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- Title
Probing the role of the C<sub>2</sub>F domain of otoferlin.
- Authors
Han Chen; Qinghua Fang; Benseler, Fritz; Brose, Nils; Moser, Tobias
- Abstract
Afferent synapses of cochlear inner hair cells (IHCs) employ a unique molecular machinery. Otoferlin is a key player in this machinery, and its genetic defects cause human auditory synaptopathy. We employed site-directed mutagenesis in mice to investigate the role of Ca2+ binding to the C2F domain of otoferlin. Substituting two aspartate residues of the C2F top loops, which are thought to coordinate Ca2+- ions, by alanines (OtofD1841/1842A) abolished Ca2+-influx-triggered IHC exocytosis and synchronous signaling in the auditory pathway despite substantial expression (~60%) of the mutant otoferlin in the basolateral IHC pole. Ca2+ influx of IHCs and their resting membrane capacitance, reflecting IHC size, as well as the number of IHC synapses were maintained. The mutant otoferlin showed a strong apexto-base abundance gradient in IHCs, suggesting impaired protein targeting. Our results indicate a role of the C2F domain in otoferlin targeting and of Ca2+ binding by the C2F domain for IHC exocytosis and hearing.
- Subjects
HAIR cells; AUDITORY pathways; SITE-specific mutagenesis; EXOCYTOSIS
- Publication
Frontiers in Molecular Neuroscience, 2023, p1
- ISSN
1662-5099
- Publication type
Article
- DOI
10.3389/fnmol.2023.1299509