The Role of Sulfenic Acid Modification in the Regulation of the Cardiovascular Voltage-Gated Potassium Channel, Kv1.5.

Abstract

Atrial fibrillation, the most common cardiac arrhythmia in the United States, is a significant cause of morbidity and mortality. Environmental exposures such as cigarette smoking, as well as pre-existing cardiovascular disease, increase the risk of atrial fibrillation. This condition is strongly associated with oxidative stress, and with reduced expression of the voltage-dependent potassium (Kv) channel, Kv1.5. Kv1.5 underlies IKur, the major repolarizing current in the human atrium. Numerous studies suggest that this channel is redox-sensitive; however, a molecular link between oxidative stress and altered Kv1.5 expression/activity has not been established. Formation of sulfenic acid on cysteine sulfhydryl groups of proteins is a principal mechanism linking oxidative stress to altered protein function. We hypothesized that reversible, redox-sensitive modification via sulfenic acid on intracellular cysteine sulfhydryl groups of Kv1.5 modulates channel function and expression during oxidative stress. Using a novel chemical probe, we discovered that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine, in a redox-sensitive manner. Additionally, we found that sulfenic acid decreases Kv1.5 cell surface expression and channel current during acute oxidative stress. Importantly, we observed a similar increase in sulfenic acid modification to the channel, and a decrease in surface density, after treatment with cigarette smoke extract, an environmentally important and socially relevant source of oxidative stress. Consistent with these results, oxidative stress significantly reduced IKur current in dissociated cardiac myocytes. Furthermore, sulfenic acid modification impaired recycling of internalized Kv1.5 back to the cell surface, and promoted channel degradation during chronic oxidative stress. We propose that sulfenic acid modification is a fate switch, leading to altered myocyte excitability in response to oxidative stress, and triggering protein degradation in the face of chronic insult.