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

项目摘要 这个项目的长期目标是发展对控制 K2P钾通道的功能及其对小分子离子通道的识别、发展和表征 用于K2P系列的调制器。K2P是一个不同的钾选择性通道家族，负责 背景“泄漏”流。这些电流在调节神经元的兴奋性方面起着关键作用。K2P回应 不同的刺激，包括pH变化、温度和机械力。尽管K2P已经很好地建立了 在神经系统和心血管系统中发挥作用，并与疼痛、麻醉反应、 体温感觉和情绪，它们仍然是最不了解的钾通道类别。离子通道是 令人垂涎的毒品目标。作为膜蛋白，它们很容易被胞外化合物和它们的 调制使心脏和大脑中可兴奋细胞的特性发生快速变化。然而，由于 除了膜蛋白，它们还存在于许多成熟的调节剂开发方法之外。 因此，许多渠道，包括K2P家族的渠道，缺乏重要的药理作用。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。我们正在追求一种 多学科方法，包括生物物理、结构、计算和电生理 测量和化学生物学方法，以识别、剖析和表征 控制K2P功能，并定义和表征能够控制K2P活性的新的小分子。定义 控制K2p活性的分子机制和发现新的K2p调节器应该是关键 了解K2P如何发挥作用的框架和必要的工具。因为它们在人类中扮演着重要的角色 生理学方面，K2Ps是治疗慢性疼痛、中风和抑郁症的药物靶点。因此，发展中 对K2Ps功能和影响通道功能的小分子的理解不仅应该提供 分析K2P机制的强大工具，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.