The Ca2+ channel subunit β2 regulates Ca2+ channel abundance and function in inner hair cells and is required for hearing.

Hearing relies on Ca 2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca 2+ channel subunit Ca V β 2 in hearing. Of the Ca V β 1–4 mRNAs, IHCs predominantly contained Ca V β 2 . Hearing was severely impaired in mice lacking Ca V β 2 in extracardiac tissues ( Ca V β 2 −/− ). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca V β 2 −/− mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca V β 2 −/− IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca V 1.3 channels. Confocal Ca 2+ imaging revealed presynaptic Ca 2+ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca V 1.3 channels. The coupling of the remaining Ca 2+ influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in the Ca V β 2 −/− mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca V β 2 −/− mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca V 1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca 2+ activated potassium channels in IHCs were impaired in the absence of Ca V β 2 . Moreover, we found the developmental efferent innervation to persist in Ca V β 2 -deficient IHCs. In summary, Ca V β 2 has an essential role in regulating the abundance and properties of Ca V 1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.