Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells.
Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+channels of type 1.3 (CaV1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation inCABP2that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting fromCABP2loss of function, we disruptedCabp2in mice (Cabp2LacZ/LacZ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs).Cabp2LacZ/LacZmice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings fromCabp2LacZ/LacZIHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+channels appeared normal inCabp2LacZ/LacZmice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany; tmoser@gwdg.de mm.picher@gmail.com.|Goettingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Goettingen, 37077 Goettingen, Germany.|Bernstein Center for Computational Neuroscience, University of Goettingen, 37077 Goettingen, Germany.|Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.
Maria Magdalena
MM
Picher
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany.|Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University of Goettingen Medical Center, 37075 Goettingen, Germany.
Anna
A
Gehrt
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany.
Sandra
S
Meese
Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany.
Aleksandra
A
Ivanovic
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany.
Friederike
F
Predoehl
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany.|Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Goettingen, 37075 Goettingen, Germany.|Neuro Modulation and Neuro Circuitry Group, Biomedical Sciences Institutes, Singapore Bioimaging Consortium, Biomedical Sciences Institutes, 138667 Singapore.
SangYong
S
Jung
Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium.|Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004.
Isabelle
I
Schrauwen
Otorhinolaryngology, Department of Surgery, Niguarda Ca' Granda Metropolitan Hospital, 20162 Milan, Italy.
Alberto Giulio
AG
Dragonetti
Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, 20162 Milan, Italy.|Institute of Clinical Biochemistry, Catholic University of the Sacred Heart, 00198 Rome, Italy.
Roberto
R
Colombo
Department of Medical Genetics, University of Antwerp, 2610 Antwerp, Belgium.
Guy
G
Van Camp
Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University of Goettingen Medical Center, 37075 Goettingen, Germany.
Nicola
N
Strenzke
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Goettingen, 37099 Goettingen, Germany; tmoser@gwdg.de mm.picher@gmail.com.|Goettingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Goettingen, 37077 Goettingen, Germany.|Bernstein Center for Computational Neuroscience, University of Goettingen, 37077 Goettingen, Germany.|Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany.|Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany.|Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Goettingen, 37075 Goettingen, Germany.
Tobias
T
Moser
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D003051:Cochlea / Q000378:metabolism; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D057809:HEK293 Cells; D006198:Hair Cells, Auditory / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D018069:Hair Cells, Vestibular / Q000378:metabolism; D034381:Hearing Loss / Q000378:metabolism; D006801:Humans; D051379:Mice; D018408:Patch-Clamp Techniques / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D013136:Spiral Ganglion / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; C085578:Ca-binding protein 2; D002118:Calcium
Ca2+ channel; hearing impairment; inner hair cell; ribbon synapse; synaptopathy