Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101910


Historical Background

Based on the structural features, K+ channels are classified into the voltage-gated K+ channels, Ca2+-dependent K+ channels, and leak K+ (two-pore-domain K+) channels (Fig. 1). The voltage-gated K+ channels and Ca2+-dependent K+ channels form tetramers, with each subunit containing six or seven transmembrane domains and one pore domain while leak K+ (two-pore-domain K+) channels form dimers, with each subunit containing four transmembrane domains and two pore domains (Goldstein et al. 2001; Bayliss et al. 2003). In excitable cells, a negative membrane potential is critical for electrical signaling, and it has long been considered that this key mechanism is largely mediated by leak K+ currents (Goldman 1943). However, the molecular basis for characterizing functional properties of leak K+ channel subunits remained unknown over many years. In the 1990s, the discovery of the KCNK gene family has been described whose members generate the hallmark properties of leak K+ currents (Goldstein et al. 2001). In mammalians, 15 subunits have been identified and were further divided into six subfamilies (TWIK; tandem of P domains in a weak inward rectifying K+, TREK; TWIK-related K+, TASK; TWIK-related acid-sensitive K+, THIK; TWIK-related halothane-inhibited K+, TRESK; TWIK-related spinal cord K+ and TALK; TWIK-related alkali-activated sensitive K+) on the basis of sequence similarity and functional resemblance (Goldstein et al. 2001; Enyedi and Czirjak 2010) (Table 1). The TWIK group includes the weakly inwardly rectifying channels (TWIK1, TWIK2, and the nonfunctional KCNK7); the THIK group includes halothane-inhibited THIK1 channel and related nonfunctional THIK2; the TREK group includes the arachidonic acid and mechanosensitive channels (TREK1, TREK2, and TRAAK); the TALK group includes the alkaline-activated channels (TASK2, TALK1, and TALK2/TASK4); the TASK group includes acid-sensitive channels (TASK1, TASK3, and the nonfunctional TASK5); and the TRESK group includes Ca2+-activated channels (TRESK1).
Task, Fig. 1

Three majorK + channel gene families. (a) Voltage/Ca2+-gated K+ channels have six (or seven) transmembrane segments and one pore domain. These channels form as tetramers. (b) Inwardly rectifying K+ (Kir) channels have two transmembrane segments and one pore domain. These channels form as tetramers. (c) Leak K+ channels have four transmembrane segments and two pore domain, each one resembling two Kir channels arranged in tandem. These channels form as dimers

Task, Table 1

The 15 human leak K+ channels



Subunit names



(tandem of P domains in a weak inward rectifying K+)



Weak inward rectification






(TWIK-related halothane-inhibited K+)






Inhibition by halothane


(TWIK-related K+)



Activation by lipid, temperature, and mechanical stimuli






(TWIK-related acid-sensitive K+)



Inhibition by extracellular pH

(pK ~6.5–7.5)







(TWIK-related alkali-activated sensitive K+)



Inhibition by extracellular pH

(pK > 8)






(TWIK-related spinal cord K+)



Activation by calcium

TASK1 was cloned from mouse and rat tissues, and its mRNA was shown to be expressed in heart tissue (Duprat et al. 1997). Subsequently, it was found that TASK1 mRNA is expressed in the brain (Karschin et al. 2001; Talley et al. 2001). TASK1 is also expressed in the testis, spleen, lung, kidney, vascular tissue, and adrenal cortex. TASK3 was cloned from rat, guinea pig, and human tissues, and its mRNA was highly expressed in the brain but was very weakly expressed in other tissues. (Kim et al. 2000; Rajan et al. 2000). TASK2 (KCNK5, K2p5.1, TASK-2, KCNK5b, potassium two-pore-domain channel subfamily K member 5) was cloned from human kidney (Reyes et al. 1998). TASK2 was initially named as TASK2 because of its sensitivity to the extracellular pH. However, TASK2 was later reassigned as TALK group since this channel has a low sequence similarity to other two-pore-domain K+ channels, TWIK1, TREK1, TASK1, and TRAAK (18–22% of amino acid identity) (Reyes et al. 1998). TASK-2 mRNA expression was expressed in the kidney, pancreas, and liver whereas its expression in the brain was relatively low (Enyedi and Czirjak 2010).

TASK Subgroup of the KCNK Gene Family

The TASK subgroup of the KCNK gene family is two-pore-domain K+ channels that generate pH-sensitive K+ currents with little time-dependence and weak rectification (Goldstein et al. 2001; Bayliss et al. 2003). This subgroup includes TASK1 (also known as K2P3.1), TASK3 (K2P9.1), and TASK5 (K2P15.1). In heterologous expression systems, TASK1 and TASK3 channels were able to form functional homomeric channels in vitro and in vivo (Czirjak and Enyedi 2002; Berg et al. 2004; Lazarenko et al. 2010) whereas TASK5 channels were found to be inactive (Kim and Gnatenco 2001). TASK3 channels share 54% amino acid identity with TASK1 but less than 30% with other leak K+ channels (Kim et al. 2000). TASK1 channels are abundantly expressed in cerebellar granule neurons, somatic motoneurons, and the locus coeruleus, while TASK3 channels are also abundantly and more widely distributed, with particularly high expression in somatic motoneurons, cerebellar granule neurons, the locus coeruleus and raphe nuclei, and in various nuclei of the thalamus and hypothalamus (Talley et al. 2001; Bayliss et al. 2003). These channels seem to be coexpressed in granule neurons, somatic motoneurons, locus coeruleus neurons, and thalamic neurons. It could be noted that TASK1 and TASK3 subunits are not merely coexpressed, but they readily form functional heteromers (Czirjak and Enyedi 2002; Berg et al. 2004). The unitary conductance of TASK3 channel (∼28 ps) is about two times larger than that of TASK1 channel (∼14 pS) (Kim et al. 1999, 2000; Lesage 2003; Kim et al. 2009). The single-channel conductance of the TASK1/3 heterodimer equals that of the TASK3 homodimer (Kang et al. 2004). Although the macroscopic currents arising from TASK1 and TASK3 channels are similar, the sensitivity to extracellular pH is different. TASK1 and TASK3 channels show different extracellular pH sensitivity. The pK for TASK1 channel inhibition is ∼7.4 while that for TASK3 channel is ∼6.7 (Kim et al. 1999, 2000; Bayliss et al. 2003; Bayliss and Barrett 2008). TASK1 and TASK3 channels are inhibited by extracellular acidification and local anesthetics (Bayliss et al. 2003; Bayliss and Barrett 2008; Enyedi and Czirjak 2010). These channels are also inhibited by hormones and transmitters (e.g., muscarinic M3, thyrotropin-releasing hormone 1, and AT1a angiotensin II receptors) that act through Gq/11-coupled receptors (Czirjak et al. 2000; Millar et al. 2000). It had been reported that depletion of the PLC substrate, phosphatidylinositol-4,5-bisphosphate, PIP2, may be the signal triggering channel deactivation (Lopes et al. 2005; Chen et al. 2006). However, it has recently been shown that diacylglycerol (DAG) inhibits TASK channels, and channel activity is independent of PIP2 (Wilke et al. 2014). TASK1 and TASK3 channels are activated by volatile anesthetics such as halothane and isoflulane (Bayliss et al. 2003; Bayliss and Barrett 2008; Enyedi and Czirjak 2010) (Fig. 2). Interaction of TASK channels with partner proteins such as 14-3-3, β-COP, and p11 influence functional cell surface expression of the channels (Fig. 3).
Task, Fig. 2

Regulatory mechanisms of TASK1 channels. TASK1 channels are activated by general anesthetics such as halothane and isoflulane. In contrast, TASK1 channels are inhibited by local anesthetics such as lidocaine and bupivacaine, acidic pH, and Gq-coupled signaling transduction. TASK1 channels are also inhibited by hypoxia

Task, Fig. 3

pH sensitivity of TASK channels. The open probability of homomeric TASK3 channels at pH 7.3 is almost maximal, while that of homommeric TASK1 channels is less than 40% of the maximal probability. The pH sensitivity of TASK1/3 heteromeric channels is intermediate between those of TASK1 and TASK3 homomeric channels

TASK1 and TASK3 channels have been well studied, because they are considered to play essential physiological roles. Until now, functional significances of TASK channels have been increasingly elucidated (Enyedi and Czirjak 2010). This chapter will focus on the function of the TASK channels as signaling molecules in neurological disorders and pain.

TASK Channels and Neurological Disorders

When ischemic state occurs, the transient membrane depolarization is induced in neurons. Consequently, the release of neurotransmitters such as glutamate, neuropeptide, and Zn2+ is enhanced (Koh et al. 1996). TASK1 and TASK3 channels are sensitive to acidic pH and hypoxic conditions. In addition, TASK3 homomeric channels are selectively suppressed by Zn2+ (Clarke et al. 2008). Considering that acidic pH and hypoxia are observed and the release of Zn+ is enhanced during ischemic conditions, TASK1 and TASK3 channels are likely to be involved in the development of ischemic stroke. Indeed, the roles of these channels in the ischemic stroke development have been revealed by pharmacological inhibitors and genetic knockout mice (KO). In a transient middle cerebral artery occlusion model of cerebral ischemia in TASK1 KO mice, the infarct volume was significantly larger than that in control mice. By contrast, the infarct volume in TASK3 KO mice was unchanged (Meuth et al. 2009). The same observation was reported in another study (Muhammad et al. 2010). The increased infarct volume could be mimicked by the TASK1 inhibitor anandamide (Meuth et al. 2009). Interestingly, it was found that male TASK1 KO mice displayed reduced blood pressure, presumably explaining the increased infarct volume seen after permanent middle cerebral artery occlusion (Muhammad et al. 2010). These findings suggest TASK1 in the brain decreases neuronal damage when stroke occurs.

In pathological conditions such as ischemia and epilepsy, it has been demonstrated that the extracellular pH changed in the brain (Mutch and Hansen 1984; Xiong and Stringer 2000). In the CA1 hippocampal areas, recurrent epileptiform activity caused biphasic pH shifts, consisting of an initial extracellular alkalinization followed by a slower acidification (Xiong and Stringer 2000). The authors indicated that the distinct extracellular pH shifts between CA1 and dentate gyrus might have caused the regional differences in seizure susceptibility between these two areas (Xiong and Stringer 2000). Because TASK channels are highly sensitive to changes in extracellular pH, several studies implicated the involvements of these channels in the generation of epilepsy. The changes in neuronal excitability within the hippocampus are one of the hallmarks of temporal lobe epilepsy (Wasterlain et al. 1993). Therefore, it is conceivable that TASK channels in the hippocampus play essential roles in the generation of epilepsy. Firstly, the role of TASK1 channels in epilepsy was investigated in the hippocampus of gerbils (Kim et al. 2007). In adult SS gerbil hippocampus, TASK1 immunoreactivity in astrocytes was higher compared to the adult SR gerbil hippocampus. After seizure events, TASK1 immunoreactivity was significantly downregulated in astrocytes of the SS gerbil hippocampus. Furthermore, several antiepileptic drugs selectively reduced the TASK1 immunoreactivity in astrocytes of the SS gerbil hippocampus (Kim et al. 2007). These findings indicated that upregulation of TASK1 channels in astrocytes may be responsible for the seizure activity of adult SS gerbils and that downregulation of TASK1 channels in astrocytes may suppress the seizure activity.

Several studies reported the discovery of epilepsy-related mutations in genes encoding TASK channel proteins. Childhood absence epilepsy is an idiopathic, generalized, nonconvulsive epilepsy that occurs in otherwise normal children. The KCNK9 gene coding for the TASK3 channel is present on chromosome 8 in a locus that shows positive genetic linkage to the human absence epilepsy phenotype (Fong et al. 1998). Furthermore, in the genetic absence epilepsy rats from Strasbourg (GAERS), an additional alanine residue in a polyalanine tract within the C-terminal intracellular domain was detected in the KCNK gene. For this reason, TASK3 channels were regarded as a promising candidate gene for absence epilepsy. However, there were no significant differences in the physiological properties between the wild-type and mutant TASK3 channels (Holter et al. 2005). In addition, leak K+ currents were almost similar between thalamocortical neuros in GAERS and nonepileptic animals (Holter et al. 2005). These observations suggest that TASK3 gene was not associated with absence epilepsy. On the other hand, a mutation analysis of the TASK3 gene was performed in patients with children and juvenile absence epilepsy (Kananura et al. 2002). Only one silent polymorphism was detected in exon 2 of the TASK-3 coding region. However, since there was no relationship between the exon 2 polymorphism and absence epilepsy (Kananura et al. 2002), the human TASK3 appears not to be involved in the absence epilepsy.

Previous studies revealed that the expression of TASK channels may substantially affect cell viability in either direction (Lauritzen et al. 2003). It has been demonstrated that TASK3 channels are responsible for K+-dependent apoptosis in cultured cerebellar granule neurons. Neuronal death was caused by apoptosis when cerebellar granule neurons were cultured in vitro in physiological K+ concentration, but was prevented when they were cultured in high K+ concentration. The cell death of granule neurons was also suppressed by pharmacological inhibition of TASK3 channels with extracellular acidosis and ruthenium red. The cell death was in parallel with the expression level of TASK3 channels (Lauritzen et al. 2003). These results indicate a direct relationship between the activity of TASK3 channels and programmed cell death which is necessary for shaping the appropriate cerebellar structure. The authors have also shown that genetic transfection of TASK subunits into cultured hippocampal neurons induced apoptotic effect. On the other hand, viral overexpression of TASK3 in cultured hippocampal slices increased cell survival during cellular stress conditions such as an oxygen-glucose deprivation injury (Liu et al. 2005). These results suggested that the activation of TASK3 channels can also be protective in neurons under cellular stress conditions.

TASK1 and TASK3 channels are widely expressed in the central nervous system, suggesting that TASK1 and/or TASK3 channels are critically involved in learning and memory. However, in TASK1 KO mice, the higher brain functions were almost similar to the wild-type mice (Linden et al. 2006). For example, there were no appreciable differences in anxiety-related behavior and stress-induced hyperthermia between the wild-type and TASK1 KO mice, although the deletion of TASK1 enhanced the sensitivity to thermal nociceptive stimuli (Linden et al. 2006). By contrast, TASK3 KO mice exhibited pronounced behavioral changes in relation to memory functions compared with the TASK1 KO mice (Linden et al. 2007). In T-maze spontaneous alternation test, the performance in the TASK3 KO mice was poorer compared to the wild-type mice, indicating that working memory was impaired. In addition, during training for the Morris water-maze spatial memory task, the TASK3 KO mice were slower to find the hidden platform, suggesting the impairment of learning (Linden et al. 2007). In TASK3 KO mice, the action potential generation and sustained repetitive firing to suprathreshold depolarization were impaired in the granule neurons (Brickley et al. 2007). Since long-term synaptic changes induced by spike activity are believed to underlie learning and memory (Tsodyks 2002), it is possible that the reduced working memory is ascribed to the impaired spike activity caused by the deletion of TASK3.

TASK Channels and Pain

The involvement of TASK channels in nociceptive behavior was demonstrated by using KO animals. First, the TASK1 knockout mice showed increased sensitivity to thermal nociception in a hot-plate test but not in a tail-flick test (Linden et al. 2006). Furthermore, the analgesic, sedative, and hypothermic effects of a cannabinoid agonist were reduced in these mice (Linden et al. 2006). These findings suggest that TASK1 channels expressed in supraspinal pathway are involved in the nociceptive behavior. In rat or mouse DRG neurons, high levels of TRESK mRNA and moderate or low levels of TASK1, TASK3, TRAAK, TREK1, TREK2, TWIK1, and TWIK2 mRNAs are expressed (Talley et al. 2001; Dobler et al. 2007; Marsh et al. 2012). However, during inflammation, mRNA levels of TASK1 and TASK3 channels were reduced, and this decrease was associated with the spontaneous pain behavior (spontaneous foot lifting) (Marsh et al. 2012). These findings indicate that the downregulation of TASK1 and TASK3 channels are closely correlated with inflammation-induced neuropathic pain. It has recently been shown that TASK3 channels are highly expressed TRPM8-expressing cold neurons and that the thermal threshold of TRPM8-expressing cold neurons is decreased during TASK3 inhibition and in TASK3 KO mice (Morenilla-Palao et al. 2014). Especially, TASK3 KO mice displayed hypersensitivity to cold. These findings suggest that TASK3 channels could be involved in the development of cold hypersensitivity during inflammatory and/or neuropathic conditions (Choi et al. 1994).


TASK channels that are distributed widely in the central and peripheral nervous system produce background K+ currents that are time- and voltage-independent, and play crucial roles in setting the resting membrane potential and controlling the K+ homeostasis. These channels in the central nervous system are critically involved in pathophysiological conditions including ischemia, epilepsy, apoptosis, learning impairment, and pain. Therefore, TASK channel subunits can serve as the molecular targets for treatment of diseases of the central nervous system. Future studies on the TASK channels will be able to provide even more revealing insights into the pathophysiological conditions.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Neuroscience and Oral PhysiologyOsaka University Graduate School of DentistrySuitaJapan