CARDIOVASCULAR ROLE OF SYMPATHETIC K+ CHANNEL GENES

交感 K 通道基因的心血管作用

• 批准号: 6637501
• 负责人: PETER R BRINK
• 金额: $ 27.72万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637501
• 关键词: cardiovascular function; cardiovascular pharmacology; immunoprecipitation; potassium channel; protein isoforms; protein localization; protein structure function; sympathetic nervous system; tissue /cell culture

Sympathetic neuronal activity regulates such cardiovascular variables as heart rate, arterial blood pressure and myocardial contractility. The excitability of sympathetic neurons is determined in large part by a conductance known as the M-current. These investigators have recently determined that the M-current is encoded by the KCNQ2 and KCNQ3 genes. Increased understanding of these genes is a prerequisite to further investigation of 1) how the M-current is regulated during sympathetic activity, 2) the developmental control of this current and 3) the targeting of the M-current, and the pathways involved in its regulation, for pharmacological interventions in cardiovascular pathologies. The overall goal of the present application is to understand at a molecular level the subunit interactions that generate the constituent channels of the M-current. The projects outlined in Specific Aim 1 use knock-out and gain-of-function experiments to confirm our hypothesis that the M-current of sympathetic neurons is encoded by KCNQ2 and KCNQ3. Specific Aim 2 would test the hypothesis that the formation of the M-current involves protein interaction between the KCNQ2 and KCNQ3 subunits. Specific Aim 3 would test the corollary that protein interaction between the subunits facilitates the movement of subunit proteins from the endoplasmic reticulum to the cell membrane. Specific Aim 4 would test the hypothesis that specific splice variants of the KCNQ2 and KCNQ3 genes encode the M-channel of sympathetic neurons.

交感神经元活动调节此类心血管 变量如心率、动脉血压和心肌收缩力。 交感神经元的兴奋性在很大程度上是由 电导称为 M 电流。这些调查人员最近 确定 M 电流由 KCNQ2 和 KCNQ3 基因编码。 加深对这些基因的了解是进一步研究的先决条件 研究 1) M 电流在交感神经活动期间如何调节， 2）当前的发展控制和 3）目标 M-电流，以及参与其调节的途径，用于药理学 心血管病理干预。 本申请的总体目标是从分子角度理解 平衡产生组成通道的亚基相互作用 M-电流。具体目标 1 中概述的项目使用淘汰赛和 功能增益实验证实了我们的假设，即 M 电流 交感神经元由 KCNQ2 和 KCNQ3 编码。具体目标 2 将测试 M 电流的形成涉及蛋白质相互作用的假设 KCNQ2 和 KCNQ3 亚基之间。具体目标 3 将测试推论 亚基之间的蛋白质相互作用促进了 亚基蛋白从内质网到细胞膜。具体的 目标 4 将检验 KCNQ2 和 KCNQ2 的特定剪接变体的假设 KCNQ3 基因编码交感神经元的 M 通道。