MOLECULAR ASPECTS OF VOLTAGE ACTIVATION IN ION CHANNELS

这项提案的长期目标是深入了解电压如何 依赖的离子通道在分子方面起作用，并定义 与跨膜相关的不同蛋白质构象变化 电压变化和通道选通。离子电流和门控电流 将会被测量。门控电流是电的表现形式 电压传感器的移动。这些实验计划是为了 克隆了K通道。两个主要的初步发现是 这个提议是：1.发现电荷的早期峰值成分 在高带宽(200千赫)上记录的运动和2.趋势 选通电流速率，使其在极端电势下饱和。最早的 分量和随门控电流电压变化的饱和趋势 速率与航道大量传输的观点一致 状态，就像电荷沿着能量扩散的过程 用障碍物和水井塑造的景观。具体目标是：1. 研究门控电流的早期分量。开启和关闭门控 电流的前面有一个快速分量。2.调查 当前利率趋于饱和的潜在机制 带电压的。门控电流速率在高时趋于饱和 潜力。电荷沿能量扩散的模型 用障碍物和水井塑造的景观将进行测试。3.为了获得 通过对门控电流的描述来洞察通道功能 噪声和定义所涉及的带电残基。的属性 将对门控噪声进行调查。4.探讨心力衰竭的发病机制(S) 通过离子电流和门控电流的特性来实现缓慢失活 在长去极化过程中的特性。我们将检验这一假设 有两种类型的缓慢失活和5.要获得一个 从离子电流和门控电流建立振荡器K通道函数的整体模型 数据。这些确定与门控电流噪声相结合 测量，应该为预测提供明确定义的约束 在通道选通期间发生的构象变化。这 研究离子通道的基本性质对研究离子通道具有重要意义。 治疗药物的设计和测试。

The long term goals of this proposal are to gain insight on how voltage dependent ion channels function in molecular terms, and to define the different protein conformational changes associated with transmembrane voltage changes and channel gating. Ionic currents and gating currents will be measured. The gating currents are the electrical manifestation of the movement of the voltage sensor. The experiments are planned for cloned K channels. Two main preliminary findings are key aspects of this proposal: 1. the discovery of an early peak component of charge movement recorded at high bandwidth (200 kHz) and 2. a tendency of gating current rates to saturate at extreme potentials. The early component and the tendency to saturation with voltage of gating current rates are consistent with the view the channel transits a large number of states, like in a diffusion process of the charge along an energy landscape shaped with barriers and wells. The specific aims are: 1. To investigate the early component of gating currents. ON and OFF gating currents were preceded by a fast component. 2. To investigate the mechanism underlying the tendency of gating current rates to saturate with voltage. The gating current rates tend to saturate at high potentials. A model in which the charge diffuses along an energy landscape shaped with barriers and wells will be tested. 3. To gain insight on channel function via a characterization of the gating current noise and to define the charged residues involved. The properties of gating noise will be investigated. 4. To investigate mechanism(s) of slow inactivation by a characterization of ionic and gating current properties during long depolarizations. We will test the hypothesis that there are two types of slow inactivation and 5. To obtain a global model of Shaker K channel function from ionic and gating current data. These determinations, in conjunction with gating current noise measurements, should provide well defined constraints for the prediction of the conformational changes occurring during channel gating. This research on fundamental properties of ion channel should be valuable to the design and test therapeutic drugs.