Genetic Regulation of Kappa(Na) Channels in Neuronal Excitability

描述(申请人提供)：离子通道选择性地控制离子流入和流出细胞。不同通道表达的协调对于维持适当的兴奋性模式和神经元之间的准确交流是必不可少的。一种特殊的钾通道被称为钠激活钾通道，K(Na)通道调节神经元放电的速度，以维持刺激，并在低氧条件下保护神经元免受损伤。Slack基因编码K(Na)通道，该通道在中枢神经系统中高度表达，尤其在嗅觉细胞和听觉脑干中表达水平特别高。Slack基因由不同的启动子调控，这些启动子产生不同的氨基末端亚型。一种异构体，Slack-A，对去极化反应非常迅速，而另一种，Slack-B，激活相对较慢。Slack亚基激活动力学的不同决定了神经元适应的总体速度。这项训练计划的目的是确定CMS中Slack通道表达模式的遗传复杂性，以及这如何塑造自然神经元的电特性。本培训计划中的实验将使用分子、生化和电生理技术来检测K(Na)电流的遗传多样性和调节。由于K(Na)通道可以保护神经元和心肌细胞免受缺氧性损伤，了解K(Na)通道的遗传调控及其在正常和病理条件下的生物学功能将有助于脑缺血和中风的治疗。此外，这些研究可能有助于更好地了解癫痫发作期间兴奋性的病理变化。

DESCRIPTION (provided by applicant): Ion channels selectively control the flow of ions in and out of cells. The coordination of expression of various on channels is essential for maintaining appropriate patterns of excitability and accurate communication between neurons. One special class of potassium channels called sodium-activated potassium, K(Na), channels regulate the rate at which neuronal firing adapts to maintain stimulation and can protect neurons from injury during hypoxic conditions. The Slack gene encodes a K(Na) channel that is highly expressed in the central nervous system with particularly high levels of expression in olfactory cells and the auditory brainstem. The Slack gene is regulated by alternative promoters that give rise to different amino-terminal isoforms. One isoform, Slack-A, activates very rapidly in response to depolarization while the other, Slack-B, activates relatively slowly. The difference in activation kinetics of Slack subunits could determine the overall rate of adaptation of neuron. The purpose of this training proposal is to determine the genetic complexity of expression patterns of Slack channels in the CMS and how this shapes the electrical properties of native neurons. Experiments in this training proposal will use molecular, biochemical and electrophysiological techniques to examine the genetic diversity and regulation of K(Na) currents. Because K(Na) channels may protect neurons and cardiac cells from hypoxic injury, an understanding of the genetic regulation of K(Na) channels and their biological function in both normal and pathological conditions will lead to therapeutically useful treatments for cerebral ischemia and stroke. In addition, these studies could lead to a greater understanding of the pathological changes in excitability during epileptic seizures.