TARGETING OF THE CARDIAC VOLTAGE-GATED SODIUM CHANNEL 1.5

Dissertation under the direction of Professor Peter J. Mohler The focus of this project is determining if an ankyrin-G-based pathway controls the membrane expression of the voltage-gated sodium channel 1.5 (Nav1.5) in cardiomyocytes. Disruption of the normal localization of Nav1.5 can lead to a fatal cardiac arrhythmia termed Brugada Syndrome and has been linked to myopathic cardiac disease. This project defines that an ankyrin-G-based pathway controls the expression, localization, and function of Nav1.5 at the cardiomyocyte plasma membrane. These studies were accomplished by developing a primary cell culture system where ankyrin-G could be reduced and selectively restored to define if Nav1.5 targeting was truly dependent on a direct interaction with an ankyrin-G-based mechanism. Moreover, these studies have identified the residues on ankyrin-G necessary for the interaction of Nav1.5 and ankyrin-G. Together, these findings provide critical clues in understanding the molecular mechanism of Nav1.5 targeting in the cardiomyocyte and have developed exciting new tools for studying the targeting pathway. To my lovely wife Cheryl for her incredible support and counsel in both bad and good times, and our beloved family for their motivation iii ACKNOWLEDGEMENTS This work would not have been possible without the financial