Project Summary/Abstract Cardiac electrical rhythm disturbances (arrhythmias) contribute to over 500,000 deaths each year in patients with cardiovascular disease (CVD). Despite considerable advances in defining the specific cell- and organ-level remodeling changes associated with CVD, the precise mechanisms driving increased susceptibility to arrhythmia remain to be defined. At the same time, existing anti-arrhythmic therapies are limited by efficacy, low patient tolerance, risk of procedural complications, and/or cost. In particular, the development of new anti- arrhythmic drugs has been hampered by high profile failed clinical trials involving compounds that target major cardiac ion channels, leading to a shift away from the pursuit of population wide, “blockbuster” therapies and towards more precise, patient-specific approaches. Essential for this effort will be the development of novel adjuvant therapies that tune cardiac excitability without introducing large scale perturbations in the cardiac action potential. Here, we explore the two-pore K+ channel TREK-1 as an ideal, although understudied, candidate for next generation “precision” therapeutics based on: 1) endogenous expression in cardiomyocytes across species, including mouse and human; 2) multiple regulatory modes for tuning of channel activity; and 3) recent emergence as a highly druggable target. Importantly, TREK-1 is sensitive to a wide range of environmental stimuli, including mechanical membrane deformation, β-adrenergic stimulation, polyunsaturated fatty acids, and intracellular pH. While defects in TREK-1 expression/function have been identified in inherited and acquired models of arrhythmia and in human patients, little is known about the mechanism linking neurohumoral/biomechanical stress stimuli to TREK-1 dysfunction, or the specific role for TREK-1 in modulating arrhythmia risk. This proposal is further motivated by mounting data that TREK-1 displays noncanonical activity beyond its primary function as a repolarizing K+ current. At the same time, our unexpected preliminary data indicate that TREK-1 ion selectivity depends on the integrity of the spectrin-based cytoskeleton in cardiac myocytes. Together, these findings provide a potential link between stress-induced changes in the cytoskeleton, TREK-1 dysfunction and downstream remodeling relevant to arrhythmia in the setting of CVD. Our long-term goal is to define new regulatory pathways underlying adverse remodeling and arrhythmia in the setting of CVD, and to identify novel anti-arrhythmia strategies in CVD patients. The central hypothesis of this proposal is that TREK-1 functions as a multimodal stress sensor in heart, as well as therapeutic “lever” that may be tuned to modulate cardiac excitability through association with the spectin-based cytoskeleton. Further, we expect that chronic biomechanical/neurohumoral stress induces noncanonical TREK-1 activity thereby promoting dysregulation of ion homeostasis in cardiac myocytes and increased risk for arrhythmia.

Existing therapies for cardiac electrical rhythm disturbances (arrhythmias) face important limitations, motivating the search for novel therapeutic targets to support a more personalized approach to preventing arrhythmias in human patients. Our interdisciplinary and comprehensive studies are motivated by unexpected preliminary data identifying the two pore K+ channel TREK-1 as an ideal, although understudied, candidate for next generation “precision” therapeutics. We expect this project will define the functional role of TREK-1 in cardiac pathophysiology and open new therapeutic avenues for tuning cardiac excitability and reducing arrhythmia susceptibility in human patients