Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

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Comparison of the Effects of Na+ and K+ Channel Blockers on the Electrophysiological Properties of the Pulmonary Veins in Patients with Atrial Fibrillation

Journal of Arrhythmia ◽

10.1016/s1880-4276(10)80025-0 ◽

2010 ◽

Vol 26 (4) ◽

pp. 259-266 ◽

Cited By ~ 4

Author(s):

Tomoo Yasuda ◽

Koichiro Kumagai ◽

Masahiro Ogawa ◽

Hideko Nakashima ◽

Bo Zhang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Pulmonary Veins ◽

K Channel ◽

Channel Blockers ◽

Electrophysiological Properties

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The Insensitivity of TASK-3 K2P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure

International Journal of Molecular Sciences ◽

10.3390/ijms19082437 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2437 ◽

Cited By ~ 4

Author(s):

Guierdy Concha ◽

Daniel Bustos ◽

Rafael Zúñiga ◽

Marcelo Catalán ◽

Leandro Zúñiga

Keyword(s):

Functional Role ◽

Simulation Analysis ◽

K Channel ◽

Channel Blockers ◽

Tyrosine Residue ◽

K Channels ◽

Enhanced Sensitivity ◽

K2p Channels ◽

Pore Domain

Two-pore domain K+ channels (K2P) display a characteristic extracellular cap structure formed by two M1-P1 linkers, the functional role of which is poorly understood. It has been proposed that the presence of the cap explains the insensitivity of K2P channels to several K+ channel blockers including tetraethylammonium (TEA). We have explored this hypothesis using mutagenesis and functional analysis, followed by molecular simulations. Our results show that the deletion of the cap structure of TASK-3 (TWIK-related acid-sensitive K+ channel) generates a TEA-sensitive channel with an IC50 of 11.8 ± 0.4 mM. The enhanced sensitivity to TEA displayed by the cap-less channel is also explained by the presence of an extra tyrosine residue at position 99. These results were corroborated by molecular simulation analysis, which shows an increased stability in the binding of TEA to the cap-less channel when a ring of four tyrosine is present at the external entrance of the permeation pathway. Consistently, Y99A or Y205A single-residue mutants generated in a cap-less channel backbone resulted in TASK-3 channels with low affinity to external TEA.

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Therapeutic targeting of two-pore-domain potassium (K2P) channels in the cardiovascular system

Clinical Science ◽

10.1042/cs20150533 ◽

2016 ◽

Vol 130 (9) ◽

pp. 643-650 ◽

Cited By ~ 28

Author(s):

Felix Wiedmann ◽

Constanze Schmidt ◽

Patrick Lugenbiel ◽

Ingo Staudacher ◽

Ann-Kathrin Rahm ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ion Channel ◽

Cardiovascular System ◽

Key Words ◽

K Channel ◽

Therapeutic Targeting ◽

K2p Channel ◽

K2p Channels ◽

Pore Domain

Key words: anti-arrhythmic therapy, arrhythmia, atrial fibrillation, ion channel, K2P channel, TWIK-related acid-sensitive K+ channel 1 (TASK-1).

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Complexity of the outward K+ current of the rat megakaryocyte

AJP Cell Physiology ◽

10.1152/ajpcell.1997.272.5.c1525 ◽

1997 ◽

Vol 272 (5) ◽

pp. C1525-C1531 ◽

Cited By ~ 5

Author(s):

E. Romero ◽

R. Sullivan

Keyword(s):

K Channel ◽

Delayed Rectifier ◽

Channel Blockers ◽

Excitable Cells ◽

Electrophysiological Properties ◽

Relative Contribution ◽

Delayed Rectifier Current ◽

Dependent Inactivation ◽

Voltage Dependent ◽

K Current

Megakaryocytes isolated from rat bone marrow express a voltage-dependent, outward K+ current with complex kinetics of activation and inactivation. We found that this current could be separated into at least two components based on differential responses to K+ channel blockers. One component, which exhibited features of the "transient" or "A-type" K+ current of excitable cells, was more strongly blocked by 4-aminopyridine (4-AP) than by tetrabutylammonium (TBA). This current, which we designated as "4-AP-sensitive" current, activated rapidly at potentials more positive than -40 mV and subsequently underwent rapid voltage-dependent inactivation. A separate current that activated slowly was blocked much more effectively by TBA than by 4-AP. This "TBA-sensitive" component, which resembled a typical delayed rectifier current, was much more resistant to voltage-dependent inactivation. The relative contribution of each of these components varied from cell to cell. The effect of charybdotoxin was similar to that of 4-AP. Our data indicate that the voltage-dependent K+ current of resting megakaryocytes is more complex than heretofore believed and support the emerging concept that megakaryocytes possess intricate electrophysiological properties.

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In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

International Journal of Molecular Sciences ◽

10.3390/ijms22031265 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1265

Author(s):

Jieyun Bai ◽

Yijie Zhu ◽

Andy Lo ◽

Meng Gao ◽

Yaosheng Lu ◽

...

Keyword(s):

Atrial Fibrillation ◽

Antiarrhythmic Drugs ◽

Drug Effects ◽

Ionic Currents ◽

Tissue Level ◽

Drug Binding ◽

Class I ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Upstroke Velocity

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

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Effect of Na and K channel blockers on the spatial and temporal dispersions of atrial refractoriness during atrial fibrillation.

Japanese Journal of Electrocardiology ◽

10.5105/jse.18.433 ◽

1998 ◽

Vol 18 (4) ◽

pp. 433-442 ◽

Cited By ~ 2

Author(s):

Kaori Shinagawa ◽

Hideo Mitamura ◽

Toshiaki Sato ◽

Hideaki Kanki ◽

Seiji Takatsuki ◽

...

Keyword(s):

Atrial Fibrillation ◽

K Channel ◽

Channel Blockers ◽

Atrial Refractoriness

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Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-030920-111536 ◽

2021 ◽

Vol 61 (1) ◽

pp. 401-420 ◽

Cited By ~ 2

Author(s):

Alistair Mathie ◽

Emma L. Veale ◽

Kevin P. Cunningham ◽

Robyn G. Holden ◽

Paul D. Wright

Keyword(s):

Small Molecule ◽

Drug Targets ◽

Cell Activity ◽

Therapeutic Benefit ◽

Resting Membrane Potential ◽

Screening Programs ◽

K2p Channel ◽

K2p Channels ◽

Pharmacological Regulation ◽

Pore Domain

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

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Modeling of the Pore Domain of the GLUR1 Channel: Homology with K+ Channel and Binding of Channel Blockers

Biophysical Journal ◽

10.1016/s0006-3495(02)75538-0 ◽

2002 ◽

Vol 82 (4) ◽

pp. 1884-1893 ◽

Cited By ~ 36

Author(s):

Denis B. Tikhonov ◽

Jan R. Mellor ◽

Peter N.R. Usherwood ◽

Lev G. Magazanik

Keyword(s):

K Channel ◽

Channel Blockers ◽

Pore Domain

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Molecular Pharmacology of K2P Potassium Channels

Cellular Physiology and Biochemistry ◽

10.33594/000000339 ◽

2021 ◽

Vol 55 (S3) ◽

pp. 87-107

Keyword(s):

Potassium Channels ◽

Binding Sites ◽

Drug Targets ◽

Therapeutic Potential ◽

Drug Binding ◽

Channel Blockers ◽

Molecular Pharmacology ◽

K2p Channel ◽

Channel Inhibition ◽

K2p Channels

Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K2P channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K2P channel blockers and activators.

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