BK channel regulation in auditory hair cells

描述(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的兴奋性，影响耳蜗内的感觉处理，并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。在神经元和感觉感受器细胞中，这些通道限制钙离子的流动，并影响钙离子触发的神经传递。在耳蜗区，BK通道功能减弱会导致严重的听觉缺陷。因此，正确的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，我们已经证明了BK通道的钙亲和力和动力学在紧张轴上以一种分级的方式变化。然而，这种张力变化的机制，以及毛细胞BK电流的发育习得和高钙敏感性，目前还知之甚少。离子通道调节是通过多种手段来实现的。在这个提案中，我们将探索通过选择性剪接(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)以及运输到特定的细胞微域(目标4)来调控BK。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。这些实验将提供对听觉毛细胞分子生理学的基本见解，并可能为耳蜗区功能梯度的产生和维持提供一个窗口。错误的离子通道功能是许多神经疾病的基础。我们的建议涉及一种重要的钾通道变化(BK)在听觉感觉细胞中的调节方式。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，从而导致通过BK通道调节针对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.