Long-Term Regulation of Potassium Channels

钾通道的长期调节

• 批准号: 7047452
• 负责人: EDWIN S LEVITAN
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-20 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047452
• 关键词: NAD(P)H dehydrogenase; angiotensin II; apoptosis; cardiac myocytes; cardiovascular function; electrophysiology; enzyme activity; free radical oxygen; high throughput technology; laboratory rat; membrane proteins; neurons; neurophysiology; phosphorylation; potassium channel; protein structure function; single cell analysis; tissue /cell culture; vascular smooth muscle; voltage gated channel

DESCRIPTION (provided by applicant): 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 known 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.

描述(申请人提供)：钾通道控制神经元、平滑肌细胞和心肌细胞等兴奋性细胞的功能。钾通道调节在多种细胞类型的细胞程序性死亡中也是重要的。虽然人们对钾通道的功能和急性调节有了很多了解，但对钾通道功能的长期调控知之甚少。然而，调控血管平滑肌细胞、心肌细胞和神经元的钾通道表达可能是控制高血压、减少心律失常和癫痫发作的一种有价值的治疗方法。在这里，我们追求三个目标，专注于我们正在进行的钾通道表达和活性的研究。目的1确定血管紧张素II(Ang II)如何作用于心肌细胞以下调Kv4.3通道的表达。实验将验证Ang II通过NADPH氧化酶产生的活性氧物种(ROS)作用于破坏通道信使RNA的3‘非翻译区稳定的假设。目标2将确定高通量筛选确定的蛋白质和化学物质如何刺激Kir2.1活性。由于总的通道表达不受影响，实验将集中在这两个激活剂是否影响通道交易和功能。目标3将确定电压门控钾(Kv)通道活性是如何缓慢增加的，作为细胞凋亡的关键步骤。我们将确定磷酸化是否触发在细胞表面插入新的同源Kv2.1通道。此外，我们将测试在血管平滑肌和心脏中发现的天然通道是否受到类似的调节。这一提议将揭示对心脏、血管和大脑中钾通道活动产生长期调节的新的生理、药理学和病理机制的基本见解。