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Voltage Sensor Movement in the HERG Potassium Channel

HEG 钾通道中的电压传感器移动

基本信息

批准号：
7340392
负责人：
MARTIN TRISTANI-FIROUZI
金额：
$ 35.44万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-15 至 2009-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goals of this proposal are to define the structural basis of voltage sensor movement and the mechanism of coupling sensor movement to opening of HERG delayed rectifier K+ channels. HERG is one of several voltage-gated IC channels that mediate repolarization of the cardiac action potential. HERG channel dysfunction, caused by mutations or commonly prescribed medications, is associated with life-threatening arrhythmias. The critical role of HERG in the maintenance of normal cardiac electrical activity derives from its unusual gating properties: slow channel activation and fast inactivation. Activation and inactivation gating are voltage dependent, implying that these processes are coupled to movement of charged residues within the membrane. The structural basis of voltage sensor movement and mechanism of coupling sensor movement to HERG channel opening are not known. In this proposal, we provide the first description of HERG voltage sensor movement as measured by gating current. We hypothesize (1) the domains surrounding the S4 domain (the putative voltage sensor) influence the rate of S4 movement and account for the slow activation of HERG ionic current, (2) inactivation and activation gating are coupled to the same fundamental voltage sensing mechanism and (3) voltage sensor movement is coupled to channel opening via a direct interaction between the intracellular S4-S5 linker and the S6 domain. The aims of this proposal are to determine the structural basis of slow activation in HERG channels, to define the voltage sensor movement associated with fast HERG inactivation and to determine the mechanism whereby movement of the voltage sensor is coupled to channel opening. These aims will be accomplished using site-directed mutagenesis, chimeric constructs between HERG and the structurally related EAG channel, biochemical assays, two microelectrode voltage clamp and cut-open oocyte voltage clamp techniques. Insight into the molecular basis of voltage sensing in the HERG channel will advance our understanding of how this channel contributes to normal electrical stability in the heart and may advance our understanding of arrhythmia susceptibility.

描述（由申请人提供）：本提案的总体目标是定义电压传感器移动的结构基础以及传感器移动与HERG延迟整流K+通道开放耦合的机制。HERG是介导心脏动作电位复极化的几种电压门控IC通道之一。由突变或常用处方药引起的HERG通道功能障碍与危及生命的心律失常有关。HERG在维持正常心脏电活动中的关键作用源于其不寻常的门控特性：慢通道激活和快速失活。激活和失活门控是电压依赖性的，这意味着这些过程与膜内带电残基的移动相耦合。电压传感器运动的结构基础和将传感器运动耦合到HERG通道开口的机制尚不清楚。在本提案中，我们提供了HERG电压传感器运动的第一个描述，通过门控电流测量。我们假设（1）围绕S4结构域的结构域（假定的电压传感器）影响S4运动的速率并解释HERG离子电流的缓慢激活，（2）失活和激活门控耦合到相同的基本电压感测机制，以及（3）电压传感器移动经由细胞内S4-S6之间的直接相互作用耦合到通道开放。S5接头和S6结构域。该提案的目的是确定HERG通道中缓慢激活的结构基础，定义与快速HERG失活相关的电压传感器运动，并确定电压传感器运动与通道开放耦合的机制。这些目标将使用定点诱变、HERG和结构相关的EAG通道之间的嵌合构建体、生化测定、双微电极电压钳和切开卵母细胞电压钳技术来实现。深入了解HERG通道中电压感知的分子基础将促进我们对该通道如何有助于心脏正常电稳定性的理解，并可能促进我们对心律失常易感性的理解。