BK channel regulation in auditory hair cells

听觉毛细胞中的 BK 通道调节

基本信息

批准号：
7540803
负责人：
ROBERT K DUNCAN
金额：
$ 8.14万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7540803
关键词：
Address Affect Afferent Neurons Affinity Age Alternative Splicing Apical Asses Auditory Auditory Physiology Behavior Biological Models Botulinum Toxins Calcium Calcium Channel Cell physiology Cell surface Cells Chickens Cleaved cell Cochlea Code Complement component C1s Coupled Cyclic AMP-Dependent Protein Kinases Cyclodextrins Data Development Diffuse Disruption Distant Dominant-Negative Mutation Electrophysiology (science)Embryo Endoplasmic Reticulum Estrogens Exhibits Exons Functional disorder Gated Ion Channel Generations Genes Goals Golgi Apparatus Hair Cells Hearing Immunohistochemistry In Situ Hybridization Ion Channel Kinetics Label Lead Localized Maintenance Membrane Microdomains Messenger RNA Molecular Muscle Neurons Potassium Potassium Channel Prevalence Probability Property Protein Isoforms Proteins RNA Splicing Range Receptor Cell Regulation Regulatory Pathway Research Reverse Transcriptase Polymerase Chain Reaction Secretory Cell Sensory Sensory Process Shapes Source Soyasaponin Staging Surface Synapses System Techniques Testing Therapeutic Toxin Variant Vertebrates base day insight interest large-conductance calcium-activated potassium channels nervous system disorder neurotransmission prevent research study syntaxin syntaxin 1 syntaxin 1A trafficking voltage

项目摘要

Our long-term goal is to understand how voltage-gated ion channels regulate hair cell excitability, influence sensory processing in the cochlea, and contribute to normal and abnormal auditory function. Calcium-sensitive potassium (BK) channels are widely distributed in neurons, muscle, and secretory cells. In neurons and sensory receptor cells, these channels constrain Ca2+ flux and influence Ca2+-triggered neurotransmission. In the cochlea, diminished BK channel function leads to profound auditory deficits. Therefore, the molecular mechanisms underlying proper channel function are of primary interest. The chicken cochlea provides a model system where we have shown that BK channel Ca2+ affinity and kinetics vary in a graded manner along the tonotopic axis. However, the mechanisms underlying this tonotopic variation, as well as the developmental acquisition and high Ca2+ sensitivity of hair cell BK currents, are poorly understood. Ion channel regulation is accomplished by a variety of means. In this proposal, we will explore BK regulation by alternative splicing (Aim 1), co-assembly with auxiliary (3 subunits (Aim 2), interaction with synaptic proteins (Aim 3), and trafficking to specific cellular microdomains (Aim 4). Quantitative molecular techniques, immunohistology, and electrophysiology will be used to identify the molecular determinants of hair cell BK channel behavior. These experiments will provide fundamental insight into the molecular physiology of auditory hair cells and may provide a window into the generation and maintenance of functional gradients along the cochlea. Errant ion channel function underlies numerous neurological disorders. Our proposal addresses the ways in which an important potassium channel variety (BK) is regulated in auditory sensory cells. This research provides the framework for understanding how changes in ion channel behavior affect normal and abnormal auditory function, leading to therapeutic strategies that target hair cell excitability through BK channel modulation.

我们的长期目标是了解电压门控离子通道如何调节毛细胞兴奋性，影响耳蜗的感觉处理，并有助于正常和异常的听觉功能。钙敏感钾（BK）通道广泛分布于神经元、肌肉和分泌细胞中。在神经元和感觉受体细胞，这些通道限制 Ca2+ 通量并影响 Ca2+ 触发神经传递。在耳蜗中，BK 通道功能减弱会导致严重的听觉缺陷。因此，正确通道功能背后的分子机制是人们最感兴趣的。这鸡耳蜗提供了一个模型系统，我们在其中展示了 BK 通道 Ca2+ 亲和力和动力学沿着音调轴以分级方式变化。然而，这个主题背后的机制变异，以及毛细胞 BK 电流的发育获取和高 Ca2+ 敏感性，不太了解。离子通道调节可以通过多种方式实现。在本提案中，我们将通过选择性剪接探索 BK 调节（目标 1）、与辅助（3 个亚基）共组装（目标 2）、与突触蛋白的相互作用（目标 3），以及运输到特定的细胞微结构域（目标 4）。定量分子技术、免疫组织学和电生理学将用于鉴定毛细胞 BK 通道行为的分子决定因素。这些实验将提供基础深入了解听觉毛细胞的分子生理学，并可能为了解听觉毛细胞的产生和产生提供一个窗口维持耳蜗的功能梯度。错误的离子通道功能是许多神经系统疾病的根源。我们的建议解决了听觉感觉细胞中重要的钾通道种类（BK）的调节方式。这研究为理解离子通道行为的变化如何影响正常和听觉功能异常，导致通过 BK 靶向毛细胞兴奋性的治疗策略信道调制。