K4.3 Expression Modulates Na1.5 Sodium Current.

In cardiomyocytes, the voltage-gated transient outward potassium current (I) is responsible for the phase-1 repolarization of the action potential (AP). Gain-of-function mutations in , the gene encoding the I carrying K4.3 channel, have been associated with Brugada syndrome (BrS). While the role of I in the pro-arrhythmic mechanism of BrS has been debated, recent studies have suggested that an increased I may directly affect cardiac conduction. However, the effects of an increased I on AP upstroke velocity or sodium current at the cellular level remain unknown. We here investigated the consequences of K4.3 overexpression on Na1.5 current and consequent sodium channel availability. We found that overexpression of K4.3 protein in HEK293 cells stably expressing Na1.5 (HEK293-Na1.5 cells) significantly reduced Na1.5 current density without affecting its kinetic properties. In addition, K4.3 overexpression decreased AP upstroke velocity in HEK293-Na1.5 cells, as measured with the alternating voltage/current clamp technique. These effects of K4.3 could not be explained by alterations in total Na1.5 protein expression. Using computer simulations employing a multicellular model, we furthermore demonstrate that the experimentally observed increase in K4.3 current and concurrent decrease in Na1.5 current may result in a loss of conduction, underlining the potential functional relevance of our findings. This study gives the first proof of concept that K4.3 directly impacts on Na1.5 current. Future studies employing appropriate disease models should explore the potential electrophysiological implications in (patho)physiological conditions, including BrS associated with gain-of-function mutations.