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

Roberto Colombo, Maria Magdalena Picher, Anna Gehrt, Sandra Meese, Aleksandra Ivanovic, Friederike Predoehl, Sangyong Jung, Isabelle Schrauwen, Alberto Giulio Dragonetti, Guy Van Camp, Nicola Strenzke, Tobias Moser

Risultato della ricerca: Contributo in rivistaArticolo in rivista

20 Citazioni (Scopus)

Abstract

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 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 (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/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+ channels appeared normal in Cabp2LacZ/LacZ mice, 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.
Lingua originaleEnglish
pagine (da-a)E1717-E1726
Numero di pagine10
RivistaProceedings of the National Academy of Sciences of the United States of America
Volume114
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Ca2+ channel
  • Hearing impairment
  • Inner hair cell
  • Multidisciplinary
  • Ribbon synapse
  • Synaptopathy

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