Regulation of auditory calcium channels

在耳蜗内毛细胞（IHC）中，Cav1.3 L型电压门控性Ca 2+通道介导Ca 2+动作电位 在听觉和Ca2+信号开始之前，触发神经递质从IHC胞吐到听觉 神经传入Cav1.3的这些功能对于听力的发展和维持至关重要：小鼠 缺乏Cav1.3的小鼠先天性耳聋，由于甲状腺激素导致Cav1.3通道上调的小鼠也是如此。 缺陷因此，调节这些通道的因素可以深刻地影响听觉神经元中的第一个突触。 通路在本提案中，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，其是钙调素样Ca2+结合蛋白家族，和（3）harmonin，其是 对应于Usher综合征的基因位点，Usher综合征是导致耳聋和失明的主要原因， 人类我们认为Cav1.3与蛋白质如harmonin和CaBPs的大分子组装 决定了IHC中Ca2+信号的强度和定位，对于发育和 保持听觉传递。本提案的目标是表征分子机制 和这些Cav1.3相互作用的功能后果，以及它们对听力的生理意义。 实现这一目标将阐明听觉Cav1.3通道的调节作用，这可能是 在新的策略中靶向治疗，以抵消涉及遗传性形式的 耳聋

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.