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). Here, we report a newly identified mutation in that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from loss of function, we disrupted in mice ( ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from IHCs revealed enhanced Ca-channel inactivation. The voltage dependence of activation and the number of Ca channels appeared normal in mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits Ca1.3 Ca-channel inactivation, and thus sustains the availability of Ca1.3 Ca channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.