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

Abstract

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 <i>CABP2</i> that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from <i>CABP2</i> loss of function, we disrupted <i>Cabp2</i> in mice (<i>Cabp2</i>^{<i>LacZ/LacZ</i>} ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). <i>Cabp2</i>^{<i>LacZ/LacZ</i>} mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from <i>Cabp2</i>^{<i>LacZ/LacZ</i>} IHCs revealed enhanced Ca²⁺-channel inactivation. The voltage dependence of activation and the number of Ca²⁺ channels appeared normal in <i>Cabp2</i>^{<i>LacZ/LacZ</i>} 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.