# Role of TREK-1 in modulating cardiac excitability and arrhythmia

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $418,139

## Abstract

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
my...

## Key facts

- **NIH application ID:** 10783003
- **Project number:** 5R01HL156652-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Thomas Jeffrey Hund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,139
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783003

## Citation

> US National Institutes of Health, RePORTER application 10783003, Role of TREK-1 in modulating cardiac excitability and arrhythmia (5R01HL156652-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10783003. Licensed CC0.

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