Conformational Dynamics of hERG Potassium Channels

人etherago-go相关基因（hERG，KCNH2）钾通道具有特殊的临床意义 重要性是因为它们在心脏中起着重要作用，在心脏中它们产生使心脏复极化电流 动作电位hERG通道的突变和药物抑制导致hERG降低， 对于遗传性和获得性心脏病，称为长QT综合征（LQTS）， 强调了这些通道在正常生理功能中的重要性。LQT的获得形式是 由于抑制hERG的处方药的非现场效应，并且是一种普遍和严重的临床 问题. hERG通道具有高度专业化的门控（打开和关闭）特性，可优化它们 因为它们在心脏中的细胞作用和也控制通道门控的专门亚基组装特性。 hERG与其他调节蛋白或辅助蛋白的结合也是研究的主要领域。 了解hERG通道是如何调节的。所提出的实验的目标是了解 这些特化的分子机制以及它们如何控制hERG电流。我们将 测试最近的结构，显示直接的N-和C-末端结构域相互作用的hERG，我们首先显示， 使用生物化学，电生理学和荧光测量，以及这些域的相互作用 控制通道的门控。我们的方法是尖端的，因为我们将使用电生理记录， 研究通道构象变化和荧光显微镜，以研究结构相互作用 控制通道门控和调节。我们将利用非规范氨基酸生物学的优势来介绍 在结构引导的位置引入金属结合位点， 运动与过渡金属FRET和电压。完成这些研究将导致更大的 了解hERG通道门控的基本机制，并深入了解细胞内结构域如何 通道调节打开和关闭。我们的研究结果有望导致合理的生物医学 治疗心律失常的新策略和新的分子靶点。

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.