verbatim): Mutations in the human ether-a-go-go related gene (HERG) are linked to acquired and inherited forms of the long QT syndrome (LQTS), which can provoke the life-threatening arrythmia, Torsades de Pointes. Acquired LQTS is induced by a variety of drugs, many of which block HERG, underscoring the importance of this voltage-gated K+ channel in the maintenance of normal cardiac rhythm. Accessory proteins (beta subunits) are known to modify the current and drug sensitivity of various voltage-gated K+ channels, including HERG. We will study HERG function and accessory protein interactions in vivo using the model organism, C. elegans. An orthologue of HERG, unc-103, has been identified in C. elegans. We will test the hypothesis that unc-103 possesses biophysical and pharmacologic features characteristic of HERG, and that C. elegans can be used as a model organism for identifying and isolating HERG-interacting proteins. To accomplish this goal we will: 1. Determine if HERG and UNC-l03 have analogous function, using complemenatary approaches of a) electrophysiological characterization of unc-103 biophysics and drug sensitivity, in a heterologous expression system and b) in vivo pharmacologic characterization of worms that carry an unc-103 gain-of-function (gf mutation. 2. Characterize candidate UNC-103-interacting proteins, using similar heterologous electrophysiologic and in vivo assays, and 3. Isolate novel UNC-103 interacting proteins using a genetic mutagenesis screen in the C. elegans unc-103 gf background. These studies will improve our understanding of HERG and HERG/accessory protein interactions, and will facilitate drug design and aid in the prevention of life-threatening arrythmias.
|Petersen, Christina I; McFarland, Toni R; Stepanovic, Svetlana Z et al. (2004) In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia. Proc Natl Acad Sci U S A 101:11773-8|