Allosteric mechanisms of Ca-activated K channel gating

描述(申请人提供)：离子通道动态调节 通过它们打开和关闭(门)的能力来实现膜的通透性 对各种刺激的反应。在识别和识别和 鉴定参与的通道蛋白的功能成分 这种选通过程包括检测刺激的“传感器”和 调节离子在通道孔中的流动。然而，构象 将传感器和门的动作联系在一起的事件和交互仍然存在 在很大程度上是未知的，很可能对理解 渠道是如何正常工作的，以及它们是如何被内源性因素调制的， 毒品或疾病。要确定传感器和 盖茨我以前(在理查德·奥尔德里奇的实验室里)研究过 大电导钙激活钾通道的功能 它既能感觉电压，又能感觉细胞内的钙离子。存在变构机制 通过它传感器的激活和气孔的打开看起来 表示构象上截然不同的事件，这些事件彼此影响很大 但也可以单独发生。MSLO提供了一个独特的学习机会 传感器/星门通信。通过研究极端条件下的MSLO和采取 该通道的特殊动力学和稳态特性的优势在于 能够在隔离状态下研究传感器的激活、通道的打开和 传感器与闸门之间的相互作用。此外，方法和分析工具 以前为WT通道开发的现在可以应用于突变的MSLO通道 以确定传感器/门通信中涉及的残留物。这个 结果不仅对于理解MSLO的门控将是重要的，而且 还用于阐明其他KY中传感器和门之间的耦合 频道。

DESCRIPTION (provided by the applicant): Ion channels dynamically regulate membrane permeability through their ability to open and close (gate) in response to various stimuli. Progress has been made in identifying and characterizing functional components of channel proteins that are involved in this gating process including "sensors" that detect stimuli, and "gates" that regulate the flow of ions through the channel pore. However the conformational events and interactions that link the action of sensors and gates remain largely unknown and are likely to be of fundamental importance in understanding how channels normally work and how they are modulated by endogenous factors, drugs or disease. To determine the nature of communication between sensors and gates I have previously studied (in the laboratory of Richard Aldrich) the function of a large conductance Ca2+ -activated K channel (mSlo); a channel that senses both voltage and intracellular Ca2+. An allosteric mechanism exists by which the activation of sensors and the opening of the pore appear to represent conformationally distinct events that strongly influence each other but can occur in isolation. mSlo offers a unique opportunity for studying sensor/gate communication. By studying mSlo under extreme conditions and taking advantage of particular kinetic and steady state properties of this channel we are able to study, in isolation, sensor activation, channel opening and the interaction between sensor and gate. Moreover, the methods and analytical tools developed previously for WT channels can now be applied to mutant mSlo channels to identify residues that are involved in sensor/gate communication. The results will be important not only for understanding the gating of mSlo but also for elucidating the coupling between sensors and gates in other Ky channel.