Long-Term Regulation of Potassium Channels

钾通道控制神经元、平滑肌细胞等兴奋性细胞的功能 和心肌细胞。钾离子通道调节在神经细胞程序性死亡中也起重要作用 多种细胞类型。尽管人们对它的功能和急性调制有很多了解 在钾离子通道中，对钾离子通道功能的长期调控知之甚少。然而， 调控血管平滑肌细胞、心肌细胞和心肌细胞钾通道的表达 神经元可能是控制高血压和降低血压的一种有价值的治疗方法 心律失常和癫痫发作的发生率。在这里，我们追求三个重点目标 我们正在进行的钾通道表达和活性研究。 目标1将确定血管紧张素II(Ang II)如何作用于心肌细胞以下调 Kv4.3通道表达。实验将验证Ang II通过NADPH氧化酶发挥作用的假设- 产生的活性氧物种(ROS)使通道的3‘非翻译区不稳定 信使核糖核酸。 目标2将确定高通量筛选如何识别一种蛋白质和一种化学物质 刺激Kir2.1的活性。由于总渠道表达不受影响，因此实验将重点放在 这两个激活剂是否影响渠道交易和功能。 目标3将确定电压门控钾(Kv)通道活性是如何随着 细胞凋亡中的关键步骤。我们将确定磷酸化是否触发新的插入 细胞表面存在同源Kv2.1通道。此外，我们将测试本地频道是否 在血管平滑肌和心脏中发现的都受到类似的调节。 这一提议将揭示对新的生理学、药理学和 心肌细胞钾通道活性长期调节的病理机制 心脏、血管和大脑。

Potassium channels control the function of excitable cells such as neurons, smooth muscle cells and cardiac myocytes. Potassium channel regulation is also important in programmed cell death in a variety of cell types. Although a great deal is understood about the function and acute modulation of potassium channels, little is know about long-term control of potassium channel function. Yet, manipulating potassium channel expression in vascular smooth muscle cells, cardiac myocytes and neurons could be a valuable therapeutic approach for controlling high blood pressure and reducing the incidence of cardiac arrhythmias and epileptic seizures. Here we pursue three aims focused on our ongoing studies of potassium channel expression and activity. Aim 1 will determine how Angiotensin II (Ang II) acts on cardiac myocytes to downregulate Kv4.3 channel expression. Experiments will test the hypothesis Ang II acts via NADPH oxidase- generated reactive oxygen species (ROS) to destabilize the 3' untranslated region of the channel messenger RNA. Aim 2 will determine how a protein and a chemical identified by high throughput screening stimulate Kir2.1 activity. Since total channel expression is unaffected, experiments will focus on whether these two activators affect channel trafficking and function. Aim 3 will determine how voltage-gated potassium (Kv) channel activity is slowly increased as a critical step in apoptosis. We will determine whether phosphorylation triggers insertion of new homomeric Kv2.1 channels in the cell surface. Furthermore, we will test whether native channels found in vascular smooth muscle and the heart are subject to similar regulation. This proposal will reveal fundamental insights into novel physiological, pharmacological and pathological mechanisms that produce long-term regulation of potassium channel activity in the heart, blood vessels and the brain.