Genetic and chemical biological studies of K2P structure, function, andmodulation

项目摘要 本项目的长期目标是了解控制 K2P钾通道的功能，并识别，开发和表征小分子，离子通道 K2P家族的调节剂。K2Ps是一个多样化的钾选择性通道家族， 背景“泄漏”电流。这些电流是调节神经元兴奋性的关键。K2P响应 不同的刺激，包括pH值的变化，温度和机械力。尽管K2P已经建立了良好的 在神经和心血管系统中的作用，并与疼痛，麻醉反应， 温度感觉和情绪，它们仍然是最不了解的钾通道类别。离子通道是 梦寐以求的药物目标作为膜蛋白，它们容易被胞外化合物和它们的 调制引起心脏和大脑中可兴奋细胞的性质的快速变化。但随着 膜蛋白，它们也超出了许多成熟的调节剂开发方法。 因此，许多通道，包括K2P家族中的通道，缺乏显著的药理学作用。这个问题 导致我们将离子通道基因与体内功能联系起来的能力存在差距。我们正在寻找一个 包括生物物理学、结构学、计算学和电生理学的多学科方法 测量和化学生物学方法来识别，解剖和表征核心元素， 控制K2P功能和定义和表征可以控制K2P活性的新的小分子。限定 控制K2P活性的分子机制和发现新的K2P调节剂应该提供关键的 了解K2P如何运作的框架和必要工具。由于它们在人类中的重要作用， 在生理学上，K2Ps是用于治疗慢性疼痛、中风和抑郁症的药物的靶标。因此，发展 了解K2Ps的功能和影响通道功能的小分子不仅可以提供 这是剖析K2P机制的有力工具，但应有助于开发新的治疗药物， 一系列人类疾病。

Project Summary The long-term goals of this project are to develop an understanding of the fundamental mechanisms that control the function of K2P potassium channels and to identify, develop, and characterize small molecule, ion channel modulators for the K2P family. K2Ps are a diverse family of potassium-selective channels that are responsible for background ‘leak’ currents. These currents are pivotal in modulating the excitability of neurons. K2Ps respond to varied stimuli that include pH changes, temperature, and mechanical force. Although K2Ps have well-established roles in the nervous and cardiovascular systems and are implicated in pain, anesthetic responses, thermosensation, and mood, they remain the least well-understood potassium channel class. Ion channels are coveted drug targets. As membrane proteins, they are readily accessible to extracellular compounds and their modulation brings about rapid changes in the properties of excitable cells in the heart and brain. However, as membrane proteins, they also reside beyond many well-established approaches for modulator development. Consequently, many channels, including those in the K2P family, lack significant pharmacologies. This problem leads to a gap in our ability to connect ion channel genes with in vivo function. We are pursuing a multidisciplinary approach that includes biophysical, structural, computational, and electrophysiological measurements and chemical biology approaches to identify, dissect, and characterize the core elements that control K2P function and to define and characterize new small molecules that can control K2P activity. Defining the molecular mechanisms that control K2p activity and uncovering new K2P modulators should provide the key framework and necessary tools for understanding how K2Ps function. Because of their important roles in human physiology, K2Ps are targets for drugs for the treatment of chronic pain, stroke, and depression. Thus, developing an understanding of how K2Ps function and small molecules that affect channel function should not only provide powerful tools for dissecting K2P mechanism but should aid in the development of new therapeutic agents for a range of human diseases.