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

Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1717-E1726. doi: 10.1073/pnas.1617533114.

Maria Magdalena Picher ¹ ² ³ ⁴, Anna Gehrt ⁵ ⁶, Sandra Meese ⁵, Aleksandra Ivanovic ⁷, Friederike Predoehl ⁵, SangYong Jung ⁵ ⁴ ⁸ ⁹, Isabelle Schrauwen ¹⁰ ¹¹, Alberto Giulio Dragonetti ¹², Roberto Colombo ¹³ ¹⁴, Guy Van Camp ¹⁰, Nicola Strenzke ⁶, Tobias Moser ¹ ² ³ ⁴ ⁷ ⁸

Affiliations

1 Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany; [email protected] [email protected].
2 Goettingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Goettingen, 37077 Goettingen, Germany.
3 Bernstein Center for Computational Neuroscience, University of Goettingen, 37077 Goettingen, Germany.
4 Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
5 Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany.
6 Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University of Goettingen Medical Center, 37075 Goettingen, Germany.
7 Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany.
8 Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Goettingen, 37075 Goettingen, Germany.
9 Neuro Modulation and Neuro Circuitry Group, Biomedical Sciences Institutes, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 138667 Singapore.
10 Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium.
11 Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004.
12 Otorhinolaryngology, Department of Surgery, Niguarda Ca' Granda Metropolitan Hospital, 20162 Milan, Italy.
13 Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, 20162 Milan, Italy.
14 Institute of Clinical Biochemistry, Catholic University of the Sacred Heart, 00198 Rome, Italy.

PMID: 28183797 DOI: 10.1073/pnas.1617533114

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.

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