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; NeuroCure Cluster of Excellence, Charité Universitätsmedizin Berlin, Berlin, Germany. Electronic address: Jentsch@fmp-berlin.de.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107436. Date of Electronic Publication: 2024 Jun 04.
DOI:	10.1016/j.jbc.2024.107436
Abstrakt:	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 Lrrc8a -/- 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. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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