DISTRIBUTION AND STRUCTURE OF HERG POTASSIUM CHANNELS

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HERG has been identified as the locus of one form of long QT syndrome, LQT2, which can result in cardiac arrhythmias often leading to sudden death. Heterologous expression of HERG results in potassium currents very similar (but not identical) to the endogenous potassium current IKr which contributes to repolarization in the human heart. The goal of this research proposal is to determine the expression levels of HERG in the human heart and to determine if HERG is associated with other potassium channels subunits in human ventricular and atrial myocytes. The specific aims are as follows: 1) to determine the relative expression levels of HERG mRNA and protein human ventricles and atria using RNase protection and Western blot analyses; 2) to immunoprecipitate HERG from human atrial and ventricular membrane preparations and to identify any coassembling proteins using immunoblots; and 3) to express ventricular cardiac myocytes from characterization for the resultant potassium currents and comparison to human ventricular and atrial IKr. Determination of the molecular composition of functional human atrial and ventricular IKr will enable the production of stable cell lines expressing these IKr channels. These will be useful for detailed studies of channel biophysics, biosynthesis, assembly and post translational processing and, importantly, for testing therapeutic agents targeted against IKr channels.