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 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^LacZ/LacZ ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2^LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2^LacZ/LacZ IHCs revealed enhanced Ca²⁺-channel inactivation. The voltage dependence of activation and the number of Ca²⁺ channels appeared normal in Cabp2^LacZ/LacZ 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.

Keywords: Ca2+ channel; hearing impairment; inner hair cell; ribbon synapse; synaptopathy.