Probing the role of the C2F domain of otoferlin

2023 | journal article. A publication with affiliation to the University of Göttingen.

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​Probing the role of the C2F domain of otoferlin​
Chen, H.; Fang, Q.; Benseler, F.; Brose, N. & Moser, T.​ (2023) 
Frontiers in Molecular Neuroscience16 art. 1299509​.​ DOI: 

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Chen, Han; Fang, Qinghua; Benseler, Fritz; Brose, Nils; Moser, Tobias
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 Ca 2+ binding to the C 2 F domain of otoferlin. Substituting two aspartate residues of the C 2 F top loops, which are thought to coordinate Ca 2+ -ions, by alanines ( Otof D1841/1842A ) abolished Ca 2+ -influx-triggered IHC exocytosis and synchronous signaling in the auditory pathway despite substantial expression (~60%) of the mutant otoferlin in the basolateral IHC pole. Ca 2+ 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 apex-to-base abundance gradient in IHCs, suggesting impaired protein targeting. Our results indicate a role of the C 2 F domain in otoferlin targeting and of Ca 2+ binding by the C 2 F domain for IHC exocytosis and hearing.
Issue Date
Frontiers in Molecular Neuroscience 
EXC 2067: Multiscale Bioimaging 
Working Group
RG Brose 
RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding) 
External URL
Open-Access-Publikationsfonds 2023



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