Investigation of cardiac ion channel modulation in mouse models

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Human KCNQ1 and HERG genes encode ¿-subunits of voltage-gated potassium-channels that mediate IKs and, respectively, IKr-. The currents are major determinants of ventricular action potential repolarization. Mutations in KCNQ1 and HERG are associated with an abnormally prolonged electrocardiographic QT interval, the long QT syndrome (LQTS). Physical and emotional stress often precipitates in LQTS patients life threatening episodes of ventricular tachycardias with a high risk of sudden death. The molecular basis of the trigger which connects mutant IKr or IKs channel expression to episodic occurrence of ventricular arrhythmia, is not clear. We hypothesize that a ventricular arrhythmia may eventually occur because mutant IKr or IKs channels do not properly respond to adrenergic signaling pathways in ventricular myocytes. Specifically, we plan to test this hypothesis in transgenic mouse lines that express LQT mutants which produce in heterologous expression systems functional channels, but are insensitive to adrenergic signaling pathways. Furthermore, we want to investigate the importance of multiprotein signaling complexes for spatiotemporal regulation of cardiac IKs and/or IKr channel activity. The results are expected to further our understanding of dynamic regulation of IKs and/or IKr channel activity by adrenergic signaling pathways and its pathophysiological consequences.