Structural studies of ion channel assembly and signaling

描述（由申请人提供）：该项目的长期目标是发展对离子通道功能和调控的高分辨率理解。我们正在研究KCNQ家族的电压门控钾通道。这些通道在听觉、心脏和大脑功能中起着核心作用。由于通道功能取决于亚基组成和与细胞信号网络蛋白质的相互作用，我们正在研究这两种现象的分子基础。由于研究哺乳动物膜蛋白结构的困难，我们目前的工作主要集中在了解对通道组装和细胞信号因子募集重要的细胞质结构域的功能。我们正在寻求一种多学科的方法，包括生化、生物物理、x射线晶体学和电生理测量来解剖KCNQ通道功能。由于其在人体生理中的重要作用，KCNQ通道的突变导致多种遗传性疾病，包括先天性耳聋、心律失常和癫痫。我们特别感兴趣的是了解疾病突变如何改变通道特性以及与其他蛋白质的相互作用。KCNQ通道是治疗心律失常、癫痫和记忆障碍药物的靶点。因此，了解它们的结构和作用机制可能会导致开发新的、有价值的治疗剂。

DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a high-resolution understanding of ion channel function and regulation. We are investigating the KCNQ family of voltage-gated potassium channels. These channels play central roles in auditory, cardiac, and brain function. Because channel function depends on subunit composition and interactions with proteins of cellular signaling networks, we are investigating the molecular bases for both of these phenomena. Due to difficulties in studying mammalian membrane protein structure, our present efforts are focused on understanding the function cytoplasmic domains that are important for channel assembly and for the recruitment of cellular signaling factors. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect KCNQ channel function. Because of their important roles in human physiology, mutations of KCNQ channels lead to a variety of hereditary diseases including congenital deafness, cardiac arrhythmias, and epilepsy. We are particularly interested in understanding how disease mutations change channel properties and interactions with other proteins. KCNQ channels are the targets for drugs directed at cardiac arrhythmias, seizures, and memory disorders. Thus, understanding their structures and mechanisms of action may lead to the development of new, valuable therapeutic agents.