Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells
Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells
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DOI：
10.1073/pnas.1617533114
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发表时间：
2017-02-28
影响因子：
11.1
通讯作者：
Moser, Tobias
中科院分区：
文献类型：
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作者：
Picher, Maria Magdalena;Gehrt, Anna;Moser, Tobias
Ca 2+结合蛋白2（CaBP 2）抑制1.3型（Ca（V）1.3）异源表达的电压门控性Ca 2+通道的失活，并且在人类常染色体隐性耳聋93（DFNB 93）中是有缺陷的。在这里，我们报告了一个新发现的CABP 2突变，它可能通过无义介导的CABP 2-mRNA衰变引起中度听力障碍。为了研究由CABP 2功能丧失导致的听力损伤的机制，我们破坏小鼠中的Cabp 2（Cabp 2（LacZ/LacZ））。CaBP 2在耳蜗毛细胞中表达，优先在内毛细胞中表达，而在突触后螺旋神经节神经元中表达缺失。Cabp 2（LacZ/LacZ）小鼠表现出完整的耳蜗放大，但受损的听觉脑干反应。Cabp 2（LacZ/LacZ）IHC的膜片钳记录显示增强的Ca 2+通道失活。Ca 2+通道激活的电压依赖性和Ca 2+通道数量在Cabp 2（LacZ/LacZ）小鼠中表现正常，带状突触计数也正常。单个SGN的记录显示自发和声音诱发的放电率降低。我们认为CaBP 2抑制Ca（V）1.3 Ca 2+通道失活，从而维持Ca（V）1.3 Ca 2+通道用于突触声音编码的可用性。因此，我们认为人类耳聋DFNB 93是一种听觉突触病。
Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+ channels of type 1.3 (Ca(V)1.3) 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(V)1.3 Ca2+-channel inactivation, and thus sustains the availability of Ca(V)1.3 Ca2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.