Regulation of auditory calcium channels

项目摘要 在耳蜗内毛细胞中，Cav1.3 L型电压门控性钙通道介导钙离子动作电位 在听力和引发神经递质从IHC胞吐到听觉的钙信号出现之前 神经传入。Cav1.3的这些功能对听力的发育和维持至关重要：小鼠 缺少Cav1.3的小鼠是先天性耳聋，因为甲状腺激素导致Cav1.3通道上调的小鼠也是如此 缺乏症。因此，调节这些通道的因素可以深刻地影响听觉中的第一个突触 路径。在本提案中，我们将描述我们发现的两个调节IHC中的Cav1.3通道的因素： (1)CaBPs，这是一个类似钙调素的钙结合蛋白家族；和(3)Harmonin，一种可以 与亚瑟综合征的一个遗传位点相对应，亚瑟综合征是导致耳聋和失明的主要原因 人类。我们提出了Cav1.3与Harmonin和CaBPs等蛋白质的大分子组装 决定了钙信号在IHC中的强度和定位，对IHC的发育和 听觉传递的维持。这项提议的目标是描述分子机制。 以及这些Cav1.3相互作用的功能后果，以及它们对听力的生理意义。 实现这一目标将澄清听觉Cav1.3通道的调制影响，这可能是 在新策略中有针对性地药理学，以抵消与遗传形式有关的病理变化 耳聋。 1

Project Summary In cochlear inner hair cells (IHCs), Cav1.3 L-type voltage-gated Ca2+ channels mediate Ca2+ action potentials before the onset of hearing and Ca2+ signals that trigger exocytosis of neurotransmitter from IHCs onto auditory nerve afferents. These functions of Cav1.3 are crucial for the development and maintenance of hearing: mice lacking Cav1.3 are congenitally deaf, as are mice with upregulated Cav1.3 channels due to thyroid hormone deficiency. Thus, factors that regulate these channels can profoundly impact this first synapse in the auditory pathway. In this proposal, we will characterize two factors we have found to regulate Cav1.3 channels in IHCs: (1) CaBPs, which are a family of calmodulin-like Ca2+-binding proteins and (3) harmonin, a protein that corresponds to a genetic locus of Usher syndrome, a leading cause of combined deafness and blindness in humans. We propose that the macromolecular assembly of Cav1.3 with proteins such as harmonin and CaBPs dictates the strength and localization of Ca2+ signals in IHCs, and is crucial for the development and maintenance of auditory transmission. The goal of this proposal is to characterize the molecular mechanisms and functional consequences of these Cav1.3 interactions, and their physiological significance for hearing. Accomplishing this objective will clarify the modulatory influences of auditory Cav1.3 channels, which may be targeted pharmacologically in novel strategies to offset pathological changes involved in hereditary forms of deafness. 1