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， 影响耳蜗内的感觉处理，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。在……里面 神经元和感觉感受器细胞，这些通道限制钙离子流动并影响钙离子触发 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。这个 鸡耳蜗提供了一个模型系统，我们已经在其中展示了BK通道的钙亲和力和动力学 沿着色调轴以分级的方式变化。然而，这种单调背后的机制 毛细胞BK电流的变异以及发育获得和高钙敏感性是 人们对此知之甚少。离子通道调节是通过多种手段来实现的。在这项提案中，我们将 探索BK的选择性剪接调控(目标1)，与辅助的共组装(3个亚基(目标2)， 与突触蛋白的相互作用(目标3)，并运输到特定的细胞微域(目标4)。 将使用定量分子技术、免疫组织学和电生理学来鉴定 毛细胞BK通道行为的分子决定因素。这些实验将提供基本的 洞察听觉毛细胞的分子生理学，并可能提供一个窗口，了解 维持沿耳蜗线的功能梯度。 错误的离子通道功能是许多神经疾病的基础。我们的建议解决了 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 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 频道调制。

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.