Regulation of auditory calcium channels

描述(申请人提供)：在耳蜗内毛细胞中，Cav1.3 L型电压门控钙通道介导听力开始前的钙动作电位和触发内毛细胞神经递质向听神经传入的胞吐的钙信号。Cav1.3的这些功能对听力的发育和维持至关重要：缺乏Cav1.3的小鼠是先天性耳聋，因为甲状腺激素缺乏导致Cav1.3通道上调的小鼠也是如此。因此，调节这些通道的因素可以深刻地影响听觉通路中的第一个突触。在这项提案中，我们将描述我们发现的调节IHC中Cav1.3通道的两个因素：(1)CaBP，这是一个类似钙调素的钙结合蛋白家族；(3)Harmonin，一种对应于Usher综合征遗传位点的蛋白质，是人类混合性耳聋和失明的主要原因。我们认为，Cav1.3与Harmonin和CaBPs等蛋白质的大分子组装决定了IHC中Ca~(2+)信号的强度和定位，对听觉传递的发育和维持至关重要。这项提议的目的是描述这些Cav1.3相互作用的分子机制和功能后果，以及它们对听力的生理意义。完成这一目标将阐明听觉Cav1.3通道的调节影响，这可能是新的策略的药理学靶点，以抵消遗传性耳聋所涉及的病理变化。这项拟议的研究将对听觉毛细胞中的电压门控钙通道进行调制。我们将阐明新的结构/功能关系和调节机制，这些可能会在遗传性耳聋中改变。

DESCRIPTION (provided by applicant): 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. The proposed research will modulate voltage-gated Ca2+ channels in auditory hair cells. We will elucidate new structure/function relationships and modulatory mechanisms, which may be altered in hereditary forms of deafness.