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.
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