Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
Otolaryngology Head-Neck Surgery, University of Iowa, Iowa City, IA 52242, USA.
Mol Cell Neurosci. 2018 Apr;88:342-352. doi: 10.1016/j.mcn.2018.03.005. Epub 2018 Mar 13.
CaBP1 is a Ca binding protein that is widely expressed in neurons in the brain, retina, and cochlea. In heterologous expression systems, CaBP1 interacts with and regulates voltage-gated Ca Ca channels but whether this is the case in neurons is unknown. Here, we investigated the cellular functions of CaBP1 in cochlear spiral ganglion neurons (SGNs), which express high levels of CaBP1. Consistent with the role of CaBP1 as a suppressor of Ca-dependent inactivation (CDI) of Ca1 (L-type) channels, Ca1 currents underwent greater CDI in SGNs from mice lacking CaBP1 (C-KO) than in wild-type (WT) SGNs. The coupling of Ca1 channels to downstream signaling pathways was also disrupted in C-KO SGNs. Activity-dependent repression of neurite growth was significantly blunted and unresponsive to Ca1 antagonists in C-KO SGNs in contrast to WT SGNs. Moreover, Ca1-mediated Ca signals and phosphorylation of cAMP-response element binding protein were reduced in C-KO SGNs compared to WT SGNs. Our findings establish a role for CaBP1 as an essential regulator of Ca1 channels in SGNs and their coupling to downstream pathways controlling activity-dependent transcription and neurite growth.
钙结合蛋白 1（CaBP1）是一种广泛表达于脑、视网膜和耳蜗神经元中的钙结合蛋白。在异源表达系统中，CaBP1 与电压门控钙通道相互作用并调节其功能，但在神经元中是否如此尚不清楚。在这里，我们研究了 CaBP1 在耳蜗螺旋神经节神经元（SGNs）中的细胞功能，SGNs 中高度表达 CaBP1。与 CaBP1 作为钙依赖性失活（CDI）钙通道（L 型）的抑制剂的作用一致，与野生型（WT）SGNs 相比，缺乏 CaBP1（C-KO）的 SGNs 中的钙电流经历了更大的 CDI。钙通道与下游信号通路的偶联在 C-KO SGNs 中也被破坏。与 WT SGNs 相比，活性依赖性抑制神经突生长的作用明显减弱且对钙通道拮抗剂无反应，这在 C-KO SGNs 中发生。此外，与 WT SGNs 相比，C-KO SGNs 中的钙 1 介导的钙信号和环磷酸腺苷反应元件结合蛋白的磷酸化减少。我们的研究结果确立了 CaBP1 作为 SGNs 中钙通道的重要调节剂及其与调节活性依赖性转录和神经突生长的下游途径偶联的作用。
