Regulation of auditory calcium channels

听觉钙通道的调节

• 批准号: 8854193
• 负责人: AMY LEE
• 金额: $ 2.28万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854193
• 关键词: Acoustic Nerve; Adverse effects; Animal Model; Auditory; Binding; Binding Proteins; Biochemical; Brain; Brain Stem; Calcium Channel; Calmodulin; Cardiovascular system; Cell surface; Cells; Complex; Exhibits; Exocytosis; Family member; Functional disorder; Genes; Goals; Hair Cells; Health; Hearing problem; Heart; Human; Image; In Vitro; Inherited; Inner Hair Cells; Knowledge; Mediating; Molecular; Molecular Genetics; Mus; Mutation; Neurologic; Neurotransmitters; Outcome; Pathogenesis; Physiological; Process; Property; Protein Family; Proteins; Regulation; Research; Role; Scaffolding Protein; Sensory; Shapes; Signal Transduction; Synapses; System; Techniques; Testing; Tissues; Ubiquitin; Usher Syndrome; auditory pathway; base; caldendrin; cell type; deafness; density; hearing impairment; human disease; innovation; loss of function; macromolecular assembly; mouse model; multicatalytic endopeptidase complex; ribbon synapse; sound; spiral ganglion; synaptic function; therapeutic development; transmission process; voltage; Acoustic Nerve; Adverse effects; Animal Model; Auditory; Binding; Binding Proteins; Biochemical; Brain; Brain Stem; Calcium Channel; Calmodulin; Cardiovascular system; Cell surface; Cells; Complex; Exhibits; Exocytosis; Family member; Functional disorder; Genes; Goals; Hair Cells; Health; Hearing problem; Heart; Human; Image; In Vitro; Inherited; Inner Hair Cells; Knowledge; Mediating; Molecular; Molecular Genetics; Mus; Mutation; Neurologic; Neurotransmitters; Outcome; Pathogenesis; Physiological; Process; Property; Protein Family; Proteins; Regulation; Research; Role; Scaffolding Protein; Sensory; Shapes; Signal Transduction; Synapses; System; Techniques; Testing; Tissues; Ubiquitin; Usher Syndrome; auditory pathway; base; caldendrin; cell type; deafness; density; hearing impairment; human disease; innovation; loss of function; macromolecular assembly; mouse model; multicatalytic endopeptidase complex; ribbon synapse; sound; spiral ganglion; synaptic function; therapeutic development; transmission process; voltage

DESCRIPTION (provided by applicant): In cochlear inner hair cells (IHCs), Cav1.3 L-type voltage-gated Ca2+ channels mediate Ca2+ signals that trigger exocytosis of neurotransmitter from IHCs onto auditory nerve afferents. This function of Cav1.3 is crucial for hearing: loss-of-function alterations in Cav1.3 cause deafness in humans and animal models. Cav1.3 channels exhibit distinct properties in IHCs compared to other cell-types, but little is known about what underlies these differences or their relevance for sound encoding by the IHCs. Filling this gap in knowledge is expected to reveal fundamental processes that are required for the unique role of Cav1.3 channels at this first synapse in the auditory pathway. The long-term goal of our research is to define the mechanisms that regulate voltage- gated Cav Ca2+ channels in order to discover what causes, and how to cure, human disease. To this end, we have identified new forms of Cav1.3 modulation in IHCs. First, we found that the cell-surface density of Cav1.3 channels in IHCs is controlled by interactions with harmonin, a protein implicated in the pathogenesis of Usher syndrome. Harmonin enhances degradation of Cav1.3 by the ubiquitin-proteosome (UPS) system, and this process is disrupted in a mouse model of Usher syndrome. Second, we discovered that CaBP2, a Ca2+ binding related to calmodulin (CaM), inhibits Ca2+-dependent inactivation of Cav1.3; this effect is impaired by a human mutation in the CaBP2 gene that causes autosomal-recessive hearing loss. Third, we found that Cav1.3 associates with RIBEYE, the major component of "ribbon" synapses in IHCs and other sensory cell-types. This interaction may regulate not only the localization, but also the function of Cav1.3 at the IHC active zone. Based on our findings, we hypothesize that the macromolecular assembly of Cav1.3 with proteins such as harmonin, CaBP2, and RIBEYE, dictate the strength and localization of Ca2+ signals in IHCs, and is therefore crucial for auditory transmission. The objective of this proposal is to test this hypothesis using molecular, genetic, and electrophysiological techniques. The rationale is that the proposed research will reveal essential signaling complexes that shape the synaptic function of IHCs, and how dysregulation of such complexes may contribute to the pathophysiology of inherited or acquired forms of hearing loss.

描述（由申请人提供）：在人工耳蜗内毛细胞（IHC）中，CAV1.3 L型电压门控Ca2+通道介导CA2+信号，这些信号会触发来自IHC的神经递质胞吞和来自听觉神经传入的神经递质的胞毒性。 Cav1.3的这种功能对于听力至关重要：CAV1.3的功能丧失改变引起人类和动物模型的耳聋。与其他细胞类型相比，CAV1.3通道在IHC中表现出不同的特性，但对这些差异或IHC与声音编码的相关性知之甚少。填补知识的差距有望揭示Cav1.3通道在听觉途径中第一次突触中独特作用所必需的基本过程。我们研究的长期目标是定义调节电压CAV CA2+通道的机制，以发现原因以及如何治愈人类疾病。为此，我们确定了IHC中CAV1.3调制的新形式。首先，我们发现IHC中Cav1.3通道的细胞表面密度受到与Harmonin相互作用的控制，Harmonin与Harmonin相互作用，该蛋白与Usher综合征的发病机理有关。 Harmonin通过泛素 - 蛋白酶（UPS）系统增强了CAV1.3的降解，并且在Usher综合征的小鼠模型中破坏了此过程。其次，我们发现与钙调蛋白（CAM）相关的Ca2+结合CABP2抑制了Ca2+依赖性cav1.3的失活。 CABP2基因中的人类突变会损害这种效果，从而导致常染色体不必要的听力损失。第三，我们发现CAV1.3与肋眼相关，Ribeye是IHC和其他感觉细胞类型中“色带”突触的主要组成部分。这种相互作用不仅可以调节本地化，还可以调节cav1.3在IHC处的功能 活动区。根据我们的发现，我们假设Cav1.3与Harmonin，CabP2和Ribeye等蛋白质的大分子组装决定了IHC中Ca2+信号的强度和定位，因此对于听觉透射至关重要。该建议的目的是使用分子，遗传和电生理技术检验该假设。理由是拟议的研究将揭示塑造IHC突触功能的基本信号复合物，以及这种复合物的失调如何有助于遗传或获得形式的听力损失形式的病理生理学。