Ca²⁺-binding protein 2 inhibits Ca²⁺-channel inactivation in mouse inner hair cells

Ca²⁺-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca²⁺ channels of type 1.3 (Ca_V1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2 ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2 mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2 IHCs revealed enhanced Ca²⁺-channel inactivation. The voltage dependence of activation and the number of Ca²⁺ channels appeared normal in Cabp2 mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits Ca_V1.3 Ca²⁺-channel inactivation, and thus sustains the availability of Ca_V1.3 Ca²⁺ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.