Activity-Dependent Phosphorylation by CaMKIIδ Alters the Ca Affinity of the Multi-C-Domain Protein Otoferlin.

Otoferlin is essential for fast Ca-triggered transmitter release from auditory inner hair cells (IHCs), playing key roles in synaptic vesicle release, replenishment and retrieval. Dysfunction of otoferlin results in profound prelingual deafness. Despite its crucial role in cochlear synaptic processes, mechanisms regulating otoferlin activity have not been studied to date.

Ca-binding protein 2 inhibits Ca-channel inactivation in mouse inner hair cells.

Ca-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca channels of type 1.3 (Ca1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93).

Disruption of adaptor protein 2μ (AP-2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing.

Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2μ (AP-2μ) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2μ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval.