Probing the Role of the CF Domain of Otoferlin

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2023 Dec 28

PMID 38152587

Authors

Han Chen

Qinghua Fang

Fritz Benseler

Nils Brose

Tobias Moser

Affiliations

Soon will be listed here.

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 Ca binding to the CF domain of otoferlin. Substituting two aspartate residues of the CF top loops, which are thought to coordinate Ca-ions, by alanines () abolished Ca-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 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 CF domain in otoferlin targeting and of Ca binding by the CF domain for IHC exocytosis and hearing.

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