A Deafness Associated Protein TMEM43 Interacts with KCNK3 (TASK-1) Two-pore Domain K+ (K2P) Channel in the Cochlea

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.

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The two-pore domain K2P channel TASK2 drives human NK-cell proliferation and cytolytic function

European Journal of Immunology ◽

10.1002/eji.201445208 ◽

2015 ◽

Vol 45 (9) ◽

pp. 2602-2614 ◽

Cited By ~ 7

Author(s):

Andreas Schulte-Mecklenbeck ◽

Stefan Bittner ◽

Petra Ehling ◽

Frank Döring ◽

Erhard Wischmeyer ◽

...

Keyword(s):

Cell Proliferation ◽

Nk Cell ◽

K2p Channel ◽

Cytolytic Function ◽

Pore Domain

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GI-530159, a novel, selective, mechanosensitive two-pore-domain potassium (K2P ) channel opener, reduces rat dorsal root ganglion neuron excitability

British Journal of Pharmacology ◽

10.1111/bph.14098 ◽

2017 ◽

Vol 175 (12) ◽

pp. 2272-2283 ◽

Cited By ~ 25

Author(s):

Alexandre J C Loucif ◽

Pierre-Philippe Saintot ◽

Jia Liu ◽

Brett M Antonio ◽

Shannon G Zellmer ◽

...

Keyword(s):

Dorsal Root Ganglion ◽

Dorsal Root Ganglion Neuron ◽

Dorsal Root ◽

Ganglion Neuron ◽

K2p Channel ◽

Channel Opener ◽

Neuron Excitability ◽

Pore Domain

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

Cells ◽

10.3390/cells10112914 ◽

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.

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Regulation And Function Of The Two-Pore-Domain Potassium (K2P) Channel Trek-1 In Acute Lung Injury

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a4235 ◽

2011 ◽

Author(s):

Andreas Schwingshackl ◽

Bin Teng ◽

Patrudu S. Makena ◽

Vijay K. Gorantla ◽

Alina N. West ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

K2p Channel ◽

And Function ◽

Pore Domain

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

e-Neuroforum ◽

10.1515/s13295-015-0007-x ◽

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.

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Faculty Opinions recommendation of Tandem pore domain halothane-inhibited K+ channel subunits THIK1 and THIK2 assemble and form active channels.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718541814.793500211 ◽

2014 ◽

Author(s):

Douglas Bayliss

Keyword(s):

K Channel ◽

Active Channels ◽

Pore Domain

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A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555220976126 ◽

2020 ◽

pp. 247255522097612

Author(s):

David McCoull ◽

Emma Ococks ◽

Jonathan M. Large ◽

David C. Tickle ◽

Alistair Mathie ◽

...

Keyword(s):

Mammalian Cells ◽

Point Of View ◽

Resting Membrane Potential ◽

Small Molecule Activation ◽

Target Class ◽

Index Set ◽

Diverse Range ◽

K2p Channels ◽

Additional Approach ◽

Pore Domain

Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a “target class” approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration–response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

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