Two-Pore Domain TASK Potassium Channels: Comparison
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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. 

  • TASK channels
  • biophysical properties
  • gating profiles
  • biological roles
  • targeted compounds

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][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][11][12][13]. 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[14][15][16],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.

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][17]. 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][18] (Figure 1). The structures of TASK-1 channel are from protein data bank (PDB) and are generated by PyMOL 2.5.
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.

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][19][20]. It is lower in the prostate, stomach, small intestine, and heart and lowest in the liver, spleen, skeletal muscles, and testes [17][19]. 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][16][21]. 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][19]. 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][21][22][23]. 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][24]. 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][25]. TASK channel currents are outwardly rectified and insensitive to potassium channel blockers, such as Ba2+, Cs+, TEA, and 4-AP [114][26]. 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[27][28],116], whereas anandamide has a more potent blocking effect on TASK-1 than the TASK-3 channel [117][29]. In addition, TASK-1 and TASK-3 channel proteins can form functional heterodimers and are insensitive to mechanical forces [71,118][22][30]. The second messenger diacylglycerol can also inhibit TASK channels by activating G protein-coupled receptors [119,120][31][32]. TASK channels are sensitive to changes in extracellular pH but not intracellular pH, and can be blocked by external protons [121][33]. 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][34][35]. 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][36][37][38].
Molecules 27 08296 g002 550
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.

3. The Biological Roles of TASK Channels

3.1. 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][39][40][41]. 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][42]. 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][43]. 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][44]. 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][45]. 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][1][40][46][47].

3.2. 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][48][49][50]. 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][51][52]. Human PASMCs express only TASK-1 potassium channels [26][53].

3.3. 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][54][55][56]. The TASK-1 channel is known to be involved in the pathophysiology of cardiovascular diseases [37,38,39][57][58][59]. It has been found that TASK-1 KO mice have a significantly prolonged action potential duration [40][60] 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][61]. 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][62][63].

3.4. 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][64]. Furthermore, statistical analyses indicated that KCNK3 (TASK-1) variants are associated with hyperaldosteronism and hypertension [53][65]. 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][66] Several other studies also indicated that TASK channels participate in the modulation of aldosterone secretion [55,56,57][67][68][69].

3.5. 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][22][70]. 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][71][72][73][74]. Several studies have shown that TASK channels are closely associated with pain [58,59,72][75][76][77].
Marsh et al. [60][78] 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][79]. 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][80]. Liao et al. [74][81] 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][82] 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.

3.6. Anesthetics

3.6.1. 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][83]. 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][84][85] 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][86]. 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][87] 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][88] 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][17][89]. 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][90].

3.7. 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][91][92][93][94][95][96][97][98]. 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][99][100]. 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][101]. 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][102]. These confirmed that the TASK-3 channel is a promising target for the treatment of malignancies that express KCNK9 [87][103].

3.8. Neurological Activities and/or Disorders

3.8.1. 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][104]. 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][105]. 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][106]. 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][107][108].

3.9. Other Roles

Several studies have shown that the TASK-1 channels found in the pancreas participate in the regulation of glucose homeostasis [69,70][109][110]. Using the highly specific “RNAscope” method of in situ mRNA hybridization in combination with pharmacological antagonists and genetic deletion tools, Wen et al. [100][111] 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.

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