The Role of SUMO Modification in the Regulation of Kv1.5, a Major Cardiovascular Potassium Channel.

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States. A major limitation to current antiarrhythmic medications used to treat AF is the occurrence of potentially life-threatening, proarrhythmic, ventricular side effects. The voltage-gated potassium channel Kv1.5 represents a promising target for the development of new ventricular-sparing, AF medications. Kv1.5 mediates the repolarizing current during phase-two of the action potential in human atrial myocytes, but is not expressed in human ventricular myocytes. Inhibition of Kv1.5 may thus serve to selectively prolong the atrial action potential and refractoriness to disorganized electrical activity without affecting ventricular activity. The overall goal of my dissertation was to explore mechanisms that regulate the function of Kv1.5 and that may provide novel therapeutic opportunities for AF. As a result of these efforts, we have found that Kv1.5 is post-translationally regulated by members of the Small Ubiquitin-like Modifier (SUMO) family of proteins, and that these modifications affect the activity of the channel. Using heterologous cell types, as well as primary mouse and human cardiomyocytes, we have found that either disrupting or promoting SUMOylation can have significant effects on the inactivation properties of Kv1.5-mediated currents. Furthermore, we have found that disruption of SUMOylation in mouse cardiomyocytes leads to the inhibition of Kv1.5-mediated currents and a significant prolongation of phase-two of the action potential. Remarkably, SUMOylation had no effect on the passive electrical properties or on the other major outward potassium currents in these cells. These studies identify SUMOylation as a novel form of post-translational regulation of Kv1.5 and indicate that pharmacological intervention into this mechanism may open new opportunities for atrial-specific antiarrhythmic therapy. Furthermore, these findings represent, to our knowledge, the first report of the SUMO modification of a voltage-gated ion channel and one of the first examples of the SUMOylation of a protein at the plasma membrane. As such, these studies expand the list of known functions of SUMOylation and reveal that, in addition to its more established role in the regulation of nuclear proteins, this modification plays important roles at the plasma membrane.