| First Author | Chen H | Year | 2023 |
| Journal | Front Mol Neurosci | Volume | 16 |
| Pages | 1299509 | PubMed ID | 38152587 |
| Mgi Jnum | J:344236 | Mgi Id | MGI:7569580 |
| Doi | 10.3389/fnmol.2023.1299509 | Citation | Chen H, et al. (2023) Probing the role of the C(2)F domain of otoferlin. Front Mol Neurosci 16:1299509 |
| abstractText | 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. |
