BK channel regulation in auditory hair cells

听觉毛细胞中的 BK 通道调节

• 批准号: 7036203
• 负责人: ROBERT K DUNCAN
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036203
• 关键词: botulinum toxins; calcium flux; calcium ion; chemical kinetics; chick embryo; chickens; cochlea; ear hair cell; electrophysiology; estrogen analog; gene expression; genetic regulatory element; immunocytochemistry; intracellular transport; lipid raft; molecular assembly /self assembly; polymerase chain reaction; potassium channel; protein kinase A; protein protein interaction; protein structure function; protein transport; syntaxin; tamoxifen; transfection /expression vector

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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以及如何促进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中，这些通道限制 Ca2+ 通量并影响 Ca2+ 触发的神经传递。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。鸡耳蜗提供了一个模型系统，我们已经证明 BK 通道 Ca2+ 亲和力和动力学沿着音位轴以分级方式变化。然而，人们对这种音调变化的机制以及毛细胞 BK 电流的发育获得和高 Ca2+ 敏感性知之甚少。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（目标 1）、与辅助（3 个亚基）共组装（目标 2）、与突触蛋白相互作用（目标 3）以及运输到特定细胞微结构域（目标 4）来探索 BK 调节。定量分子技术、免疫组织学和电生理学将用于识别毛细胞 BK 通道行为的分子决定因素，这些实验将为听觉的分子生理学提供基础见解。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。这项研究为理解离子通道行为的变化如何影响正常和异常的听觉功能提供了框架，从而制定了通过 BK 通道调节针对毛细胞兴奋性的治疗策略。