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

2016 ◽  
Vol 130 (9) ◽  
pp. 643-650 ◽  
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).

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

2017 ◽  
Vol 95 (11) ◽  
pp. 1313-1318 ◽  
Author(s):  
Ursula Ravens
Keyword(s):  
Atrial Fibrillation ◽  
Drug Targets ◽  
Antiarrhythmic Drugs ◽  
Drug Effects ◽  
K Channel ◽  
Channel Blockers ◽  
Electrophysiological Properties ◽  
Cardiac Functions ◽  
K2p Channels ◽  
Pore Domain

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.

Tandem Pore Domain Potassium Channels

2019 ◽  
Author(s):  
Douglas A. Bayliss
Keyword(s):  
Single Channel ◽  
Resting Membrane Potential ◽  
K2p Channel ◽  
Physiological Processes ◽  
System A ◽  
Wide Range ◽  
K2p Channels ◽  
To Come ◽  
A Site ◽  
Pore Domain

The KCNK gene family encodes two-pore-domain potassium (K2P) channels, which generate the background (“leak”) K+ currents that establish a negative resting membrane potential in cells of the nervous system. A pseudotetrameric K+-selective pore is formed by pairing channel subunits, each with two pore-domains, in homo- or heterodimeric conformations. Unique features apparent from high-resolution K2P channel structures include a domain-swapped extracellular cap domain, a lateral hydrophobic-lined fenestration connecting the lipid bilayer to the channel vestibule, and an antiparallel proximal C-terminal region that links the paired subunits and provides a site for polymodal channel modulation. Individual channels transition between open and closed states, with the channel gate located at the selectivity filter. In general, K2P channels display relatively modest voltage- and time-dependent gating, together with distinct single-channel rectification properties, that conspire to yield characteristic weakly rectifying macroscopic currents over a broad range of membrane potentials (i.e., background K+ currents). Of particular note, K2P channel activity can be regulated by a wide range of physicochemical factors, neuromodulators, and clinically useful drugs; a distinct repertoire of activators and inhibitors for different K2P channel subtypes endows each with unique modulatory potential. Thus, by mediating background currents and serving as targets for multiple modulators, K2P channels are able to dynamically regulate key determinants of cell-intrinsic electroresponsive properties. The roles of specific K2P channels in various physiological processes and pathological conditions are now beginning to come into focus, and this may portend utility for these channels as potential therapeutic targets.

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

2018 ◽  
Vol 19 (8) ◽  
pp. 2437 ◽  
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.

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

2021 ◽  
Vol 61 (1) ◽  
pp. 401-420 ◽  
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.

scholarly journals Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2914
Author(s):  
Felix Wiedmann ◽  
Norbert Frey ◽  
Constanze Schmidt
Keyword(s):  
Action Potential ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Cell Types ◽  
Resting Membrane Potential ◽  
K2p Channel ◽  
K2p Channels ◽  
Pore Domain

Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

TASK, TREK & Co.: a mutable potassium channel family for diverse tasks in the brain

e-Neuroforum ◽  
2015 ◽  
Vol 21 (2) ◽  
Author(s):  
P. Ehling ◽  
Stefan Bittner ◽  
Sven G. Meuth ◽  
Thomas Budde
Keyword(s):  
Neurological Diseases ◽  
Outward Current ◽  
Resting Membrane Potential ◽  
K2p Channel ◽  
Membrane Pores ◽  
Open Questions ◽  
K2p Channels ◽  
In The Beginning ◽  
Pore Domain ◽  
The Brain

AbstractDiscovered during the 1990s and in the beginning regarded as passive membrane pores, the family of two-pore domain potassium (K2P)-channels initially received only little attention. Today the view on this channel family comprising 15 ubiquitously expressed members in mammals has greatly changed. K2P-channels carry potassium outward current that counterbalances membrane depolarization and stabilizes the resting membrane potential. Thereby they are important regulators for the excitability and the firing behaviour especially in neurons. The long list of modulating mechanisms underlines the channels’ relevance. K2P-channels in the thalamus contribute to the regulation of the sleep-wake cycle. They also mediate the effect of volatile anaesthetics by supporting the thalamic activity mode that is also typical for sleep. This review summarizes our knowledge about K2P-channel physiology in the brain, provides an idea of the role of these channels in neurological diseases and lists open questions as well as technical challenges in K2P-channel research.

Mechanosensitive TREK-1 two-pore-domain potassium (K2P) channels in the cardiovascular system

2020 ◽  
Author(s):  
Felix Wiedmann ◽  
Susanne Rinné ◽  
Birgit Donner ◽  
Niels Decher ◽  
Hugo A. Katus ◽  
...  
Keyword(s):  
Cardiovascular System ◽  
K2p Channels ◽  
Pore Domain

Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1

2018 ◽  
Vol 113 (4) ◽  
Author(s):  
Felix Wiedmann ◽  
Jan S. Schulte ◽  
Bruna Gomes ◽  
Maria-Patapia Zafeiriou ◽  
Antonius Ratte ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Disease Models ◽  
K2p Channels ◽  
Pore Domain

scholarly journals Physical basis for distinct basal and mechanically-gated activity of the human K+ channel TRAAK

2021 ◽  
Author(s):  
Robert A Rietmeijer ◽  
Em Sorum ◽  
Baobin Li ◽  
Stephen G. Brohawn
Keyword(s):  
Ion Channel ◽  
Short Duration ◽  
Neurodevelopmental Disorder ◽  
K Channel ◽  
Nodes Of Ranvier ◽  
Long Duration ◽  
Structural Differences ◽  
Pore Domain ◽  
Surrounding Membrane ◽  
High Conductance

TRAAK is a mechanosensitive two-pore domain K+ (K2P) channel localized to nodes of Ranvier in myelinated neurons. TRAAK deletion in mice results in mechanical and thermal allodynia and gain-of-function mutations cause the human neurodevelopmental disorder FHEIG. TRAAK displays basal and stimulus-gated activities typical of K2Ps, but the mechanistic and structural differences between these modes are unknown. Here, we demonstrate that basal and mechanically-gated openings are distinguished by their conductance, kinetics, and structure. Basal openings are low conductance, short duration, and occur through a channel with an interior cavity exposed to the surrounding membrane. Mechanically-gated openings are high conductance, long duration, and occur through a channel that is sealed to the surrounding membrane. Our results explain how dual modes of activity are produced by a single ion channel and provide a basis for the development of state-selective pharmacology with the potential to treat disease.

Ion Channel Remodelling in Atrial Fibrillation

2011 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Niels Voigt ◽  
Dobromir Dobrev ◽  
◽  
Keyword(s):  
Atrial Fibrillation ◽  
Ion Channel ◽  
Antiarrhythmic Drugs ◽  
Current Knowledge ◽  
Bleeding Complications ◽  
Large Size ◽  
Cardiovascular Morbidity And Mortality ◽  
Number Of Patients ◽  
Life Threatening ◽  
Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

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