权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Conformational Dynamics of hERG Potassium Channels

hERG 钾通道的构象动力学

基本信息

批准号：
10324588
负责人：
MATTHEW C TRUDEAU
金额：
$ 30.9万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324588
关键词：
Action Potentials Amino Acids Area Arrhythmia Biochemical Biology Biophysical Process C-terminal Cardiac Cardiac Myocytes Cells Clinical Cryoelectron Microscopy Data Drug Prescriptions Electrophysiology (science)Engineering Environment Ethers Fluorescence Fluorescence Microscopy Fluorescence Resonance Energy Transfer Fluorometry Frequencies Genes Goals Heart Heart Diseases Human Inherited Lead Ligands Link Location Long QT Syndrome Malignant Neoplasms Measurement Measures Membrane Metal Binding Site Molecular Molecular Conformation Motion Movement Mutation N-terminal N33 gene Neurons Outcome Pharmaceutical Preparations Physiological Play Positioning Attribute Potassium Channel Property Proteins Recovery Regulation Resolution Roentgen Rays Role Schizophrenia Science Site Structure Subcellular structure Sudden Death Testing Time Transition Elements experimental study insight interest molecular targeted therapies mutant neoplastic new therapeutic target novel patch clamp response structural biology sudden cardiac death tool voltage voltage clamp

项目摘要

Human ether á go-go related gene (hERG, KCNH2) potassium channels are of extraordinary clinical importance because they play a prominent role in heart where they generate a current that repolarizes cardiac action potentials. Mutations in hERG channels and inhibition by drugs cause a reduction in hERG and account for inherited and acquired forms of a type of heart disease known as long QT syndrome (LQTS) which emphasizes the importance of these channels in normal physiological function. The acquired form of LQT is due to the off-site effects of prescription drugs which inhibit hERG, and are a prevalent and serious clinical problem. hERG channels have highly specialized gating (opening and closing) properties that optimize them for their cellular roles in the heart and specialized subunit assembly properties that also control channel gating. The association of hERG with other regulatory or accessory proteins is also a major area of interest for understanding how hERG channels are regulated. The goal of the proposed experiments is to understand the molecular mechanisms that underlie these specializations and how they control hERG current. We will be testing recent structures showing direct N- and C-terminal domain interactions of hERG that we first showed using biochemical, electrophysiological and fluorescence measurements, and how these domain interactions control gating of the channels. Our approach is cutting-edge as we will use electrophysiological recordings to investigate channel conformational changes and fluorescence microscopy to study how structural interactions control channel gating and regulation. We will take advantage of non-canonical amino acid biology to introduce small probes to hERG and introduce metal binding sites at locations guided by structures and probe for movements with transition metal FRET and voltage. Completion of these studies will lead to a greater understanding of the basic mechanisms for hERG channel gating and insight into how intracellular domains of the channel regulate opening and closing. Our outcomes are anticipated to lead to rational biomedical strategies and new molecular target for the treatment of cardiac arrhythmias.

人类乙醚-GO相关基因(HERG，KCNH2)钾通道具有非凡的临床意义之所以重要，是因为它们在心脏中扮演着重要的角色，在那里它们产生一种电流，使心脏重新极化动作电位。HERG通道突变和药物抑制导致HERG和Account减少对于一种称为长QT综合征(LQTS)的遗传性和获得性心脏病强调这些通道在正常生理功能中的重要性。LQT的收购形式为由于处方药的非现场作用，抑制了HERG，是一种流行和严重的临床有问题。HERG通道具有高度专业化的门控(打开和关闭)属性，可对其进行优化因为它们在心脏中的细胞作用以及也控制通道门控的专门亚单位组装特性。 HERG与其他调节蛋白或辅助蛋白的关联也是研究的一个主要领域了解HERG通道是如何被监管的。提议的实验的目标是了解这些特化背后的分子机制以及它们如何控制Herg电流。我们会的测试我们首次展示的显示HERG的N-末端和C-末端结构域直接相互作用的最新结构使用生化、电生理和荧光测量，以及这些结构域如何相互作用控制通道的选通。我们的方法是尖端的，因为我们将使用电生理记录来研究通道构象变化和荧光显微镜，以研究结构相互作用控制通道选通和调节。我们将利用非规范氨基酸生物学的优势来介绍 HERG的小探针并在由结构引导的位置引入金属结合部位带有过渡金属振荡器和电压的机芯。这些研究的完成将导致更大的了解HERG通道门控的基本机制，并深入了解HERG通道门控的细胞内域是如何通道调节开启和关闭。我们的结果有望导致理性的生物医学心律失常的治疗策略和新的分子靶点。