BK channel regulation in auditory hair cells

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的兴奋性， 影响耳蜗中的感觉处理，并有助于正常和异常的听觉功能。 钙敏感钾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+流量，并影响Ca2+触发 神经传递在耳蜗中，BK通道功能减弱导致严重的听觉缺陷。 因此，正确的通道功能的分子机制是主要的兴趣。的 鸡耳蜗提供了一个模型系统，我们已经表明，BK通道Ca2+亲和力和动力学 以分级的方式沿音调拓扑轴沿着变化。然而，这种音调拓扑的机制 毛细胞BK电流的发育获得和高钙敏感性， 不太了解。离子通道的调节是通过多种手段完成的。在本提案中，我们将 探索BK通过选择性剪接（Aim 1），与辅助β亚基共组装（Aim 2）， 与突触蛋白的相互作用（Aim 3）和运输到特定的细胞微区（Aim 4）。 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。这些实验将提供基本的 深入了解听觉毛细胞的分子生理学，并可能提供一个窗口， 保持沿耳蜗沿着的功能梯度。 离子通道功能紊乱是许多神经系统疾病的基础。我们的建议涉及 一种重要的钾通道（BK）在听觉感觉细胞中的调节方式。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

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.