A Regulator for Eag Family Channels

描述（由申请人提供）：人类ether-a-go-go相关基因1（Hergl）通道功能障碍在心脏病中起关键作用，心脏病是美国的主要死因。Hergl在心脏中大量表达，其延迟整流钾电流有助于心脏动作电位的复极化。它是ether-a-go-go（Eag）通道家族中最具特征的成员。我们分析了Hergl和其他Eag家族通道的基因序列，以确定两个可能的配体结合位点，因此将这些通道表征为孤儿受体。该提案的总体目的是确定Hergl和其他Eag家族通道的细胞内调节剂，并表征这些调节剂如何调节通道门控。将通过细胞代谢物的高通量化学文库筛选和由内而外的膜片钳来鉴定调节剂。使用分子生物学，蛋白质生物化学和电生理学，我将确定门控特性如何受到通道调节的影响，我将定位调节剂结合通道的部位。在这个建议中的实验将有助于我们了解这些通道在生理和病理中的作用。这些实验的另一个好处是揭示了中枢神经系统中涉及的途径，如学习和记忆，或导致心律失常和癌症等疾病的过程。最终，该受体位点可能是改善许多疾病（包括长QT综合征）的潜在药物靶点。 这项研究的目的是确定一个蛋白质家族的调节因子，该蛋白质家族被称为ether-a-go-go（Eag）通道，该通道在整个大脑和心脏中表达。编码这些通道的基因突变会导致心律失常和死亡。使用细胞内代谢物的库筛选，我将确定这些通道的细胞内调节剂，并确定它们如何影响这些通道。

DESCRIPTION (provided by applicant): The human ether-a-go-go related gene 1 (Hergl) channel dysfunction plays a critical role in heart disease, a leading cause of death in the United States. Hergl is abundantly expressed in the heart, and its delayed rectifying potassium current contributes to the repolarization of the cardiac action potential. It is the bestcharacterized member of the ether-a-go-go (Eag) family of channels. We have analyzed the genetic sequence of Hergl, and other Eag family channels to identify two probable ligand-binding sites, and therefore characterize these channels as orphan receptors. The overall purpose of this proposal is to identify intracellular regulators for Hergl and other Eag family channels, and to characterize how these regulators modulate channel gating. Regulators will be identified with a high throughput chemical library screen of cellular metabolites, and inside-out patch clamp. Using molecular biology, protein biochemistry, and electrophysiology, I will determine how gating properties are affected by channel modulation and I will locate the site where the regulator binds the channel. The experiments in this proposal will contribute to our understanding of the role of these channels in physiology and pathology. Another benefit of these experiments is uncovering pathways involved in the central nervous system, such as learning and memory, or processes that underlie disease such as cardiac arrhythmia and cancer. Ultimately, this receptor site may be a potential drug target to ameliorate a number of diseases, including long QT syndrome. The goal of this study is to identify regulators for a family of proteins known as ether-a-go-go (Eag) channels, which are expressed throughout the brain and the heart. Mutations in the genes encoding these channels result in cardiac arrhythmias and death. Using a library screen of intracellular metabolites, I will identify intracellular regulators for these channels and determine how they affect these channels.