CARDIOVASCULAR ROLE OF SYMPATHETIC K+ CHANNEL GENES

交感神经活动调节这种心血管系统 变量包括心率、动脉血压和心肌收缩能力。 交感神经元的兴奋性在很大程度上是由 称为M-电流的电导。这些调查人员最近 确定M-电流由KCNQ2和KCNQ3基因编码。 增加对这些基因的了解是进一步 研究1)交感神经活动时M-电流是如何调节的， 2)这一电流的发育控制；3)靶向 药理学的M-电流及其调节途径 心血管病理学的干预。 本申请的总体目标是在分子水平上理解 将生成组成通道的子单元交互作用 M-Current。具体目标1中概述的项目使用淘汰法和 函数增益实验证实了我们的假设 交感神经元由KCNQ2和KCNQ3编码。《特定目标2》将测试 M-电流的形成涉及蛋白质相互作用的假说 在KCNQ2和KCNQ3亚基之间。具体目标3将检验推论 亚基之间的蛋白质相互作用促进了 从内质网到细胞膜的亚基蛋白质。特定的 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。

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.