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The Journal of Neuroscience, August 26, 2009, 29(34):10730-10740; doi:10.1523/JNEUROSCI.1577-09.2009

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Cellular/Molecular
The Ca²⁺ Channel Subunit β2 Regulates Ca²⁺ Channel Abundance and Function in Inner Hair Cells and Is Required for Hearing

Jakob Neef,^1,2,3 Anna Gehrt,^1,4 Anna V. Bulankina,¹ Alexander C. Meyer,¹ Dietmar Riedel,⁵ Ronald G. Gregg,^6,7 Nicola Strenzke,⁴ and Tobias Moser^1,2,3

¹InnerEarLab, Department of Otolaryngology and Center for Molecular Physiology of the Brain, ²Bernstein Center for Computational Neuroscience, ³Sensory and Motor Neuroscience Program, Göttingen Graduate School for Neurosciences and Molecular Biosciences, and ⁴Auditory Systems Physiology Group, Department of Otolaryngology, University of Göttingen, 37099 Göttingen, Germany, ⁵Laboratory of Electron Microscopy, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany, and Departments of ⁶Biochemistry and Molecular Biology and ⁷Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky 40202

Correspondence should be addressed to either of the following: Tobias Moser, InnerEarLab, Department of Otolaryngology, Göttingen University Medical School, 37099 Göttingen, Germany, Email: tmoser{at}gwdg.de; or Nicola Strenzke, Auditory Systems Physiology Group, Department of Otolaryngology, Göttingen University Medical School, 37099 Göttingen, Germany, E-mail: Email: nicola.strenzke{at}medizin.uni-goettingen.de

Hearing relies on Ca²⁺ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca²⁺ channel subunit Ca_Vβ₂ in hearing. Of the Ca_Vβ_1–4 mRNAs, IHCs predominantly contained Ca_Vβ₂. Hearing was severely impaired in mice lacking Ca_Vβ₂ in extracardiac tissues (Ca_Vβ₂^–/–). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca_Vβ₂^–/– mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca_Vβ₂^–/– IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca_V1.3 channels. Confocal Ca²⁺ imaging revealed presynaptic Ca²⁺ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca_V1.3 channels. The coupling of the remaining Ca²⁺ 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_Vβ₂^–/– mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca_Vβ₂^–/– mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca_V1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca²⁺ activated potassium channels in IHCs were impaired in the absence of Ca_Vβ₂. Moreover, we found the developmental efferent innervation to persist in Ca_Vβ₂-deficient IHCs. In summary, Ca_Vβ₂ has an essential role in regulating the abundance and properties of Ca_V1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.

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Received April 2, 2009; revised July 7, 2009; accepted July 22, 2009.

Correspondence should be addressed to either of the following: Tobias Moser, InnerEarLab, Department of Otolaryngology, Göttingen University Medical School, 37099 Göttingen, Germany, Email: tmoser{at}gwdg.de; or Nicola Strenzke, Auditory Systems Physiology Group, Department of Otolaryngology, Göttingen University Medical School, 37099 Göttingen, Germany, E-mail: Email: nicola.strenzke{at}medizin.uni-goettingen.de

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