Regulation of auditory calcium channels

听觉钙通道的调节

• 批准号: 8490543
• 负责人: AMY LEE
• 金额: $ 1.76万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490543
• 关键词: Acoustic Nerve; Action Potentials; Apical; Auditory; Binding; Binding Proteins; Biochemical; Blindness; Calcium Channel; Calmodulin; Cell physiology; Cells; Coupling; Development; Electrophysiology (science); Exocytosis; Family; Family member; Genetic; Goals; Hair; Hair Cells; Hearing; Hearing Impaired Persons; Human; Immunofluorescence Immunologic; Inherited; Inner Hair Cells; Maintenance; Mediating; Membrane; Methods; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Neurotransmitters; Physiological; Property; Proteins; Regulation; Research; Role; Screening procedure; Shapes; Signal Transduction; Site; Small Interfering RNA; Stimulus; Structure-Activity Relationship; Synapses; Thyroid Hormones; Usher Syndrome; auditory pathway; base; cellular pathology; deafness; hormone deficiency; macromolecular assembly; neurotransmitter release; novel; novel strategies; patch clamp; prevent; scaffold; transmission process; voltage

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.

描述（由申请人提供）：在耳蜗内毛细胞（IHC）中，CAV1.3 L型电压门控的Ca2+通道在听力发作和Ca2+信号开始前介导CA2+动作电位，这些动作电位会触发来自IHC的神经递质从IHC中造成听觉神经剂量的脑胞膜症。 CAV1.3的这些功能对于听力的发展和维持至关重要：缺乏CAV1.3的小鼠是先天性聋哑人，由于甲状腺激素缺乏症而引起的CAV1.3通道上调的小鼠也是聋的。因此，调节这些通道的因素可以深刻影响听觉途径中的第一次突触。在此提案中，我们将表征我们发现的两个因素来调节IHC中的CAV1.3通道：（1）CABPS，它们是一个像钙调蛋白一样的Ca2+结合蛋白的家族，以及（3）Harmonin，一种蛋白质，一种蛋白质，一种对应于USHER综合征的遗传学基因座，是聋哑人和盲目的聋哑人。我们提出，cav1.3与诸如Harmonin和Cabps之类的蛋白质的大分子组装决定了IHC中Ca2+信号的强度和定位，并且对于开发和维持听觉传播至关重要。该提案的目的是表征这些CAV1.3相互作用的分子机制和功能后果及其在听力的生理意义。实现这一目标将阐明听觉CAV1.3通道的调节影响，该频道可能是针对药理学的新型策略，以抵消遗传性耳聋形式涉及的病理变化。拟议的研究将调节听觉毛细胞中的电压门控Ca2+通道。我们将阐明新的结构/功能关系和调节机制，这可能会以遗传形式的耳聋形式改变。