Inverse remodelling of K<sub>2P</sub>3.1 K<sup>+</sup>channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy

Schmidt, Constanze; Wiedmann, Felix; Zhou, Xiaobo; Heijman, Jordi; Voigt, Niels; Ratte, Antonius; Lang, Siegfried; Kallenberger, Stefan M.; Campana, Chiara; Weymann, Alexander; Simone, Raffaele De; Szabo, Gábor; Ruhparwar, Arjang; Kallenbach, Klaus; Kretzler, Matthias; Ehrlich, Joachim R.; Baczkó, István; Borggrefe, Martin; Ravens, Ursula; Dobrev, Dobromir; Katus, Hugo A.; Thomas, Dierk

doi:10.1093/eurheartj/ehw559

Cited by 78 publications

(79 citation statements)

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“…Inhibition of TASK-1 by specific inhibitors has been described to prolong atrial APD and ERP before (Wirth et al, 2003;Wirth et al, 2007;Decher et al, 2011;Donner et al, 2011;Skarsfeldt et al, 2016). Furthermore, the nearly atrial specific expression of TASK-1 could, at least in part, explain the differential behavior of ranolazine between atrial and ventricular tissue (Limberg et al, 2011;Schmidt et al, 2015;Schmidt et al, 2017). The IC 50 of TASK-1 inhibition by ranolazine is determined at 30.64 µM in mammalian cells which is slightly beyond therapeutic free plasma levels of 2-13.35 µM (Jerling 2006;Undrovinas et al, 2006;EMA 2009;Antzelevitch et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Because of enhanced TASK-1 currents under the condition of AF, the effect is even more pronounced and thus similar to the results obtained from large animal models. APD prolongation via TASK-1 blockade is expected to suppress AF and the 'atrial selectivity' of TASK-1 blockade by limiting the mode of action to atrial tissue, thereby reducing the risk of pro-arrhythmogenic effects in the ventricles, highlights the potential clinical significance of TASK-1 blockade for the treatment of AF in patients (Schmidt et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

et al. 2019

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Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and one of the major causes of cardiovascular morbidity and mortality. Despite good progress within the past years, safe and effective treatment of AF remains an unmet clinical need. The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties via mainly late I Na and I Kr blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. Furthermore, ranolazine has been shown to be effective in the treatment of AF. TASK-1 is a two-pore domain potassium (K 2P) channel that shows nearly atrial specific expression within the human heart and has been found to be upregulated in AF, resulting in shortening the atrial APD in patients suffering from AF. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine. Methods: We used Xenopus laevis oocytes and CHO-cells as heterologous expression systems for the study of TASK-1 inhibition by ranolazine and molecular drug docking simulations to investigate the ranolazine binding site and binding characteristics. Results: Ranolazine acts as an inhibitor of TASK-1 potassium channels that inhibits TASK-1 currents with an IC 50 of 30.6 ± 3.7 µM in mammalian cells and 198.4 ± 1.1 µM in X. laevis oocytes. TASK-1 inhibition by ranolazine is not frequency dependent but shows voltage dependency with a higher inhibitory potency at more depolarized membrane potentials. Ranolazine binds within the central cavity of the TASK-1 inner pore, at the bottom of the selectivity filter. Conclusions: In this study, we show that ranolazine inhibits TASK-1 channels. We suggest that inhibition of TASK-1 may contribute to the observed antiarrhythmic effects of Ranolazine. This puts forward ranolazine as a prototype drug for the treatment of atrial arrhythmia because of its combined efficacy on atrial electrophysiology and lower risk for ventricular side effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

et al. 2019

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“…The mechanosensitive isoform K 2P 2.1 is downregulated, whereas the K 2P 10.1 isoform is upregulated in AF, which might contribute to APD changes in patients with concomitant heart failure (Schmidt et al, 2017a). In addition, K 2P 3.1 is upregulated in patients with severe systolic dysfunction and chronic AF but not in patients in sinus rhythm (Schmidt et al, 2017b). However, further investigation is needed to confirm a significant role of mechanosensitive K 2P channels in human atrial physiology and AF pathophysiology.…”

Section: A Atrial Selective Ion Channel Blockersmentioning

confidence: 97%

Mechanisms and Drug Development in Atrial Fibrillation

2018

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Atrial fibrillation is a highly prevalent cardiac arrhythmia and the most important cause of embolic stroke. Although genetic studies have identified an increasing assembly of AF-related genes, the impact of these genetic discoveries is yet to be realized. In addition, despite more than a century of research and speculation, the molecular and cellular mechanisms underlying AF have not been established, and therapy for AF, particularly persistent AF, remains suboptimal. Current antiarrhythmic drugs are associated with a significant rate of adverse events, particularly proarrhythmia, which may explain why many highly symptomatic AF patients are not receiving any rhythm control therapy. This review focuses on recent advances in AF research, including its epidemiology, genetics, and pathophysiological mechanisms. We then discuss the status of antiarrhythmic drug therapy for AF today, reviewing molecular mechanisms, and the possible clinical use of some of the new atrial-selective antifibrillatory agents, as well as drugs that target atrial remodeling, inflammation and fibrosis, which are being tested as upstream therapies to prevent AF perpetuation. Altogether, the objective is to highlight the magnitude and endemic dimension of AF, which requires a significant effort to develop new and effective antiarrhythmic drugs, but also improve AF prevention and treatment of risk factors that are associated with AF complications.

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“…K2P channels have been shown to participate in and modulate various important physiological processes, such as pain perception (Alloui et al, 2006) and cardiac activity (Decher et al, 2017;Schmidt et al, 2012;Schmidt et al, 2017). The human K2P2.1 (TREK-1, KCNK2) channel is expressed at high levels in excitable tissues, such as the nervous system (Fink et al, 1996), heart (Aimond et al, 2000), and smooth muscle (Koh et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A regulatory domain in the K_2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes

Arazi

Blecher

Zilberberg

2020

Preprint

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AbstractPotassium K2P (‘leak’) channels conduct current across the entire physiological voltage range and carry leak or ‘background’ currents that are, in part, time- and voltage-independent. K2P2.1 channels (i.e., TREK-1, KCNK2) are highly expressed in excitable tissues, where they play a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report for the first time that human K2P2.1 channel activity is regulated by monoterpenes (MTs). We found that cyclic, aromatic monoterpenes containing a phenol moiety, such as carvacrol, thymol and 4-IPP had the most profound effect on current flowing through the channel (up to a 6-fold increase). By performing sequential truncation of the carboxyl-terminal domain of the channel and testing the activity of several channel regulators, we identified two distinct regulatory domains within this portion of the protein. One domain, as previously reported, was needed for regulation by arachidonic acid, anionic phospholipids and temperature changes. Within a second domain, a triple arginine residue motif (R344-346), an apparent PIP2-binding site, was found to be essential for regulation by holding potential changes and important for regulation by monoterpenes.

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Inverse remodelling of K_2P3.1 K⁺channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy

Abstract: LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Cited by 78 publications

References 12 publications

Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

Mechanisms and Drug Development in Atrial Fibrillation

A regulatory domain in the K_2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes

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Inverse remodelling of K2P3.1 K+channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy

Abstract: LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Cited by 78 publications

References 12 publications

Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

Mechanisms and Drug Development in Atrial Fibrillation

A regulatory domain in the K2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes

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Inverse remodelling of K_2P3.1 K⁺channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy

A regulatory domain in the K_2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes