Next Article in Journal
PLGA-Lipid Hybrid Nanoparticles for Overcoming Paclitaxel Tolerance in Anoikis-Resistant Lung Cancer Cells
Previous Article in Journal
Neuroprotective Effects of the Psychoactive Compound Biatractylolide (BD) in Alzheimer’s Disease
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets

Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, China
Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang 550002, China
Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510700, China
Authors to whom correspondence should be addressed.
Molecules 2022, 27(23), 8296;
Submission received: 10 October 2022 / Revised: 9 November 2022 / Accepted: 15 November 2022 / Published: 28 November 2022
(This article belongs to the Section Chemical Biology)


TWIK-related acid-sensitive K+ (TASK) channels, including TASK-1, TASK-3, and TASK-5, are important members of the two-pore domain potassium (K2P) channel family. TASK-5 is not functionally expressed in the recombinant system. TASK channels are very sensitive to changes in extracellular pH and are active during all membrane potential periods. They are similar to other K2P channels in that they can create and use background-leaked potassium currents to stabilize resting membrane conductance and repolarize the action potential of excitable cells. TASK channels are expressed in both the nervous system and peripheral tissues, including excitable and non-excitable cells, and are widely engaged in pathophysiological phenomena, such as respiratory stimulation, pulmonary hypertension, arrhythmia, aldosterone secretion, cancers, anesthesia, neurological disorders, glucose homeostasis, and visual sensitivity. Therefore, they are important targets for innovative drug development. In this review, we emphasized the recent advances in our understanding of the biophysical properties, gating profiles, and biological roles of TASK channels. Given the different localization ranges and biologically relevant functions of TASK-1 and TASK-3 channels, the development of compounds that selectively target TASK-1 and TASK-3 channels is also summarized based on data reported in the literature.

1. Introduction

Ion channels play essential roles in a variety of cellular functions and are involved in the pathophysiology of a wide range of diseases. Currently, mammalian potassium channels are the most numerous, broadly distributed, and complicated class of ion channels that have been identified. They are classified into three main categories based on the topology of the transmembrane regions: voltage-gated potassium (Kv) channels, inwardly rectifying potassium (Kir) channels, and two-pore domain potassium (K2P) channels [1,2,3]. Among them, the family containing Kv channels is the largest. It includes approximately 40 genes, which are divided into 12 subfamilies (Kv1–Kv12), and the channels mainly consist of six transmembrane fragments and a pore structural domain [4]. Furthermore, the calcium-activated potassium channels (KCa) have either seven or six transmembrane segments and can link K+ dynamics to intracellular calcium signaling [5]. Kir channels are defined as channels that permit the inward flow of K+ under hyperpolarization but permit little or no outward K+ flow under depolarization. They can be grouped into seven subfamilies (Kir1–7), and these channels have two transmembrane fragments and a pore structural domain [6]. K2P channels have a dimeric structure instead of a tetrameric structure, and each subunit consists of four transmembrane fragments and two pore domains. These subunits are organized into six subgroups based on their various architectures and functions [7]. K2P channels can be regulated by diverse chemical, physical, and metabolic factors, such as extra- or intra-cellular pH, temperature, mechanical stimuli, G proteins, and signaling lipids [8]. They play an important role in stabilizing resting membrane conductance and repolarizing the action potential of excitable cells [9].
The tandem of pore domains in a weakly inward rectifying K+ channel 1 (TWIK-1) was the first K2P channel to be discovered and identified [10], and TWIK-related acid-sensitive K+ channel 1 (TASK-1) was the first cloned mammalian potassium channel that was found to create the characteristic background potassium currents [11]. TASK channels comprise TASK-1 (K2P3.1 or KCNK3), TASK-3 (K2P9.1 or KCNK9), and TASK-5 (K2P15.1 or KCNK15), which are composed of 394, 374, and 330 amino acids, respectively, in humans [11,12,13] (Table 1). Among them, TASK-1 shares 58.9% amino acid sequence homology with TASK-3 and 51.4% homology with TASK-5, whereas TASK-3 shares 55.1% homology with TASK-5 [14,15,16], and TASK-5 was not found to be functionally expressed in the recombinant system [13]. TASK channels are important members of the K2P channel family and are widely involved in pathophysiological conditions. Therefore, an improved understanding of the biological mechanisms and functions of TASK channels will greatly assist in the future development of novel, potent, and selective target compounds.
In this review, we emphasize the recent advances in our understanding of the biophysical properties, gating profiles, and biological roles of TASK channels. Given the different localization ranges and biologically relevant functions of TASK-1 and TASK-3 channels, the development of compounds that selectively target either TASK-1 or TASK-3 channels is also summarized.

2. The Structure, Localization, and Electrophysiological Properties of TASK Channels

2.1. Structure

As the closest homologue, the crystal structure of the human TASK-1 (hTASK-1) channel has currently been resolved at a resolution of 3.0 Å using X-ray crystallography [101]. Similar to other members of the K2P family, TASK channels have two-fold symmetry, with each subunit containing four transmembrane α-helices (M1–M4), an inner pore region located between M1 and M2, an inner pore region located between M3 and M4, two pore helices (PH1 and PH2) suspended like cradles in their respective pores, and two selectivity filters (SF1 and SF2) shaped by four pore loops that interact with each other to determine the ionic selectivity of the channels [102] (Figure 1). The structures of TASK-1 channel are from protein data bank (PDB) and are generated by PyMOL 2.5.
The special structure of the extracellular caps (EC1 and EC2) formed by the conserved M1-P1 linkers is a structural hallmark of all K2P channels. These caps project externally and create two tunnel-like side gates in the membrane to allow for the bilateral exit of potassium ions [101,103]. The extracellular ion pathway (EIP) behind the selective filters also plays an important role in regulating the sensitivity of TASK channels to extracellular pH levels [104]. Most K2P family members have conserved cysteines at the top of the cap structure that form a covalent disulfide bond between the two subunits and stabilize the dimer structure. Along with the tandem-pore domain halothane-inhibited K+ channels (THIK), TASK channels do not have cysteines at these positions, and in this case, the dimer is mainly stabilized by interactions between the hydrophobic residues at the cap domains [101,105,106] (Figure 1A,C). The cap domains are partly responsible for the insensitivity of the TASK-3 channel to external tetraethylammonium [107]. In addition, the M2 transmembrane helix of TASK channels bends near the center of the membrane, producing two “lateral fenestrations” that connect the pore region to the plasma membrane [108,109].

2.2. Expression and Localization

The TASK-1 channel is abundantly expressed in the human central nervous system (CNS) and in peripheral tissues. In the human CNS, the highest expression levels of TASK-1 are in the cerebellum, thalamus, and pituitary gland, whereas the lowest expression level is in the corpus callosum. In human peripheral tissues, TASK-1 expression level is the highest in the pancreas, placenta, lungs and pulmonary arteries [17,18]. It is lower in the prostate, stomach, small intestine, and heart and lowest in the liver, spleen, skeletal muscles, and testes [17]. In rats and mice, the highest levels of TASK-1 mRNA in the CNS were observed in the cerebellum and somatic motoneurons, while the lowest levels were observed in the septum and striatum [16,110].
In humans, the TASK-3 channel is predominantly found in the CNS and is expressed in almost all regions of the brain, with the highest expression in the cerebellum and higher expression in the cerebral cortex, thalamus, nucleus accumbens, hippocampus, and hypothalamus. Its expression is lowest in the spinal cord, caudate nucleus, and corpus callosum. In addition, small amounts are expressed in peripheral tissues, such as the stomach, testes, skeletal muscles, uterus, kidney, spleen, pancreas, prostate, and small intestine. Very low levels are expressed in the heart, liver, and lungs [17]. In rat tissues, TASK-3 mRNA is widely expressed in the brain (with the highest expression levels found in the cerebellum), kidney, liver, lungs, colon, stomach, spleen, testes, and skeletal muscles. Its expression level is lowest in the heart and small intestine [71,110,111]. In humans, the TASK-5 channel is highly expressed in the pancreas and is also relatively abundantly expressed in the liver, kidney, lungs, ovary, testes, and heart [13].

2.3. Electrophysiological Properties

K2P channels are active across the entire physiological membrane potential range and generate background leaked potassium currents [112]. TASK channels are important members of the K2P channel family and have a current–voltage (I–V) relationship curve similar to the Goldman–Hodgkin–Katz equation at extra- and intra-cellularly different K+ concentrations, indicating that the generation of TASK channel currents correlates with K+ concentrations on both sides of the cell membrane. This also suggests that these channels show a high level of voltage-dependent gating despite the absence of a traditional voltage-activating domain because they have an ionic check valve located at the SF [113]. TASK channel currents are outwardly rectified and insensitive to potassium channel blockers, such as Ba2+, Cs+, TEA, and 4-AP [114]. TASK-1 and TASK-3 have different sensitivities to ruthenium red (RR or RuR), zinc, and anandamide. For instance, RR and zinc selectively block the TASK-3 channel but not the TASK-1 channel [115,116], whereas anandamide has a more potent blocking effect on TASK-1 than the TASK-3 channel [117]. In addition, TASK-1 and TASK-3 channel proteins can form functional heterodimers and are insensitive to mechanical forces [71,118]. The second messenger diacylglycerol can also inhibit TASK channels by activating G protein-coupled receptors [119,120].
TASK channels are sensitive to changes in extracellular pH but not intracellular pH, and can be blocked by external protons [121]. The histidine residue at position 98, which is near SF1, and the aspartic acid residue at position 204, which is near SF2, are the key sites for sensing extracellular pH variations [104,122]. Extracellular membrane acidification significantly inhibits TASK channels, whereas alkalization weakly activates them (Figure 2). Variations in extracellular pH also affect the ion selectivity of TASK channels, with TASK-1, TASK-3, and TWIK-1 channels becoming less permeable to potassium ions and more permeable to sodium ions when the extracellular solution becomes acidified [123,124,125].

3. Gating Profiles

Gating mechanisms are defined as changes in the spatial conformation of ion channels that affect ion influx (the open state) or efflux (the closed state) [102,126]. Potassium ion channels can be classified depending on whether they use classical gating or “C-type” gating. Ion channels belonging to the classical gating class have separate gating and filter regions that function as channel switches and ion-selective filters, respectively. However, ion channels that use “C-type” gating do not have a single gating region. Instead, the gating mechanism is based on the SF, which performs two functions simultaneously [127]. Advances in resolving the 3D spatial structures of K2P channel proteins, along with the discovery of a large number of small-molecule compounds capable of binding to them, have shown that there are multiple mechanisms for regulating their activity. However, the “N-type” inactivation mechanism, known as the “ball and chain” mechanism (generally rapid, with intracellular N-terminal amino acids obstructing the channel’s inner mouth after channel opening), has not been reported in K2P channels [1], and the principal mechanism is “C-type” gating [128,129,130]. It is dependent on potassium-dependent order-disorder transitions in the SF region, with potassium ions as the voltage-sensing particles. The SF region also has adjacent loops that respond to gating cues relayed through the SF2-M4 loop [113,131]. For two-pore domain TASK potassium channels, there are currently three known main gating site mechanisms [132].
The first gating mechanism occurs at the vestibule site. Mutations and computational calculations of a number of different TASK channel antagonists, such as A293, A1899, PK-THPP, doxapram, ML365, and DR16.1, have shown that these antagonists interact with hydrophobic residues below the SF. The residues are located in the central cavity, and the previously listed antagonists inhibit channel activity by directly plugging the channel and preventing the flow of potassium ions [133,134,135,136]. These binding sites below the SF represent conserved sites of action, and studying them has resulted in a better understanding of the TASK channel gating profiles. It has been reported that the interactions of two crossed C-terminal M4 transmembrane helices at the intracellular vestibule entrance can form the so-called “X-gate”, which includes the six amino acids 243VLRFMT248 in the TASK-1 channel and 243VLRFLT248 in the TASK-3 channel [101]. Mutations within the “X-gate” and its surrounding regions markedly influence channel activity and its responses to the activities of volatile anesthetics, neurotransmitters, and G protein-coupled receptors [62,63]. In one study, Rödström et al. [101] identified two compounds, BAY1000493 and BAY2341237, that inhibit the TASK-1 channel. Both are potent, with IC50 values of 9.5 and 7.6 nM, respectively. In addition, both were found to bind within the inner vestibule region directly below the SF with low washout rates. This type of intracellular gating mechanism has not yet been found in other members of K2P channels, with the exception of the alkaline-activated TASK-2 channel [137]. These studies will be beneficial for the future development and optimization of regulators that target TASK channels.
The second gating mechanism occurs at the keystone inhibitor site. A cationic dye, trinuclear oxo-bridged ruthenium amine ruthenium red (RuR), can selectively inhibit the homodimeric TASK-3 channel by tethering two of its subunits, and the residue at position E70 is critical for this blocking activity [138]. Using a combination of mutagenesis, X-ray crystallographic, and electrophysiological studies of an RuR-insensitive TWIK-related K+ channel 1 (TREK-1), Pope et al. [139] showed that RuR acts by binding to an acidic residue pair that comprises the keystone inhibitor site, which is located under the extracellular cap domain archway directly above the SF. One ruthenium amine moiety in the RuR molecule binds directly over the channel pore at the S0 ion site, and the remainder binds to one of the two branches of the EIP [139,140]. Thus, the keystone inhibitor site creates an electrostatic and physical barrier that prevents the flow of potassium ions through the SF and EIP. They also showed that this “finger in the dam” mechanism is independent of “C-type” gate activation.
The third gating mechanism occurs at the “lateral fenestrations” site. Based on the most recently determined structure, there are three moving parts in K2P channels. Of these, the M4 transmembrane helix is the most obvious [131,141,142,143]. Brohawn et al. [142,144] suggested that K2P channels have two states: namely “up” and “down” states. The “up” state is primarily achieved by the lateral movement of the M4 helix at its midpoint, resulting in closure of the “lateral fenestrations.” In the “down” state, the M4 helix is nearly straight, crosses the membrane at an angle of approximately 45°, and make no contact with the M2 segment of the other subunit, leaving a 5–10 Å gap that is closest to the lipid bilayer. Molecular dynamics simulations of ion channels have revealed that the “lateral fenestration” site can bind to regulators and represents a target site that should be considered in pharmaceutical development [109]. Rinné et al. [145] proposed that the local anesthetic bupivacaine binds at the “lateral fenestration” sites of TASK channels, where it acts allosterically to disrupt K+-flux gating at the SF [113].

4. The Biological Roles of TASK Channels

Many physiological and pathological conditions are related to TASK channels, and they have a diverse distribution throughout the body. This suggests that the pharmacological regulation of TASK channel activity may be of great therapeutic value (Table 1).

4.1. Breathing Rhythm

TASK channels are sensitive to extracellular pH and are expressed in multiple chemosensory nuclei or carotid bodies, which can sense PCO2 shifts in the early stages of acidosis [19,20,21]. The respiratory stimulant doxapram inhibits the activities of human TASK-1 and TASK-3 channels with effective half doses of 4 and 2.5 µM, respectively, suggesting that TASK channels are involved in regulating breathing rhythm [22]. Pharmacological and single-channel experiments revealed that TASK-1, TASK-3, and TASK-1/TASK-3 heterodimers play critical roles in the chemosensation of the carotid body and are major sensors of hypoxia and metabolic acidosis [23]. In neural recordings from electrodes implanted at the carotid body/sinus from TASK-1−/− mice, a significant reduction (49% and 68%, respectively) in chemoafferent cell firing induced by hypoxia (10% O2) and hypercapnia (3–6% CO2) was found along with a blunted ventilatory response to hypoxia. No changes in TASK-3−/− mice were observed under the same conditions, suggesting that TASK-1 in particular plays a key role in peripheral chemosensing. However, the TASK-3 channel can mediate hypoxic depolarization of normal glomus cells [24]. Studies using TASK-1 channel knockout (KO) mice also showed that pH sensitivity in serotonergic raphe neurons was abolished but was maintained in the retrotrapezoid nucleus (RTN). Because the RTN is central to the normal ventilatory response to CO2, this indicates that TASK-1 channels are not involved in the regulation of central respiratory chemosensitivity [25]. Alkaline-sensitive TASK-2 channels are widely distributed in Phox2b-expressing neurons in the brainstem RTN, which are the principal central respiratory chemoreceptors. TASK-2 KO mice displayed a diminished ventilatory reaction to CO2/H+ in vivo, indicating that TASK-2 channels play a major regulatory role in central respiratory chemoreception [1,20,137,146].

4.2. Pulmonary Artery Hypertension

Hypoxic pulmonary vasoconstriction (HPV) is an autoregulatory mechanism of the pulmonary vessels in response to hypoxia, which can reduce the ratio of ventilation and blood flow in the hypoxic alveolar region to ensure its oxygen supply. Thus, it plays an overriding role in maintaining the local ventilation/blood flow ratio and a constant arterial partial pressure of oxygen. Potassium channels play an important role in pulmonary arterial smooth muscle cells (PASMCs), and reduced potassium channel activity increases their resistance to apoptosis, cell proliferation, and vascular constriction, leading to vascular remodeling [147,148,149]. Hypoxia inhibits certain potassium channel activities, leading to cell membrane depolarization, which activates voltage-dependent calcium channels. This triggers inward extracellular Ca2+ flow and the contraction of pulmonary vascular smooth muscle, which ultimately causes increased pulmonary vascular resistance and the initiation of HPV. There are five main potassium channels in PASMCs: voltage-gated potassium (Kv) channels, Ca2+-activated potassium (KCa) channels, ATP-sensitive potassium (KATP) channels, inward rectifier potassium (Kir) channels, and K2P channels [150,151]. Human PASMCs express only TASK-1 potassium channels [26].
Pulmonary artery hypertension (PAH) is a devastating and lethal disease in which the loss of the TASK-1 channel causes cell depolarization, which in turn increases the tension of PASMCs, leading to PAH [26,27]. Loss of function of KCNK3, the gene that edits the TASK-1 channel, is an important contributor to the pathogenesis of PAH [28]. Six heterozygous missense variants of the TASK-1 channel were first reported in 2013, and all of them resulted in a loss of function and were found to be the cause of both familial and idiopathic PAH in patients [29]. Several more mutations in the TASK-1 channel have been identified since then [30,31,32,33,149]. However, whether pharmacological inhibition of the TASK-1 channel can also contribute to the development of PAH remains unclear. Vitamin D deficiency is strongly associated with pulmonary hypertension. Restoring vitamin D levels improves endothelial function and increases TASK-like potassium currents, and this can alleviate PAH [34,35]. It has been shown that pharmacological activation of KCNK3 with ONO-RS-082 in vivo can alleviate the symptoms of pulmonary hypertension (PH) caused by monocrotaline in rats [36]. Therefore, restoring KCNK3 expression in the pulmonary vasculature through gene therapy may be a remedy for PAH.

4.3. Cardiac Arrhythmia

TASK-1 potassium channels are atrial-specific, and protein blotting experiments have shown that the TASK-1 channel in the human heart is expressed at 14–16-fold higher levels in the atria than that in the ventricles [152,153,154]. The TASK-1 channel is known to be involved in the pathophysiology of cardiovascular diseases [37,38,39]. It has been found that TASK-1 KO mice have a significantly prolonged action potential duration [40] and that the use of the TASK-1 blocker A293 significantly prolonged the action potential duration in rat ventricular muscle. This suggests that TASK-1 channels are not only involved in maintaining the resting membrane potential of cardiac myocytes but also help in regulating the outward current during the plateau phase of the action potential [41]. Class III antiarrhythmic drugs prolong action potentials and inhibit atrial and ventricular arrhythmias. Among these drugs, amiodarone inhibits open and closed TASK-1 channels in a concentration-dependent manner, with an IC50 value of 0.4 μM in oocytes. This is a possible mechanism for the efficacy of these agents [42,43].
Atrial fibrillation (AF) is the most common persistent arrhythmia, with a prevalence rate of up to 4% and an increasing trend in the population. It is strongly associated with increased mortality and stroke rates [155]. Although the risk of stroke can be significantly reduced with anticoagulation drugs, there is still a significant need for medicines that can treat other AF-related symptoms. It has been found that TASK-1 mRNA and protein levels in atrial tissue are upregulated in patients with chronic AF, which can result in the shortening of action potentials in these patients [44,45]. In addition, it has been found that the experimental TASK-1 channel inhibitor A293 can control the rhythm of persistent AF in a porcine large animal model [46]. Furthermore, the breathing stimulant compound doxapram inhibits human TASK-1 and TASK-3 channels with equal potency and can be used in a novel pharmacological strategy for cardioversion of acute episodes of paroxysmal AF as well as the rhythm control of persistent AF [47]. Several other experiments have also shown that the targeted inhibition of TASK-1 channels can effectively treat AF, confirming that it is an antiarrhythmic target in general [48,49,50,51]. In addition to the regulation of vascular tone in pulmonary arteries, TASK-1 channels also play an important vasomotor role in systemic arteries under specific conditions or at certain stages of ontogenesis. It was reported that TASK-1 channels oppose vasocontraction of renal arteries under conditions of metabolic alkalosis [156]. Moreover, TASK-1 channels play an important anticontractile role in systemic circulation of newborn rats [157]. Thus, potential vasopressor actions of TASK-1 channel blockers should be considered in the recently suggested TASK-1 channel-targeted treatment of cardiac arrhythmia.

4.4. Aldosterone Secretion

It has been found that TASK−/− channel KO mice exhibit non-tumorigenic primary hyperaldosteronism with overproduction of autonomous aldosterone that was neither suppressed by high dietary sodium intake nor corrected using the angiotensin II receptor 1 antagonist candesartan. These results suggested that TASK channels are possible therapeutic targets for primary hyperaldosteronism [52]. Furthermore, statistical analyses indicated that KCNK3 (TASK-1) variants are associated with hyperaldosteronism and hypertension [53]. Another study reported that deleting TASK-1 and TASK-3 channels in the zona glomerulosa of the adrenal tissue causes aldosterone-driven angiotensin II-independent hypertension [54] Several other studies also indicated that TASK channels participate in the modulation of aldosterone secretion [55,56,57].

4.5. Pain

Tissue acidification can cause acute and chronic pain, and TASK channels are very sensitive to extracellular acidification. For example, exposing the channel to an extracellular pH of 6.0 can reduce its current by 96% [71,158]. Acid inhibition of TASK channels may be an important mechanism for the sustained depolarization of cells due to tissue acidification. This suggests that they could also be potential targets for tissue acidification-induced nociceptive transmission [159,160,161,162]. Several studies have shown that TASK channels are closely associated with pain [58,59,72].
Marsh et al. [60] found that the mRNA levels of TASK channels in the spinal dorsal root ganglion (DRG) were correlated with spontaneous foot lifting after intradermal complete Freund’s adjuvant injections, indicating that TASK channels are associated with inflammation-induced pain. The activity of TASK channels is also altered in pathological models of nerve injury. The mRNA expression of TASK-3 and TWIK-1 channels was found to be downregulated in L4-L5 DRG ipsilateral to the neuropathic lesion one week after spared nerve injury surgery, whereas TASK-1 channel expression remained unchanged [73]. In addition, it has been reported that the TASK-3 channel co-locates with the transient receptor potential cation channel subfamily M member 8 (TRPM8) in sensory neurons. TRPM8 is a cold- and menthol-activated ion channel that participates in thermosensation [163]. Liao et al. [74] designed a peripherally acting selective agonist, CHET3, for the TASK-3 channel and used it to show that the TASK-3 channel is an intrinsic regulator of pain sensation. They proved that CHET3 could attenuate thermal hyperalgesia and mechanical allodynia in different rodent pain models. They also predicted that CHET3 would bind under the SF and close to the M2 and M4 regions, which would alter the gating activity of the channel by affecting the SF conformation. García et al. [61] found that spinal TASK-1 and TASK-3 channels are involved in the regulation of inflammatory and neuropathic pain and that intrathecal pretreatment with the activator terbinafine could reduce formalin-induced flinching and nociceptive hyperalgesia in rats with neuropathy.

4.6. Anesthetics

4.6.1. Volatile Anesthetics

TASK channels are expressed in CNS sites relevant to anesthetic actions and are the targets of many general anesthetics. Volatile anesthetics were the first group of TASK channel modulators to be extensively studied. Volatile anesthetics, such as halothane and isoflurane, activate TASK channels at clinically relevant concentrations to hyperpolarize cell membranes and reduce excitability [62]. This is especially true for brainstem motor and thalamocortical neurons and helps explain the loss of consciousness and motor ability that general anesthetics induce [164,165] It has been reported that the hyperpolarizing effects of halothane and isoflurane were reduced in TASK-1/TASK-3 KO mice, and the corresponding anesthetic effects of sedation, hypnosis, and immobilization were also diminished [64]. However, it has also been reported that high concentrations of isoflurane (0.8 mM) activate the TASK-3 channel and the heterodimeric TASK-1/TASK-3 channel, but inhibit the TASK-1 channel. This suggested that different concentrations of volatile anesthetics can regulate the activities of TASK channels in both directions [65] Studies have shown the presence of a binding region for volatile anesthetics in the structures of TASK channels, which includes the residue M159 at the cytoplasmic terminus of the M3 segment [66] and, in particular, residues 243 to 248 at the beginning of the cytoplasmic C-terminus, a region also known as the halothane-responsive region [63,101]. In addition, it has been shown that halothane and isoflurane can inhibit calcium current in smooth muscle cells of the coronary arteries to directly dilate coronary arteries and increase coronary flow during anesthesia [166].

4.6.2. Local Anesthetics

Local anesthetics inhibit TASK channels with low affinity, and inhibiting TASK channels could reduce seizures caused by toxic concentrations of local anesthetics [67,68]. Using functional mutagenesis screens, in silico drug docking, and molecular dynamics simulations, Rinné et al. [145] showed that the binding site of bupivacaine is located in the “lateral fenestration” sites in TASK channels and that bupivacaine preferentially interacts with the second pore helices independent of the extracellular potassium concentration. This allosteric block mechanism disrupting the K+-flux gating at the selectivity filter resulted in an inward-rectification and then a voltage-dependent inhibition under symmetrical potassium concentrations in TASK channels. This mechanism is different from those of pore blockers, such as A1899, A293, and doxapram [167].

4.7. Cancers

The TASK-3 channel is highly expressed in breast cancer, ovarian carcinoma, and melanoma cells, and it has been suggested that it promotes tumor growth and proliferation [75,76,77,78,79,80,81,82]. Thus far, only the TASK-3 channel in the K2P family has been identified to be expressed in the inner mitochondrial membrane, and silencing it induces apoptosis of human melanoma cells [83,84]. In addition, a study using a short hairpin RNA (shRNA)-mediated knockdown of the TASK-3 channel confirmed that the TASK-3 channel is involved in migration and cell survival in gastric cancer. Thus, it represents a potential therapeutic target for gastric cancer treatment [85]. Moreover, the addition of Y4, a monoclonal antibody against the TASK-3 channel extracellular domain, to KCNK9-expressing carcinoma cells can inhibit tumor growth and metastasis [86]. These confirmed that the TASK-3 channel is a promising target for the treatment of malignancies that express KCNK9 [87].

4.8. Neurological Activities and/or Disorders

4.8.1. Sleep

Synchronized burst firing and tonic action potential generation in the thalamocortical system of the brain mainly occur during sleep and waking states, respectively [168]. The switch between these two firing modes is critically modulated by the bidirectional regulation of TASK and TWIK-related K+ channels (TREK) in thalamic relay neurons.
It has been found that the genetic KO of TASK-1 did not change sleep/wake times in mice [169]. One study analyzed the locomotor activity and circadian rhythms of TASK-3 KO mice and found that, when compared to wild-type litter controls, both had normal circadian rhythms. However, TASK-3 KO mice had significantly increased nocturnal activity (38%), suggesting that the TASK-3 channel plays an important role in the regulation of sleep [88]. Another study based on continuous electroencephalogram and electromyogram recordings of TASK-3 KO mice revealed that they had a slower transition from wakefulness to sleep and more fragmented sleep episodes and rapid eye movement (REM) theta wave (4–9 Hz) oscillations during sleep [89,90].

4.8.2. Mental Retardation

Mutations of G236R or A237D in the TASK-3 channel can lead to maternally inherited Birk–Barel intellectual disability syndrome (BBIDS), characterized by varying degrees of mental retardation, congenital hypotonia, generalized or proximal weakness, and craniofacial deformities, including an elongated face, bilateral temporal stenosis, severe micrognathia, cleft palate, depressed upper lip, short pharynx, atypical ear shape, upward arching eyebrows, and long eyelids [91,92,93]. An additional gain-of-function mutation in the TASK-3 channel (A237T), the non-steroidal anti-inflammatory drug flufenamic acid, and terbinafine can reduce the decrease in channel currents caused by the G236R mutation. This combination may provide a strategy for the treatment of BBIDS [94,95]. Inhibition of histone deacetylation also rescued the phenotype of mental retardation syndrome in the Birk–Barel mouse model, as shown by the second-generation histone deacetylase inhibitor CI-994 [96].

4.8.3. Depression

Depression is a polygenic and highly complex psychiatric disorder that involves multiple environmental and somatic developmental factors. It is often difficult to treat, is extremely heterogenous, and is a significant burden on society. Current pharmacological treatments for depression can cause many unwanted side effects. Furthermore, they do not have any effect on many patients [170,171]. TASK and TREK-1 channels have been found to be associated with the mechanisms of several depressive disorders [90,97]. The gene encoding TASK-3, KCNK9, is located on chromosome 8q24, and TASK-3 KO mice display antidepressant effects, implying that TASK-3 is a therapeutic target for antidepressant action [90]. A marker of depression treatment is the inhibition of REM sleep, which was significantly reduced in wild-type animals when fluoxetine was administered but did not have the same effect in mice lacking TASK-3 channels. This confirms the potential of TASK-3 channels as targets for the treatment of depression [98,99].

4.9. Other Roles

Several studies have shown that the TASK-1 channels found in the pancreas participate in the regulation of glucose homeostasis [69,70]. Using the highly specific “RNAscope” method of in situ mRNA hybridization in combination with pharmacological antagonists and genetic deletion tools, Wen et al. [100] reported the first evidence that the TASK-3 channel is abundantly expressed in retinal ganglion cells and plays a critical role in visual processing in the retina.

5. Development of Selectively Targeted Compounds

TASK-1 and TASK-3 have different ranges of distribution and biologically relevant functions, even though they are closely related. Some compounds have been discovered that specifically target TASK-1 or TASK-3 channels, and using them has facilitated our understanding of the diverse molecular pharmacology and physiological roles of TASK channels (Table 2). The chemical structures can be seen in Figure 3.

5.1. Compounds That Target the TASK-1 Channel

Few compounds that specifically activate the TASK-1 channel have been discovered. Maingret et al. [117] found that methanandamide is a direct and relatively selective blocker of the TASK-1 channel, with an IC50 value of 0.7 μM. In addition, there is some evidence supporting the effect of anandamide on ion channels other than TASK-1, with effective concentration ranges for “side effect” and blockade of TASK-1 channels overlapping significantly. In the rat coronary artery, anandamide promoted the development of vasodilation by activating large-conductance Ca2+-activated K+ channels [178]. In isolated rat aortic smooth muscle cells, anandamide and methanandamide caused a decrease in the amplitude of the current mediated by Kv channels [179]. Thus, associating these effects with the direct effects of anandamide and methanandamide on potassium channels does not involve the activation of cannabinoid receptors. Cardiac glycosides have been used as antiarrhythmic drugs for many years, of which digitoxin and digoxin can selectively inhibit TASK-1 currents with IC50 values of 7.4 and 0.9 µM, respectively [172].
A-293 (AVE1231) is a TASK-1 selective inhibitor with IC50 values of about 0.22 against 0.95 μM of TASK-3 in Xenopus oocytes [41], and it can be used to treat atrial fibrillation [46,49]. In 2011, Decher et al. were the first to describe A-1899 (2″-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide) as a potent and highly selective small-molecule antagonist targeting the TASK-1 channel. It has IC50 values of 35.1 nM in Xenopus oocytes and 7 nM in CHO cells [173]. Bis-amide ML365 (2-methoxy-N-(3-(3-methylbenzamido)phenyl)benzamide) was also identified as a high-affinity blocker of the TASK-1 channel, with an IC50 value of 16 nM. It is a useful tool for in vitro studies of the biological functions and the development of pharmaceuticals that target the TASK-1 channel [135,174].

5.2. Compounds That Target the TASK-3 Channel

Wright et al. [95] showed that terbinafine, an antifungal agent, selectively activated TASK-3 currents with pEC50 of 6.2 (±0.12) by using the thallium flux assay, and no TASK-1 activity was observed during the electrophysiology studies. Liao et al. [74] developed and characterized the highly selective TASK-3 agonist CHET3 ((E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-hydroxy-6-((p-tolylthio)methyl)pyrimidin-2-yl) guanidine), which can selectively activate the TASK-3 channel with an EC50 of approximately 1.4 μM, and has no significant effect on TASK-1 channels, even at a concentration of 10 μM. Residues at the extracellular end of M2 (A105 and A108) and the intracellular end of M3 (E157) are important for TASK-3 channel activation, and these residues are not conserved in the TASK-1 channel. NPBA (N-(2-((4-nitro-2-(trifluoromethyl)phenyl)amino)ethyl)benzamide) binds to two distant clusters of residues and shows excellent potency and selectivity as a novel TASK-3 agonist, with an EC50 of 6.7 μM [175].
The trinuclear oxo-bridged RuR can selectively inhibit homodimeric TASK-3 but has no effect on either the TASK-1 homodimer and TASK-1/TASK-3 heterodimer, with an IC50 of 0.114 μM [138,139]. The dinuclear oxo-bridged ruthenium compound Ru360 can also selectively block the TASK-3 channel with an IC50 of 15.6 μM, which is at least 10-fold weaker than that of RuR because it carries half the positive charge of RuR [139]. Miller et al. [176] described that ML308 (4-[(1S)-1-[(1S,2R)-2-bicyclo [2.2.1]heptanyl]ethyl]-3-(furan-2-yl)-1H-1,2,4-triazole-5-thione) shows at least 50-fold selectivity for blocking the TASK-3 channel compared to the TASK-1 channel. It was identified as a novel selective inhibitor of the TASK-3 channel, with an IC50 value of 130 nM in a thallium influx fluorescent assay and 413 nM in an automated electrophysiology assay. PK-THPP (1-[1-[6-(4-phenylbenzoyl)-7,8-dihydro-5H-pyrido [4,3-d]pyrimidin-4-yl]piperidin-4-yl]butan-1-one) binds in the central cavity and is a relatively specific TASK-3 inhibitor. It has an IC50 value of 35 nM against TASK-3 but is approximately nine times weaker against TASK-1 channel, with an IC50 value of 303 nM [177].

6. Conclusions and Future Research Directions

Since the first identification of the human TASK-1 channel in 1997, we have learned a lot about the diversity and nature of the two-pore domain TASK potassium channels. In summary, recent advances in our understanding of TASK channels strongly suggest that they have enormous potential as a part of therapeutic strategies for multiple disorders. Given the diversity of K2P channel binding sites and the possibility that there are over three gating sites for TASK channels, future research should focus on the discovery of other modulators, the further exploration of potential gating mechanisms, and on determining whether these binding sites can act in tandem. Furthermore, TASK-1 and TASK-3 channels share some biological roles. Therefore, it will be necessary to further clarify whether their relative contributions to a specific disorder differ in strength and duration, even though they are often co-expressed and can form heterodimers.
TASK-1 and TASK-3 channels have different distributions in the nervous system and peripheral tissues and are involved in the pathophysiological processes of a wide range of diseases. However, potent and specific compounds targeting the TASK-1 or TASK-3 channels have remained scientifically and economically underdeveloped. Relatively few small-molecule activators and inhibitors of therapeutic importance have been studied, and even fewer have entered clinical trials. Exploring the mechanism of action of TASK channels and using rational drug design to explore compounds that target the desired site of action should be high priorities for future research.

Author Contributions

X.F., G.D. and J.L., conceptualization; Y.L., G.D. and J.L., writing—review, editing, validation and supervision; X.F., writing—original draft. All authors have read and agreed to the published version of the manuscript.


This work was supported by the National Natural Science Foundation of China Grant (81872801 to G.D., 82071557 to J.L.) and the International Cooperation Project of Sichuan Provincial Department of Science and Technology Grant (2019YFH0156 to G.D.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare that they have no conflict of interest.


  1. Sepúlveda, F.V.; Pablo Cid, L.; Teulon, J.; Niemeyer, M.I. Molecular aspects of structure, gating, and physiology of pH-sensitive background K2P and Kir K+-transport channels. Physiol. Rev. 2015, 95, 179–217. [Google Scholar] [CrossRef]
  2. Kuang, Q.; Purhonen, P.; Hebert, H. Structure of potassium channels. Cell. Mol. Life Sci. CMLS 2015, 72, 3677–3693. [Google Scholar] [CrossRef]
  3. González, C.; Baez-Nieto, D.; Valencia, I.; Oyarzún, I.; Rojas, P.; Naranjo, D.; Latorre, R. K+ channels: Function-structural overview. Compr. Physiol. 2012, 2, 2087–2149. [Google Scholar] [PubMed]
  4. Kim, D.M.; Nimigean, C.M. Voltage-Gated Potassium Channels: A Structural Examination of Selectivity and Gating. Cold Spring Harb. Perspect. Biol. 2016, 8, a029231. [Google Scholar] [CrossRef]
  5. Trombetta-Lima, M.; Krabbendam, I.E.; Dolga, A.M. Calcium-activated potassium channels: Implications for aging and age-related neurodegeneration. Int. J. Biochem. Cell Biol. 2020, 123, 105748. [Google Scholar] [CrossRef]
  6. Hibino, H.; Inanobe, A.; Furutani, K.; Murakami, S.; Findlay, I.; Kurachi, Y. Inwardly rectifying potassium channels: Their structure, function, and physiological roles. Physiol. Rev. 2010, 90, 291–366. [Google Scholar] [CrossRef] [PubMed]
  7. Lesage, F.; Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal Physiol. 2000, 279, F793–F801. [Google Scholar] [CrossRef] [PubMed]
  8. Goldstein, S.A.; Bockenhauer, D.; O’Kelly, I.; Zilberberg, N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat. Rev. Neurosci. 2001, 2, 175–184. [Google Scholar] [CrossRef]
  9. Huang, L.; Xu, G.; Jiang, R.; Luo, Y.; Zuo, Y.; Liu, J. Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels. Curr. Neuropharmacol. 2022, 20, 16–26. [Google Scholar] [CrossRef] [PubMed]
  10. Lesage, F.; Guillemare, E.; Fink, M.; Duprat, F.; Lazdunski, M.; Romey, G.; Barhanin, J. TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J. 1996, 15, 1004–1011. [Google Scholar] [CrossRef] [PubMed]
  11. Duprat, F.; Lesage, F.; Fink, M.; Reyes, R.; Heurteaux, C.; Lazdunski, M. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 1997, 16, 5464–5471. [Google Scholar] [CrossRef]
  12. Rajan, S.; Wischmeyer, E.; Xin Liu, G.; Preisig-Müller, R.; Daut, J.; Karschin, A.; Derst, C. TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J. Biol. Chem. 2000, 275, 16650–16657. [Google Scholar] [CrossRef] [PubMed]
  13. Ashmole, I.; Goodwin, P.A.; Stanfield, P.R. TASK-5, a novel member of the tandem pore K+ channel family. Pflugers Arch. 2001, 442, 828–833. [Google Scholar] [CrossRef]
  14. Brohawn, S.G.; del Mármol, J.; MacKinnon, R. Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 2012, 335, 436–441. [Google Scholar] [CrossRef] [PubMed]
  15. Cotten, J.F. TASK-1 (KCNK3) and TASK-3 (KCNK9) tandem pore potassium channel antagonists stimulate breathing in isoflurane-anesthetized rats. Anesth. Analg. 2013, 116, 810–816. [Google Scholar] [CrossRef] [PubMed]
  16. Talley, E.M.; Lei, Q.; Sirois, J.E.; Bayliss, D.A. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 2000, 25, 399–410. [Google Scholar] [CrossRef]
  17. Medhurst, A.D.; Rennie, G.; Chapman, C.G.; Meadows, H.; Duckworth, M.D.; Kelsell, R.E.; Gloger, I.I.; Pangalos, M.N. Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Brain Res. Mol. Brain Res. 2001, 86, 101–114. [Google Scholar] [CrossRef] [PubMed]
  18. Olschewski, A.; Veale, E.L.; Nagy, B.M.; Nagaraj, C.; Kwapiszewska, G.; Antigny, F.; Lambert, M.; Humbert, M.; Czirják, G.; Enyedi, P.; et al. TASK-1 (KCNK3) channels in the lung: From cell biology to clinical implications. Eur. Respir. J. 2017, 50, 1700754. [Google Scholar] [CrossRef]
  19. Koizumi, H.; Smerin, S.E.; Yamanishi, T.; Moorjani, B.R.; Zhang, R.; Smith, J.C. TASK channels contribute to the K+-dominated leak current regulating respiratory rhythm generation in vitro. J. Neurosci. 2010, 30, 4273–4284. [Google Scholar] [CrossRef]
  20. Bayliss, D.A.; Barhanin, J.; Gestreau, C.; Guyenet, P.G. The role of pH-sensitive TASK channels in central respiratory chemoreception. Pflugers Arch. 2015, 467, 917–929. [Google Scholar] [CrossRef] [Green Version]
  21. Buckler, K.J. TASK channels in arterial chemoreceptors and their role in oxygen and acid sensing. Pflügers Arch.-Eur. J. Physiol. 2015, 467, 1013–1025. [Google Scholar] [CrossRef]
  22. Cunningham, K.P.; MacIntyre, D.E.; Mathie, A.; Veale, E.L. Effects of the ventilatory stimulant, doxapram on human TASK-3 (KCNK9, K2P9.1) channels and TASK-1 (KCNK3, K2P3.1) channels. Acta Physiol. 2020, 228, e13361. [Google Scholar] [CrossRef]
  23. Kim, D.; Cavanaugh, E.J.; Kim, I.; Carroll, J.L. Heteromeric TASK-1/TASK-3 is the major oxygen-sensitive background K+ channel in rat carotid body glomus cells. J. Physiol. 2009, 587 Pt 12, 2963–2975. [Google Scholar] [CrossRef] [PubMed]
  24. Trapp, S.; Aller, M.I.; Wisden, W.; Gourine, A.V. A role for TASK-1 (KCNK3) channels in the chemosensory control of breathing. J. Neurosci. 2008, 28, 8844–8850. [Google Scholar] [CrossRef] [PubMed]
  25. Mulkey, D.K.; Talley, E.M.; Stornetta, R.L.; Siegel, A.R.; West, G.H.; Chen, X.; Sen, N.; Mistry, A.M.; Guyenet, P.G.; Bayliss, D.A. TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. J. Neurosci. 2007, 27, 14049–14058. [Google Scholar] [CrossRef]
  26. Olschewski, A.; Li, Y.; Tang, B.; Hanze, J.; Eul, B.; Bohle, R.M.; Wilhelm, J.; Morty, R.E.; Brau, M.E.; Weir, E.K.; et al. Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ. Res. 2006, 98, 1072–1080. [Google Scholar] [CrossRef] [PubMed]
  27. Cunningham, K.P.; Holden, R.G.; Escribano-Subias, P.M.; Cogolludo, A.; Veale, E.L.; Mathie, A. Characterization and regulation of wild-type and mutant TASK-1 two pore domain potassium channels indicated in pulmonary arterial hypertension. J. Physiol. 2019, 597, 1087–1101. [Google Scholar] [CrossRef] [PubMed]
  28. Lambert, M.; Capuano, V.; Boet, A.; Tesson, L.; Bertero, T.; Nakhleh, M.K.; Remy, S.; Anegon, I.; Pechoux, C.; Hautefort, A.; et al. Characterization of Kcnk3-Mutated Rat, a Novel Model of Pulmonary Hypertension. Circ. Res. 2019, 125, 678–695. [Google Scholar] [CrossRef]
  29. Ma, L.; Roman-Campos, D.; Austin, E.D.; Eyries, M.; Sampson, K.S.; Soubrier, F.; Germain, M.; Trégouët, D.A.; Borczuk, A.; Rosenzweig, E.B.; et al. A novel channelopathy in pulmonary arterial hypertension. N. Engl. J. Med. 2013, 369, 351–361. [Google Scholar] [CrossRef]
  30. Navas Tejedor, P.; Tenorio Castaño, J.; Palomino Doza, J.; Arias Lajara, P.; Gordo Trujillo, G.; López Meseguer, M.; Román Broto, A.; Lapunzina Abadía, P.; Escribano Subía, P. An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension. Clin. Genet. 2017, 91, 453–457. [Google Scholar] [CrossRef]
  31. Best, D.H.; Sumner, K.L.; Smith, B.P.; Damjanovich-Colmenares, K.; Nakayama, I.; Brown, L.M.; Ha, Y.; Paul, E.; Morris, A.; Jama, M.A.; et al. EIF2AK4 Mutations in Patients Diagnosed with Pulmonary Arterial Hypertension. Chest 2017, 151, 821–828. [Google Scholar] [CrossRef] [PubMed]
  32. Rosenzweig, E.B.; Abman, S.H.; Adatia, I.; Beghetti, M.; Bonnet, D.; Haworth, S.; Ivy, D.D.; Berger, R.M.F. Paediatric pulmonary arterial hypertension: Updates on definition, classification, diagnostics and management. Eur. Respir. J. 2019, 53, 1801916. [Google Scholar] [CrossRef] [PubMed]
  33. Higasa, K.; Ogawa, A.; Terao, C.; Shimizu, M.; Kosugi, S.; Yamada, R.; Date, H.; Matsubara, H.; Matsuda, F. A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. BMC Pulm. Med. 2017, 17, 57. [Google Scholar] [CrossRef] [PubMed]
  34. Callejo, M.; Mondejar-Parreño, G.; Morales-Cano, D.; Barreira, B.; Esquivel-Ruiz, S.; Olivencia, M.A.; Manaud, G.; Perros, F.; Duarte, J.; Moreno, L.; et al. Vitamin D deficiency downregulates TASK-1 channels and induces pulmonary vascular dysfunction. Am. J. Physiol. Lung Cell Mol. Physiol. 2020, 319, L627–L640. [Google Scholar] [CrossRef]
  35. Callejo, M.; Morales-Cano, D.; Mondejar-Parreño, G.; Barreira, B.; Esquivel-Ruiz, S.; Olivencia, M.A.; Moreno, L.; Cogolludo, A.; Perez-Vizcaino, F. Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency. Biomolecules 2021, 11, 795. [Google Scholar] [CrossRef]
  36. Antigny, F.; Hautefort, A.; Meloche, J.; Belacel-Ouari, M.; Manoury, B.; Rucker-Martin, C.; Péchoux, C.; Potus, F.; Nadeau, V.; Tremblay, E.; et al. Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension. Circulation 2016, 133, 1371–1385. [Google Scholar] [CrossRef] [PubMed]
  37. Besana, A.; Barbuti, A.; Tateyama, M.A.; Symes, A.J.; Robinson, R.B.; Feinmark, S.J. Activation of protein kinase C epsilon inhibits the two-pore domain K+ channel, TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes. J. Biol. Chem. 2004, 279, 33154–33160. [Google Scholar] [CrossRef] [PubMed]
  38. Gurney, A.; Manoury, B. Two-pore potassium channels in the cardiovascular system. Eur. Biophys. J. 2009, 38, 305–318. [Google Scholar] [CrossRef]
  39. Liang, B.; Soka, M.; Christensen, A.H.; Olesen, M.S.; Larsen, A.P.; Knop, F.K.; Wang, F.; Nielsen, J.B.; Andersen, M.N.; Humphreys, D.; et al. Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis. J. Mol. Cell. Cardiol. 2014, 67, 69–76. [Google Scholar] [CrossRef] [PubMed]
  40. Donner, B.C.; Schullenberg, M.; Geduldig, N.; Hüning, A.; Mersmann, J.; Zacharowski, K.; Kovacevic, A.; Decking, U.; Aller, M.I.; Schmidt, K.G. Functional role of TASK-1 in the heart: Studies in TASK-1-deficient mice show prolonged cardiac repolarization and reduced heart rate variability. Basic Res. Cardiol. 2011, 106, 75–87. [Google Scholar] [CrossRef] [PubMed]
  41. Putzke, C.; Wemhöner, K.; Sachse, F.B.; Rinné, S.; Schlichthörl, G.; Li, X.T.; Jaé, L.; Eckhardt, I.; Wischmeyer, E.; Wulf, H.; et al. The acid-sensitive potassium channel TASK-1 in rat cardiac muscle. Cardiovasc. Res. 2007, 75, 59–68. [Google Scholar] [CrossRef] [PubMed]
  42. Gierten, J.; Ficker, E.; Bloehs, R.; Schweizer, P.A.; Zitron, E.; Scholz, E.; Karle, C.; Katus, H.A.; Thomas, D. The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn Schmiedebergs Arch. Pharmacol. 2010, 381, 261–270. [Google Scholar] [CrossRef] [PubMed]
  43. Kraft, M.; Büscher, A.; Wiedmann, F.; L’Hoste, Y.; Haefeli, W.E.; Frey, N.; Katus, H.A.; Schmidt, C. Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option. Front. Pharmacol. 2021, 12, 638445. [Google Scholar] [CrossRef] [PubMed]
  44. Schmidt, C.; Wiedmann, F.; Zhou, X.B.; Heijman, J.; Voigt, N.; Ratte, A.; Lang, S.; Kallenberger, S.M.; Campana, C.; Weymann, A.; et al. 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. Eur. Heart J. 2017, 38, 1764–1774. [Google Scholar] [CrossRef] [PubMed]
  45. Schmidt, C.; Wiedmann, F.; Voigt, N.; Zhou, X.B.; Heijman, J.; Lang, S.; Albert, V.; Kallenberger, S.; Ruhparwar, A.; Szabó, G.; et al. Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation. Circulation 2015, 132, 82–92. [Google Scholar] [CrossRef]
  46. Wiedmann, F.; Beyersdorf, C.; Zhou, X.B.; Kraft, M.; Foerster, K.I.; El-Battrawy, I.; Lang, S.; Borggrefe, M.; Haefeli, W.E.; Frey, N.; et al. The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model. Front. Physiol. 2020, 11, 629421. [Google Scholar] [CrossRef]
  47. Wiedmann, F.; Beyersdorf, C.; Zhou, X.B.; Kraft, M.; Paasche, A.; Jávorszky, N.; Rinné, S.; Sutanto, H.; Büscher, A.; Foerster, K.I.; et al. Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy. Cardiovasc. Res. 2021, 118, 1728–1741. [Google Scholar] [CrossRef] [PubMed]
  48. Schmidt, C.; Wiedmann, F.; Beyersdorf, C.; Zhao, Z.; El-Battrawy, I.; Lan, H.; Szabo, G.; Li, X.; Lang, S.; Korkmaz-Icöz, S.; et al. Genetic Ablation of TASK-1 (Tandem of P Domains in a Weak Inward Rectifying K+ Channel-Related Acid-Sensitive K+ Channel-1) (K2P3.1) K+ Channels Suppresses Atrial Fibrillation and Prevents Electrical Remodeling. Circ. Arrhythm Electrophysiol 2019, 12, e007465. [Google Scholar] [CrossRef]
  49. Wiedmann, F.; Beyersdorf, C.; Zhou, X.; Büscher, A.; Kraft, M.; Nietfeld, J.; Walz, T.P.; Unger, L.A.; Loewe, A.; Schmack, B.; et al. Pharmacologic TWIK-Related Acid-Sensitive K+ channel (TASK-1) Potassium Channel Inhibitor A293 Facilitates Acute Cardioversion of Paroxysmal Atrial Fibrillation in a Porcine Large Animal Model. J. Am. Heart Assoc. 2020, 9, e015751. [Google Scholar] [CrossRef] [PubMed]
  50. Ratte, A.; Wiedmann, F.; Kraft, M.; Katus, H.A.; Schmidt, C. Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels. Front. Pharmacol. 2019, 10, 1367. [Google Scholar] [CrossRef] [Green Version]
  51. Wiedmann, F.; Kraft, M.; Kallenberger, S.; Büscher, A.; Paasche, A.; Blochberger, P.L.; Seeger, T.; Jávorszky, N.; Warnecke, G.; Arif, R.; et al. MicroRNAs Regulate TASK-1 and Are Linked to Myocardial Dilatation in Atrial Fibrillation. J. Am. Heart Assoc. 2022, 11, e023472. [Google Scholar] [CrossRef] [PubMed]
  52. Davies, L.A.; Hu, C.; Guagliardo, N.A.; Sen, N.; Chen, X.; Talley, E.M.; Carey, R.M.; Bayliss, D.A.; Barrett, P.Q. TASK channel deletion in mice causes primary hyperaldosteronism. Proc. Natl. Acad. Sci. USA 2008, 105, 2203–2208. [Google Scholar] [CrossRef] [PubMed]
  53. Manichaikul, A.; Rich, S.S.; Allison, M.A.; Guagliardo, N.A.; Bayliss, D.A.; Carey, R.M.; Barrett, P.Q. KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension. Hypertension 2016, 68, 356–364. [Google Scholar] [CrossRef] [PubMed]
  54. Guagliardo, N.A.; Yao, J.; Stipes, E.J.; Cechova, S.; Le, T.H.; Bayliss, D.A.; Breault, D.T.; Barrett, P.Q. Adrenal Tissue-Specific Deletion of TASK Channels Causes Aldosterone-Driven Angiotensin II-Independent Hypertension. Hypertension 2019, 73, 407–414. [Google Scholar] [CrossRef]
  55. Penton, D.; Bandulik, S.; Schweda, F.; Haubs, S.; Tauber, P.; Reichold, M.; Cong, L.D.; El Wakil, A.; Budde, T.; Lesage, F.; et al. Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology 2012, 153, 4740–4748. [Google Scholar] [CrossRef]
  56. Chen, A.X.; Nishimoto, K.; Nanba, K.; Rainey, W.E. Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals. Mol. Cell. Endocrinol. 2015, 417, 141–148. [Google Scholar] [CrossRef] [PubMed]
  57. Barrett, P.Q.; Guagliardo, N.A.; Bayliss, D.A. Ion Channel Function and Electrical Excitability in the Zona Glomerulosa: A Network Perspective on Aldosterone Regulation. Annu. Rev. Physiol. 2021, 83, 451–475. [Google Scholar] [CrossRef]
  58. Li, X.Y.; Toyoda, H. Role of leak potassium channels in pain signaling. Brain Res. Bull. 2015, 119 Pt A, 73–79. [Google Scholar] [CrossRef]
  59. Gada, K.; Plant, L.D. Two-pore domain potassium channels: Emerging targets for novel analgesic drugs: IUPHAR Review 26. Br. J. Pharmacol. 2019, 176, 256–266. [Google Scholar] [CrossRef]
  60. Marsh, B.; Acosta, C.; Djouhri, L.; Lawson, S.N. Leak K⁺ channel mRNAs in dorsal root ganglia: Relation to inflammation and spontaneous pain behaviour. Mol. Cell. Neurosci. 2012, 49, 375–386. [Google Scholar] [CrossRef]
  61. García, G.; Noriega-Navarro, R.; Martínez-Rojas, V.A.; Gutiérrez-Lara, E.J.; Oviedo, N.; Murbartián, J. Spinal TASK-1 and TASK-3 modulate inflammatory and neuropathic pain. Eur. J. Pharmacol. 2019, 862, 172631. [Google Scholar] [CrossRef] [PubMed]
  62. Patel, A.J.; Honoré, E.; Lesage, F.; Fink, M.; Romey, G.; Lazdunski, M. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat. Neurosci. 1999, 2, 422–426. [Google Scholar] [CrossRef]
  63. Talley, E.M.; Bayliss, D.A. Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: Volatile anesthetics and neurotransmitters share a molecular site of action. J. Biol. Chem. 2002, 277, 17733–17742. [Google Scholar] [CrossRef]
  64. Lazarenko, R.M.; Willcox, S.C.; Shu, S.; Berg, A.P.; Jevtovic-Todorovic, V.; Talley, E.M.; Chen, X.; Bayliss, D.A. Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics. J. Neurosci. 2010, 30, 7691–7704. [Google Scholar] [CrossRef] [PubMed]
  65. Berg, A.P.; Talley, E.M.; Manger, J.P.; Bayliss, D.A. Motoneurons express heteromeric TWIK-related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits. J. Neurosci. 2004, 24, 6693–6702. [Google Scholar] [CrossRef] [PubMed]
  66. Conway, K.E.; Cotten, J.F. Covalent modification of a volatile anesthetic regulatory site activates TASK-3 (KCNK9) tandem-pore potassium channels. Mol. Pharmacol. 2012, 81, 393–400. [Google Scholar] [CrossRef] [PubMed]
  67. Kindler, C.H.; Yost, C.S.; Gray, A.T. Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem. Anesthesiology 1999, 90, 1092–1102. [Google Scholar] [CrossRef] [PubMed]
  68. Du, G.; Chen, X.; Todorovic, M.S.; Shu, S.; Kapur, J.; Bayliss, D.A. TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures. Anesthesiology 2011, 115, 1003–1011. [Google Scholar] [CrossRef] [PubMed]
  69. Dadi, P.K.; Vierra, N.C.; Jacobson, D.A. Pancreatic β-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance. Endocrinology 2014, 155, 3757–3768. [Google Scholar] [CrossRef] [PubMed]
  70. Dadi, P.K.; Luo, B.; Vierra, N.C.; Jacobson, D.A. TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion. Mol. Endocrinol. 2015, 29, 777–787. [Google Scholar] [CrossRef] [Green Version]
  71. Kim, Y.; Bang, H.; Kim, D. TASK-3, a new member of the tandem pore K+ channel family. J. Biol. Chem. 2000, 275, 9340–9347. [Google Scholar] [CrossRef] [PubMed]
  72. Ren, W.J.; Ulrich, H.; Semyanov, A.; Illes, P.; Tang, Y. TASK-3: New Target for Pain-Relief. Neurosci. Bull. 2020, 36, 951–954. [Google Scholar] [CrossRef] [PubMed]
  73. Pollema-Mays, S.L.; Centeno, M.V.; Ashford, C.J.; Apkarian, A.V.; Martina, M. Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. Mol. Cell. Neurosci. 2013, 57, 1–9. [Google Scholar] [CrossRef] [PubMed]
  74. Liao, P.; Qiu, Y.; Mo, Y.; Fu, J.; Song, Z.; Huang, L.; Bai, S.; Wang, Y.; Zhu, J.J.; Tian, F.; et al. Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models. Sci. Transl. Med. 2019, 11, eaaw8434. [Google Scholar] [CrossRef] [PubMed]
  75. Mu, D.; Chen, L.; Zhang, X.; See, L.H.; Koch, C.M.; Yen, C.; Tong, J.J.; Spiegel, L.; Nguyen, K.C.; Servoss, A.; et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 2003, 3, 297–302. [Google Scholar] [CrossRef] [PubMed]
  76. Pei, L.; Wiser, O.; Slavin, A.; Mu, D.; Powers, S.; Jan, L.Y.; Hoey, T. Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. Proc. Natl. Acad. Sci. USA 2003, 100, 7803–7807. [Google Scholar] [CrossRef] [PubMed]
  77. Zúñiga, R.; Valenzuela, C.; Concha, G.; Brown, N.; Zúñiga, L. TASK-3 Downregulation Triggers Cellular Senescence and Growth Inhibition in Breast Cancer Cell Lines. Int. J. Mol. Sci 2018, 19, 1033. [Google Scholar] [CrossRef] [PubMed]
  78. Zúñiga, R.; Concha, G.; Cayo, A.; Cikutović-Molina, R.; Arevalo, B.; González, W.; Catalán, M.A.; Zúñiga, L. Withaferin A suppresses breast cancer cell proliferation by inhibition of the two-pore domain potassium (K2P9) channel TASK-3. Biomed. Pharmacother. 2020, 129, 110383. [Google Scholar] [CrossRef] [PubMed]
  79. Innamaa, A.; Jackson, L.; Asher, V.; Van Shalkwyk, G.; Warren, A.; Hay, D.; Bali, A.; Sowter, H.; Khan, R. Expression and prognostic significance of the oncogenic K2P potassium channel KCNK9 (TASK-3) in ovarian carcinoma. Anticancer Res. 2013, 33, 1401–1408. [Google Scholar] [PubMed]
  80. Rusznák, Z.; Bakondi, G.; Kosztka, L.; Pocsai, K.; Dienes, B.; Fodor, J.; Telek, A.; Gönczi, M.; Szucs, G.; Csernoch, L. Mitochondrial expression of the two-pore domain TASK-3 channels in malignantly transformed and non-malignant human cells. Virchows Arch. 2008, 452, 415–426. [Google Scholar] [CrossRef] [PubMed]
  81. Nagy, D.; Gönczi, M.; Dienes, B.; Szöőr, Á.; Fodor, J.; Nagy, Z.; Tóth, A.; Fodor, T.; Bai, P.; Szücs, G.; et al. Silencing the KCNK9 potassium channel (TASK-3) gene disturbs mitochondrial function, causes mitochondrial depolarization, and induces apoptosis of human melanoma cells. Arch. Dermatol. Res. 2014, 306, 885–902. [Google Scholar] [CrossRef] [PubMed]
  82. Bachmann, M.; Rossa, A.; Antoniazzi, G.; Biasutto, L.; Carrer, A.; Campagnaro, M.; Leanza, L.; Gonczi, M.; Csernoch, L.; Paradisi, C.; et al. Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3. Pharmacol. Res. 2021, 164, 105326. [Google Scholar] [CrossRef]
  83. Wrzosek, A.; Gałecka, S.; Żochowska, M.; Olszewska, A.; Kulawiak, B. Alternative Targets for Modulators of Mitochondrial Potassium Channels. Molecules 2022, 27, 299. [Google Scholar] [CrossRef] [PubMed]
  84. Yao, J.; McHedlishvili, D.; McIntire, W.E.; Guagliardo, N.A.; Erisir, A.; Coburn, C.A.; Santarelli, V.P.; Bayliss, D.A.; Barrett, P.Q. Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells. Hypertension 2017, 70, 347–356. [Google Scholar] [CrossRef] [PubMed]
  85. Cikutović-Molina, R.; Herrada, A.A.; González, W.; Brown, N.; Zúñiga, L. TASK-3 Gene Knockdown Dampens Invasion and Migration and Promotes Apoptosis in KATO III and MKN-45 Human Gastric Adenocarcinoma Cell Lines. Int. J. Mol. Sci. 2019, 20, 6077. [Google Scholar] [CrossRef] [PubMed]
  86. Sun, H.; Luo, L.; Lal, B.; Ma, X.; Chen, L.; Hann, C.L.; Fulton, A.M.; Leahy, D.J.; Laterra, J.; Li, M. A monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis. Nat. Commun. 2016, 7, 10339. [Google Scholar] [CrossRef] [PubMed]
  87. Bedoya, M.; Rinné, S.; Kiper, A.K.; Decher, N.; González, W.; Ramírez, D. TASK Channels Pharmacology: New Challenges in Drug Design. J. Med. Chem. 2019, 62, 10044–10058. [Google Scholar] [CrossRef] [PubMed]
  88. Linden, A.M.; Sandu, C.; Aller, M.I.; Vekovischeva, O.Y.; Rosenberg, P.H.; Wisden, W.; Korpi, E.R. TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J. Pharmacol. Exp. Ther. 2007, 323, 924–934. [Google Scholar] [CrossRef] [PubMed]
  89. Pang, D.S.; Robledo, C.J.; Carr, D.R.; Gent, T.C.; Vyssotski, A.L.; Caley, A.; Zecharia, A.Y.; Wisden, W.; Brickley, S.G.; Franks, N.P. An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action. Proc. Natl. Acad. Sci. USA 2009, 106, 17546–17551. [Google Scholar] [CrossRef]
  90. Gotter, A.L.; Santarelli, V.P.; Doran, S.M.; Tannenbaum, P.L.; Kraus, R.L.; Rosahl, T.W.; Meziane, H.; Montial, M.; Reiss, D.R.; Wessner, K.; et al. TASK-3 as a potential antidepressant target. Brain Res. 2011, 1416, 69–79. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Barel, O.; Shalev, S.A.; Ofir, R.; Cohen, A.; Zlotogora, J.; Shorer, Z.; Mazor, G.; Finer, G.; Khateeb, S.; Zilberberg, N.; et al. Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am. J. Hum. Genet. 2008, 83, 193–199. [Google Scholar] [CrossRef]
  92. Graham, J.M., Jr.; Zadeh, N.; Kelley, M.; Tan, E.S.; Liew, W.; Tan, V.; Deardorff, M.A.; Wilson, G.N.; Sagi-Dain, L.; Shalev, S.A. KCNK9 imprinting syndrome-further delineation of a possible treatable disorder. Am. J. Med. Genet. A 2016, 170, 2632–2637. [Google Scholar] [CrossRef] [PubMed]
  93. Šedivá, M.; Laššuthová, P.; Zámečník, J.; Sedláčková, L.; Seeman, P.; Haberlová, J. Novel variant in the KCNK9 gene in a girl with Birk Barel syndrome. Eur. J. Med. Genet. 2020, 63, 103619. [Google Scholar] [CrossRef]
  94. Veale, E.L.; Hassan, M.; Walsh, Y.; Al-Moubarak, E.; Mathie, A. Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol. Pharmacol. 2014, 85, 397–407. [Google Scholar] [CrossRef] [PubMed]
  95. Wright, P.D.; Veale, E.L.; McCoull, D.; Tickle, D.C.; Large, J.M.; Ococks, E.; Gothard, G.; Kettleborough, C.; Mathie, A.; Jerman, J. Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. Biochem. Biophys. Res. Commun. 2017, 493, 444–450. [Google Scholar] [CrossRef] [PubMed]
  96. Cooper, A.; Butto, T.; Hammer, N.; Jagannath, S.; Fend-Guella, D.L.; Akhtar, J.; Radyushkin, K.; Lesage, F.; Winter, J.; Strand, S.; et al. Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome. Nat. Commun. 2020, 11, 480. [Google Scholar] [CrossRef] [PubMed]
  97. Borsotto, M.; Veyssiere, J.; Moha Ou Maati, H.; Devader, C.; Mazella, J.; Heurteaux, C. Targeting two-pore domain K+ channels TREK-1 and TASK-3 for the treatment of depression: A new therapeutic concept. Br. J. Pharmacol. 2015, 172, 771–784. [Google Scholar] [CrossRef] [PubMed]
  98. Wichniak, A.; Wierzbicka, A.; Jernajczyk, W. Sleep as a biomarker for depression. Int. Rev. Psychiatry 2013, 25, 632–645. [Google Scholar] [CrossRef] [PubMed]
  99. Steiger, A.; Kimura, M. Wake and sleep EEG provide biomarkers in depression. J. Psychiatr. Res. 2010, 44, 242–252. [Google Scholar] [CrossRef] [PubMed]
  100. Wen, X.; Liao, P.; Luo, Y.; Yang, L.; Yang, H.; Liu, L.; Jiang, R. Tandem pore domain acid-sensitive K channel 3 (TASK-3) regulates visual sensitivity in healthy and aging retina. Sci. Adv. 2022, 8, eabn8785. [Google Scholar] [CrossRef] [PubMed]
  101. Rödström, K.E.J.; Kiper, A.K.; Zhang, W.; Rinné, S.; Pike, A.C.W.; Goldstein, M.; Conrad, L.J.; Delbeck, M.; Hahn, M.G.; Meier, H.; et al. A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature 2020, 582, 443–447. [Google Scholar] [CrossRef] [PubMed]
  102. Enyedi, P.; Czirják, G. Molecular background of leak K+ currents: Two-pore domain potassium channels. Physiol. Rev. 2010, 90, 559–605. [Google Scholar] [CrossRef] [PubMed]
  103. Miller, A.N.; Long, S.B. Crystal Structure of the Human Two–Pore Domain Potassium Channel K2P1. Science 2012, 335, 432. [Google Scholar] [CrossRef]
  104. González, W.; Zúñiga, L.; Cid, L.P.; Arévalo, B.; Niemeyer, M.I.; Sepúlveda, F.V. An extracellular ion pathway plays a central role in the cooperative gating of a K2P K+ channel by extracellular pH. J. Biol. Chem. 2013, 288, 5984–5991. [Google Scholar] [CrossRef]
  105. Goldstein, M.; Rinné, S.; Kiper, A.K.; Ramírez, D.; Netter, M.F.; Bustos, D.; Ortiz-Bonnin, B.; González, W.; Decher, N. Functional mutagenesis screens reveal the ‘cap structure’ formation in disulfide-bridge free TASK channels. Sci. Rep. 2016, 6, 19492. [Google Scholar] [CrossRef] [PubMed]
  106. Feliciangeli, S.; Chatelain, F.C.; Bichet, D.; Lesage, F. The family of K2P channels: Salient structural and functional properties. J. Physiol. 2015, 593, 2587–2603. [Google Scholar] [CrossRef] [PubMed]
  107. Concha, G.; Bustos, D.; Zúñiga, R.; Catalán, M.A.; Zúñiga, L. The Insensitivity of TASK-3 K₂P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure. Int. J. Mol. Sci 2018, 19, 2437. [Google Scholar] [CrossRef] [PubMed]
  108. Ramírez, D.; Arévalo, B.; Martínez, G.; Rinné, S.; Sepúlveda, F.V.; Decher, N.; González, W. Side Fenestrations Provide an “Anchor” for a Stable Binding of A1899 to the Pore of TASK-1 Potassium Channels. Mol. Pharm. 2017, 14, 2197–2208. [Google Scholar] [CrossRef] [PubMed]
  109. Jorgensen, C.; Darré, L.; Oakes, V.; Torella, R.; Pryde, D.; Domene, C. Lateral Fenestrations in K+-Channels Explored Using Molecular Dynamics Simulations. Mol. Pharm. 2016, 13, 2263–2273. [Google Scholar] [CrossRef] [PubMed]
  110. Talley, E.M.; Solorzano, G.; Lei, Q.; Kim, D.; Bayliss, D.A. Cns distribution of members of the two-pore-domain (KCNK) potassium channel family. J. Neurosci. 2001, 21, 7491–7505. [Google Scholar] [CrossRef]
  111. Rusznák, Z.; Pocsai, K.; Kovács, I.; Pór, A.; Pál, B.; Bíró, T.; Szücs, G. Differential distribution of TASK-1, TASK-2 and TASK-3 immunoreactivities in the rat and human cerebellum. Cell. Mol. Life Sci. 2004, 61, 1532–1542. [Google Scholar] [CrossRef] [PubMed]
  112. Zilberberg, N.; Ilan, N.; Goldstein, S.A. KCNKØ: Opening and closing the 2-P-domain potassium leak channel entails “C-type” gating of the outer pore. Neuron 2001, 32, 635–648. [Google Scholar] [CrossRef] [PubMed]
  113. Schewe, M.; Nematian-Ardestani, E.; Sun, H.; Musinszki, M.; Cordeiro, S.; Bucci, G.; de Groot, B.L.; Tucker, S.J.; Rapedius, M.; Baukrowitz, T. A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K+ Channels. Cell 2016, 164, 937–949. [Google Scholar] [CrossRef] [PubMed]
  114. O’Connell, A.D.; Morton, M.J.; Sivaprasadarao, A.; Hunter, M. Selectivity and interactions of Ba2+ and Cs+ with wild-type and mutant TASK1 K+ channels expressed in Xenopus oocytes. J. Physiol. 2005, 562 Pt 3, 687–696. [Google Scholar] [CrossRef]
  115. Wang, X.; Guan, R.; Zhao, X.; Zhu, D.; Song, N.; Shen, L. TASK1 and TASK3 Are Coexpressed With ASIC1 in the Ventrolateral Medulla and Contribute to Central Chemoreception in Rats. Front. Cell. Neurosci. 2018, 12, 285. [Google Scholar] [CrossRef] [PubMed]
  116. Clarke, C.E.; Veale, E.L.; Green, P.J.; Meadows, H.J.; Mathie, A. Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc. J. Physiol. 2004, 560 Pt 1, 51–62. [Google Scholar] [CrossRef]
  117. Maingret, F.; Patel, A.J.; Lazdunski, M.; Honoré, E. The endocannabinoid anandamide is a direct and selective blocker of the background K+ channel TASK-1. EMBO J. 2001, 20, 47–54. [Google Scholar] [CrossRef] [PubMed]
  118. Czirják, G.; Enyedi, P. Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. J. Biol. Chem. 2002, 277, 5426–5432. [Google Scholar] [CrossRef] [PubMed]
  119. Wilke, B.U.; Lindner, M.; Greifenberg, L.; Albus, A.; Kronimus, Y.; Bünemann, M.; Leitner, M.G.; Oliver, D. Diacylglycerol mediates regulation of TASK potassium channels by Gq-coupled receptors. Nat. Commun. 2014, 5, 5540. [Google Scholar] [CrossRef] [PubMed]
  120. Bista, P.; Pawlowski, M.; Cerina, M.; Ehling, P.; Leist, M.; Meuth, P.; Aissaoui, A.; Borsotto, M.; Heurteaux, C.; Decher, N.; et al. Differential phospholipase C-dependent modulation of TASK and TREK two-pore domain K+ channels in rat thalamocortical relay neurons. J. Physiol. 2015, 593, 127–144. [Google Scholar] [CrossRef] [Green Version]
  121. Lesage, F.; Barhanin, J. Molecular physiology of pH-sensitive background K2P channels. Physiology (Bethesda) 2011, 26, 424–437. [Google Scholar] [CrossRef] [PubMed]
  122. Yuill, K.; Ashmole, I.; Stanfield, P.R. The selectivity filter of the tandem pore potassium channel TASK-1 and its pH-sensitivity and ionic selectivity. Pflugers Arch. 2004, 448, 63–69. [Google Scholar] [CrossRef] [PubMed]
  123. Chen, H.; Chatelain, F.C.; Lesage, F. Altered and dynamic ion selectivity of K+ channels in cell development and excitability. Trends Pharmacol. Sci. 2014, 35, 461–469. [Google Scholar] [CrossRef] [PubMed]
  124. Ma, L.; Zhang, X.; Zhou, M.; Chen, H. Acid-sensitive TWIK and TASK two-pore domain potassium channels change ion selectivity and become permeable to sodium in extracellular acidification. J. Biol. Chem. 2012, 287, 37145–37153. [Google Scholar] [CrossRef] [PubMed]
  125. Chatelain, F.C.; Bichet, D.; Douguet, D.; Feliciangeli, S.; Bendahhou, S.; Reichold, M.; Warth, R.; Barhanin, J.; Lesage, F. TWIK1, a unique background channel with variable ion selectivity. Proc. Natl. Acad. Sci. USA 2012, 109, 5499–5504. [Google Scholar] [CrossRef]
  126. Bezanilla, F. Gating currents. J. Gen. Physiol. 2018, 150, 911–932. [Google Scholar] [CrossRef] [PubMed]
  127. Zhang, Q.; Fu, J.; Zhang, S.; Guo, P.; Liu, S.; Shen, J.; Guo, J.; Yang, H. ‘C-type’ closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel. J. Mol. Cell. Biol. 2022, 14, mjac002. [Google Scholar] [CrossRef]
  128. Bagriantsev, S.N.; Peyronnet, R.; Clark, K.A.; Honoré, E.; Minor, D.L., Jr. Multiple modalities converge on a common gate to control K2P channel function. EMBO J. 2011, 30, 3594–3606. [Google Scholar] [CrossRef] [PubMed]
  129. Lolicato, M.; Arrigoni, C.; Mori, T.; Sekioka, Y.; Bryant, C.; Clark, K.A.; Minor, D.L., Jr. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Nature 2017, 547, 364–368. [Google Scholar] [CrossRef]
  130. Piechotta, P.L.; Rapedius, M.; Stansfeld, P.J.; Bollepalli, M.K.; Ehrlich, G.; Andres-Enguix, I.; Fritzenschaft, H.; Decher, N.; Sansom, M.S.; Tucker, S.J.; et al. The pore structure and gating mechanism of K2P channels. EMBO J. 2011, 30, 3607–3619. [Google Scholar] [CrossRef] [PubMed]
  131. Lolicato, M.; Natale, A.M.; Abderemane-Ali, F.; Crottès, D.; Capponi, S.; Duman, R.; Wagner, A.; Rosenberg, J.M.; Grabe, M.; Minor, D.L., Jr. K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions. Sci. Adv. 2020, 6, eabc9174. [Google Scholar] [CrossRef]
  132. Natale, A.M.; Deal, P.E.; Minor, D.L., Jr. Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels. J. Mol. Biol. 2021, 433, 166995. [Google Scholar] [CrossRef]
  133. Wiedmann, F.; Kiper, A.K.; Bedoya, M.; Ratte, A.; Rinné, S.; Kraft, M.; Waibel, M.; Anad, P.; Wenzel, W.; González, W.; et al. Identification of the A293 (AVE1231) Binding Site in the Cardiac Two-Pore-Domain Potassium Channel TASK-1: A Common Low Affinity Antiarrhythmic Drug Binding Site. Cell. Physiol. Biochem. 2019, 52, 1223–1235. [Google Scholar] [PubMed]
  134. Chokshi, R.H.; Larsen, A.T.; Bhayana, B.; Cotten, J.F. Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore. Mol. Pharmacol. 2015, 88, 926–934. [Google Scholar] [CrossRef]
  135. Flaherty, D.P.; Simpson, D.S.; Miller, M.; Maki, B.E.; Zou, B.; Shi, J.; Wu, M.; McManus, O.B.; Aubé, J.; Li, M.; et al. Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold. Bioorg. Med. Chem. Lett. 2014, 24, 3968–3973. [Google Scholar] [CrossRef] [PubMed]
  136. Ramírez, D.; Bedoya, M.; Kiper, A.K.; Rinné, S.; Morales-Navarro, S.; Hernández-Rodríguez, E.W.; Sepúlveda, F.V.; Decher, N.; González, W. Structure/Activity Analysis of TASK-3 Channel Antagonists Based on a 5,6,7,8 tetrahydropyrido [4,3-d]pyrimidine. Int. J. Mol. Sci 2019, 20, 2252. [Google Scholar] [CrossRef]
  137. Li, B.; Rietmeijer, R.A.; Brohawn, S.G. Structural basis for pH gating of the two-pore domain K+ channel TASK2. Nature 2020, 586, 457–462. [Google Scholar] [CrossRef] [PubMed]
  138. Czirják, G.; Enyedi, P. Ruthenium red inhibits TASK-3 potassium channel by interconnecting glutamate 70 of the two subunits. Mol. Pharmacol. 2003, 63, 646–652. [Google Scholar] [CrossRef] [PubMed]
  139. Pope, L.; Lolicato, M.; Minor, D.L., Jr. Polynuclear Ruthenium Amines Inhibit K2P Channels via a “Finger in the Dam” Mechanism. Cell Chem. Biol. 2020, 27, 511–524.e4. [Google Scholar] [CrossRef] [PubMed]
  140. Braun, G.; Lengyel, M.; Enyedi, P.; Czirják, G. Differential sensitivity of TREK-1, TREK-2 and TRAAK background potassium channels to the polycationic dye ruthenium red. Br. J. Pharmacol. 2015, 172, 1728–1738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Dong, Y.Y.; Pike, A.C.; Mackenzie, A.; McClenaghan, C.; Aryal, P.; Dong, L.; Quigley, A.; Grieben, M.; Goubin, S.; Mukhopadhyay, S.; et al. K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science 2015, 347, 1256–1259. [Google Scholar] [CrossRef] [PubMed]
  142. Brohawn, S.G.; Campbell, E.B.; MacKinnon, R. Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature 2014, 516, 126–130. [Google Scholar] [CrossRef]
  143. Lolicato, M.; Riegelhaupt, P.M.; Arrigoni, C.; Clark, K.A.; Minor, D.L., Jr. Transmembrane helix straightening and buckling underlies activation of mechanosensitive and thermosensitive K2P channels. Neuron 2014, 84, 1198–1212. [Google Scholar] [CrossRef] [PubMed]
  144. Brohawn, S.G.; Su, Z.; MacKinnon, R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proc. Natl. Acad. Sci. USA 2014, 111, 3614–3619. [Google Scholar] [CrossRef] [PubMed]
  145. Rinné, S.; Kiper, A.K.; Vowinkel, K.S.; Ramírez, D.; Schewe, M.; Bedoya, M.; Aser, D.; Gensler, I.; Netter, M.F.; Stansfeld, P.J.; et al. The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels. Elife 2019, 8, e39476. [Google Scholar] [CrossRef] [PubMed]
  146. Guyenet, P.G.; Bayliss, D.A.; Stornetta, R.L.; Ludwig, M.G.; Kumar, N.N.; Shi, Y.; Burke, P.G.; Kanbar, R.; Basting, T.M.; Holloway, B.B.; et al. Proton detection and breathing regulation by the retrotrapezoid nucleus. J. Physiol. 2016, 594, 1529–1551. [Google Scholar] [CrossRef] [PubMed]
  147. Hayabuchi, Y. The Action of Smooth Muscle Cell Potassium Channels in the Pathology of Pulmonary Arterial Hypertension. Pediatr. Cardiol. 2017, 38, 1–14. [Google Scholar] [CrossRef] [PubMed]
  148. Le Ribeuz, H.; Capuano, V.; Girerd, B.; Humbert, M.; Montani, D.; Antigny, F. Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension. Biomolecules 2020, 10, 1261. [Google Scholar] [CrossRef] [PubMed]
  149. Southgate, L.; Machado, R.D.; Gräf, S.; Morrell, N.W. Molecular genetic framework underlying pulmonary arterial hypertension. Nat. Rev. Cardiol. 2019, 17, 85–95. [Google Scholar] [CrossRef]
  150. Dogan, M.F.; Yildiz, O.; Arslan, S.O.; Ulusoy, K.G. Potassium channels in vascular smooth muscle: A pathophysiological and pharmacological perspective. Fundam. Clin. Pharmacol. 2019, 33, 504–523. [Google Scholar] [CrossRef]
  151. Tennant, B.P.; Cui, Y.; Tinker, A.; Clapp, L.H. Functional expression of inward rectifier potassium channels in cultured human pulmonary smooth muscle cells: Evidence for a major role of Kir2.4 subunits. J. Membr. Biol. 2006, 213, 19–29. [Google Scholar] [CrossRef] [PubMed]
  152. Wiedmann, F.; Frey, N.; Schmidt, C. Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes. Cells 2021, 10, 2914. [Google Scholar] [CrossRef] [PubMed]
  153. Rinné, S.; Kiper, A.K.; Schlichthörl, G.; Dittmann, S.; Netter, M.F.; Limberg, S.H.; Silbernagel, N.; Zuzarte, M.; Moosdorf, R.; Wulf, H.; et al. TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes. J. Mol. Cell. Cardiol. 2015, 81, 71–80. [Google Scholar] [CrossRef] [PubMed]
  154. Staudacher, K.; Staudacher, I.; Ficker, E.; Seyler, C.; Gierten, J.; Kisselbach, J.; Rahm, A.K.; Trappe, K.; Schweizer, P.A.; Becker, R.; et al. Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels. Br. J. Pharmacol. 2011, 163, 1099–1110. [Google Scholar] [CrossRef]
  155. Rahman, F.; Kwan, G.F.; Benjamin, E.J. Global epidemiology of atrial fibrillation. Nat. Rev. Cardiol. 2014, 11, 639–654. [Google Scholar] [CrossRef]
  156. Shvetsova, A.A.; Lazarenko, V.S.; Gaynullina, D.K.; Tarasova, O.S.; Schubert, R. TWIK-Related Acid-Sensitive Potassium Channels (TASK-1) Emerge as Contributors to Tone Regulation in Renal Arteries at Alkaline pH. Front. Physiol. 2022, 13, 982. [Google Scholar] [CrossRef]
  157. Shvetsova, A.A.; Gaynullina, D.K.; Schmidt, N.; Bugert, P.; Lukoshkova, E.V.; Tarasova, O.S.; Schubert, R. TASK-1 channel blockade by AVE1231 increases vasocontractile responses and BP in 1- to 2-week-old but not adult rats. Br. J. Pharmacol. 2020, 177, 5148–5162. [Google Scholar] [CrossRef]
  158. Meadows, H.J.; Randall, A.D. Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology 2001, 40, 551–559. [Google Scholar] [CrossRef]
  159. Reeh, P.W.; Kress, M. Molecular physiology of proton transduction in nociceptors. Curr. Opin. Pharmacol. 2001, 1, 45–51. [Google Scholar] [CrossRef] [PubMed]
  160. Waldmann, R.; Champigny, G.; Bassilana, F.; Heurteaux, C.; Lazdunski, M. A proton-gated cation channel involved in acid-sensing. Nature 1997, 386, 173–177. [Google Scholar] [CrossRef] [PubMed]
  161. Plant, L.D. A Role for K2P Channels in the Operation of Somatosensory Nociceptors. Front. Mol. Neurosci. 2012, 5, 21. [Google Scholar] [CrossRef] [PubMed]
  162. Sun, W.H.; Chen, C.C. Roles of Proton-Sensing Receptors in the Transition from Acute to Chronic Pain. J. Dent. Res. 2016, 95, 135–142. [Google Scholar] [CrossRef]
  163. Morenilla-Palao, C.; Luis, E.; Fernández-Peña, C.; Quintero, E.; Weaver, J.L.; Bayliss, D.A.; Viana, F. Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep. 2014, 8, 1571–1582. [Google Scholar] [CrossRef]
  164. Sirois, J.E.; Lynch, C., 3rd; Bayliss, D.A. Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones. J. Physiol. 2002, 541 Pt 3, 717–729. [Google Scholar] [CrossRef]
  165. Meuth, S.G.; Budde, T.; Kanyshkova, T.; Broicher, T.; Munsch, T.; Pape, H.C. Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons. J. Neurosci. 2003, 23, 6460–6469. [Google Scholar] [CrossRef] [PubMed]
  166. Buljubasic, N.; Rusch, N.J.; Marijic, J.; Kampine, J.P.; Bosnjak, Z.J. Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells. Anesthesiology 1992, 76, 990–998. [Google Scholar] [CrossRef] [PubMed]
  167. Decher, N.; Rinné, S.; Bedoya, M.; Gonzalez, W.; Kiper, A.K. Molecular Pharmacology of K2P Potassium Channels. Cell. Physiol. Biochem. 2021, 55, 87–107. [Google Scholar] [PubMed]
  168. Bista, P.; Cerina, M.; Ehling, P.; Leist, M.; Pape, H.C.; Meuth, S.G.; Budde, T. The role of two-pore-domain background K+ (K2P) channels in the thalamus. Pflugers Arch. 2015, 467, 895–905. [Google Scholar] [CrossRef] [PubMed]
  169. Meuth, S.G.; Aller, M.I.; Munsch, T.; Schuhmacher, T.; Seidenbecher, T.; Meuth, P.; Kleinschnitz, C.; Pape, H.C.; Wiendl, H.; Wisden, W.; et al. The contribution of TWIK-related acid-sensitive K+-containing channels to the function of dorsal lateral geniculate thalamocortical relay neurons. Mol. Pharmacol. 2006, 69, 1468–1476. [Google Scholar] [CrossRef] [PubMed]
  170. Krishnan, V.; Nestler, E.J. The molecular neurobiology of depression. Nature 2008, 455, 894–902. [Google Scholar] [CrossRef] [Green Version]
  171. Nestler, E.J.; Barrot, M.; DiLeone, R.J.; Eisch, A.J.; Gold, S.J.; Monteggia, L.M. Neurobiology of depression. Neuron 2002, 34, 13–25. [Google Scholar] [CrossRef] [PubMed]
  172. Schmidt, C.; Wiedmann, F.; Gaubatz, A.R.; Ratte, A.; Katus, H.A.; Thomas, D. New Targets for Old Drugs: Cardiac Glycosides Inhibit Atrial-Specific K2P3.1 (TASK-1) Channels. J. Pharmacol. Exp. Ther. 2018, 365, 614–623. [Google Scholar] [CrossRef] [PubMed]
  173. Streit, A.K.; Netter, M.F.; Kempf, F.; Walecki, M.; Rinné, S.; Bollepalli, M.K.; Preisig-Müller, R.; Renigunta, V.; Daut, J.; Baukrowitz, T.; et al. A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore. J. Biol. Chem. 2011, 286, 13977–13984. [Google Scholar] [CrossRef]
  174. Zou, B.; Flaherty, D.P.; Simpson, D.S.; Maki, B.E.; Miller, M.R.; Shi, J.; Wu, M.; McManus, O.B.; Golden, J.E.; Aubé, J.; et al. ML365: Development of Bis-Amides as Selective Inhibitors of the KCNK3/TASK1 Two Pore Potassium Channel. In Probe Reports from the NIH Molecular Libraries Program; National Center for Biotechnology Information (US): Bethesda, MD, USA, 2010. [Google Scholar]
  175. Tian, F.; Qiu, Y.; Lan, X.; Li, M.; Yang, H.; Gao, Z. A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues. Mol. Pharmacol. 2019, 96, 26–35. [Google Scholar] [CrossRef] [PubMed]
  176. Miller, M.R.; Zou, B.; Shi, J.; Flaherty, D.P.; Simpson, D.S.; Yao, T.; Maki, B.E.; Day, V.W.; Douglas, J.T.; Wu, M.; et al. Development of a Selective Chemical Inhibitor for the Two-Pore Potassium Channel, KCNK9. In Probe Reports from the NIH Molecular Libraries Program; National Center for Biotechnology Information (US): Bethesda, MD, USA, 2010. [Google Scholar]
  177. Coburn, C.A.; Luo, Y.; Cui, M.; Wang, J.; Soll, R.; Dong, J.; Hu, B.; Lyon, M.A.; Santarelli, V.P.; Kraus, R.L.; et al. Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3). ChemMedChem 2012, 7, 123–133. [Google Scholar] [CrossRef]
  178. White, R.; Ho, W.S.; Bottrill, F.E.; Ford, W.R.; Hiley, C.R. Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br. J. Pharmacol. 2001, 134, 921–929. [Google Scholar] [CrossRef] [PubMed]
  179. Van den Bossche, I.; Vanheel, B. Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta. Br. J. Pharmacol. 2000, 131, 85–93. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. The structure and topology of the hTASK-1 channel. (A) Side view from the cell membrane. The hTASK-1 channel (PDB code 6RV2) consists of two homologous subunits, which are shown in blue and olive. The four transmembrane fragments (M1–M4) and two extracellular cap regions are labeled. (B) Top view of the hTASK-1 channel from the extracellular face, with the two pore helices (PH1 and PH2) highlighted in red and magenta in each subunit, respectively. The purple spheres are potassium ions. (C) Schematic topology of TASK channels: EC1 and EC2 are extracellular caps 1 and 2; P1 and P2 are pore regions 1 and 2; SF1 and SF2 are the selectivity filter of P1 and P2; OUT and IN represent the extracellular and intracellular surface, respectively.
Figure 1. The structure and topology of the hTASK-1 channel. (A) Side view from the cell membrane. The hTASK-1 channel (PDB code 6RV2) consists of two homologous subunits, which are shown in blue and olive. The four transmembrane fragments (M1–M4) and two extracellular cap regions are labeled. (B) Top view of the hTASK-1 channel from the extracellular face, with the two pore helices (PH1 and PH2) highlighted in red and magenta in each subunit, respectively. The purple spheres are potassium ions. (C) Schematic topology of TASK channels: EC1 and EC2 are extracellular caps 1 and 2; P1 and P2 are pore regions 1 and 2; SF1 and SF2 are the selectivity filter of P1 and P2; OUT and IN represent the extracellular and intracellular surface, respectively.
Molecules 27 08296 g001
Figure 2. Representative illustration of the current−voltage (I−V) relationship for TASK channels under different extracellular pH conditions. TASK channels are sensitive to changes in extracellular pH; they are significantly inhibited by acids and are weakly activated by alkalis.
Figure 2. Representative illustration of the current−voltage (I−V) relationship for TASK channels under different extracellular pH conditions. TASK channels are sensitive to changes in extracellular pH; they are significantly inhibited by acids and are weakly activated by alkalis.
Molecules 27 08296 g002
Figure 3. Chemical structures of compounds that target TASK-1 and TASK-3 channels. (A) The chemical structures of inhibitors targeting TASK-1 channel. (B) The chemical structures of activators targeting TASK-3 channel. (C) The chemical structures of inhibitors targeting TASK-3 channel.
Figure 3. Chemical structures of compounds that target TASK-1 and TASK-3 channels. (A) The chemical structures of inhibitors targeting TASK-1 channel. (B) The chemical structures of activators targeting TASK-3 channel. (C) The chemical structures of inhibitors targeting TASK-3 channel.
Molecules 27 08296 g003
Table 1. The classification and simple comparisons of mammalian TASK channels.
Table 1. The classification and simple comparisons of mammalian TASK channels.
ChannelGene NameLength in HumansDistribution in HumansIndicative Biological RolesReferences
KCNK3394Abundantly expressed in the CNS and periphery. CNS: highest in the cerebellum, thalamus and pituitary gland, and lowest in the corpus callosum.
Periphery: highest in the pancreas, placenta, lungs and pulmonary arteries, and lower in the prostate, stomach, small intestine, and heart, and lowest in the liver, spleen, skeletal muscle, and testis.
Chemosensation of breathing rhythm, pulmonary artery hypertension (PAH), cardiac arrhythmia (AF), aldosterone secretion, pain, general anesthesia, local anesthetic toxicity, glucose homeostasis[11,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70]
KCNK9374Predominantly expressed in the CNS: highest in the cerebellum, higher in the cerebral cortex, thalamus, nucleus accumbens, hippocampus, and hypothalamus, and lowest in the spinal cord, caudate nucleus, and corpus callosum.
Small amounts in the periphery: stomach, testis, skeletal muscles, uterus, kidneys, spleen, pancreas, prostate, and small intestine, and lowest in the heart, liver, and lungs.
Aldosterone secretion, pain, general anesthesia, local anesthetic toxicity, cancers, sleep, BBIDS, depression, visual sensitivity[12,14,15,17,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100]
KCNK15330Highest in the pancreas, higher in the liver, kidneys, lungs, ovary, testis, and heart.No reports[13]
Table 2. List of selectively targeted compounds.
Table 2. List of selectively targeted compounds.
ChannelActivatorsCompound CategoryEC50 (μM)ReferenceInhibitorsCompound CategoryIC50 (μM)Reference
TASK-1 MethanandamideCannabinoids0.7 (MC)[117]
DigitoxinCardiac glycosides7.4 (XO)[172]
DigoxinCardiac glycosides0.9 (XO)[172]
A293Small molecules0.22 (XO)[41]
A1899Small molecules0.035 (XO), 0.007 (MC)[173]
ML365Small molecules0.016 (MC) [135,174]
TASK-3TerbinafineAntifungalsNI[95]Ruthenium redCationic dyes0.114 (XO)[139]
CHET3Small molecules1.4 (MC)[74]Ru360Polynuclear ruthenium amines15.6 (XO)[139]
NPBASmall molecules6.7 (MC)[175]ML308Small molecules0.413 (MC)[176]
PK-THPPSmall molecules0.035 (MC)[177]
XO: Xenopus oocytes, MC: mammalian cells, NI: not investigated.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Fan, X.; Lu, Y.; Du, G.; Liu, J. Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets. Molecules 2022, 27, 8296.

AMA Style

Fan X, Lu Y, Du G, Liu J. Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets. Molecules. 2022; 27(23):8296.

Chicago/Turabian Style

Fan, Xueming, Yongzhi Lu, Guizhi Du, and Jin Liu. 2022. "Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets" Molecules 27, no. 23: 8296.

Article Metrics

Back to TopTop