Involvement of TWIK-related K+ channel in cardiac disease and arrhythmia

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Project Summary Heart failure (HF) is a leading cause of death in the United States and is growing in prevalence. HF patients are at higher risk for sudden cardiac death from ventricular arrhythmias, and despite major strides in understanding the pathology of HF, current arrhythmia treatments are limited by efficacy, cost, and risk of procedural complications. Although the field has identified a host of electrophysiological and structural changes in HF, the precise link between chronic stress and arrhythmia remains to be defined. Recent studies have identified a novel role for the two-pore domain background K channel TREK1 in regulating arrhythmia susceptibility and excitability. Previous work from our lab has found that the actin- associated cytoskeletal protein βIV-spectrin orchestrates TREK1 membrane localization. However, how spectrin modulates TREK1 function, and how disruption of a TREK1/spectrin complex contributes to disease, is still largely unknown. Preliminary data from our lab suggests that in the absence of interaction with spectrin, TREK1 current-voltage relationships and reversal potentials are shifted. This suggests a change in ion permeability, which would be consistent with studies in patients and rat models that have shown that TREK1 may become permeable to Na as a result of mutations or alternative translation initiation. Based on these preliminary studies, the central hypothesis of my proposal is that loss of βIV-spectrin in response to chronic stress promotes aberrant TREK1 activity leading to altered myocyte ion homeostasis and increased arrhythmia susceptibility. I will employ a combination of optical mapping, electrophysiology, and molecular biology techniques to determine the role of the TREK1/spectrin complex in the regulation of cardiac excitability. Additionally, I will evaluate cardiac electrophysiology, Ca and Na handling, and protein co- localization of hearts subjected to pressure overload to assess whether dysregulation of TREK1 during chronic stress promotes aberrant ion homeostasis and electrical remodeling that is pro-arrhythmic. Finally, pharmacological and gene-based interventions aimed at preserving normal TREK1 activity will be evaluated for their ability to preserve cardiac electrical function in vivo during chronic stress. Overall, this study has the potential to suggest novel therapeutic approaches for preventing proarrhythmic triggers in HF patients, ultimately advancing the NIH’s mission “to enhance health, lengthen life, and reduce illness and disability.”