BK channel regulation in auditory hair cells

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。鸡耳蜗提供了一个模型系统，我们已经表明，BK通道钙离子亲和力和动力学变化的梯度方式沿着的tonotopic轴。然而，这种tonotopic变化的机制，以及发展收购和高钙敏感性的毛细胞BK电流，知之甚少。离子通道的调节是通过多种手段完成的。在这个提议中，我们将探索BK的调节通过选择性剪接（Aim 1），与辅助β 3亚基的共组装（Aim 2），与突触蛋白的相互作用（Aim 3），以及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被用来确定毛细胞BK通道行为的分子决定因素。这些实验将提供基本的洞察听觉毛细胞的分子生理学，并可能提供一个窗口的生成和维护功能梯度沿着耳蜗。离子通道功能紊乱是许多神经系统疾病的基础。我们的建议解决的方式，其中一个重要的钾通道品种（BK）的调节听觉感觉细胞。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，从而导致通过BK通道调节靶向毛细胞兴奋性的治疗策略。

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.