An oxygen‐, acid‐ and anaesthetic‐sensitive TASK‐like background potassium channel in rat arterial chemoreceptor cells

Buckler, Keith J.; Williams, B. A.; Honoré, Eric

doi:10.1111/j.1469-7793.2000.00135.x

Cited by 382 publications

(398 citation statements)

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“…They produce background K + currents that are inhibited by external acidification and G-protein-coupled receptors (15) and activated by volatile anesthetics (16). Recent evidence suggesting that Task channels are inhibited by hypoxia comes from studies showing that the O 2 -sensitive background K + currents in carotidbody type I cells have electrophysiological and pharmacological properties of Task1 and Task3 (17)(18)(19).…”

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confidence: 99%

Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Gestreau

Heitzmann

Thomas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

137

140

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Task2 K + channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including the retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost in mice bearing a Phox2b mutation that causes the human congenital central hypoventilation syndrome. In plethysmography, Task2 −/− mice showed disturbed chemosensory function with hypersensitivity to low CO 2 concentrations, leading to hyperventilation. Task2 probably is needed to stabilize the membrane potential of chemoreceptive cells. In addition, Task2 −/− mice lost the long-term hypoxia-induced respiratory decrease whereas the acute carotid-body-mediated increase was maintained. The lack of anoxia-induced respiratory depression in the isolated brainstemspinal cord preparation suggested a central origin of the phenotype. Task2 activation by reactive oxygen species generated during hypoxia could silence RTN neurons, thus contributing to respiratory depression. These data identify Task2 as a determinant of central O 2 chemoreception and demonstrate that this phenomenon is due to the activity of a small number of neurons located at the ventral medullary surface.breathing | central chemoreceptors | K2P | KCNK5 | ventral medullary surface S pontaneous breathing requires feedback controls in which detection of blood gases and pH is critical. At present, there is good understanding of the brainstem topology of respiratory centers, and functional measurements in vitro and in vivo have revealed the basic principles of the neuronal network required for respiratory rhythmogenesis and pattern generation. This network comprises several groups of respiratory neurons forming columns extending from the caudal ventrolateral medulla to the dorsolateral pons (1, 2). The activity of this network must be stable yet permanently adjusted to variations of O 2 , CO 2 , and pH during diverse physiological conditions, e.g., sleep, exercise, or high altitude (3). The precise physiological processes by which pH, CO 2 , and O 2 changes are sensed and translated into the appropriate respiratory neural output are important mechanisms that are still a matter of debate (4, 5). Changes in arterial CO 2 / pH are detected by peripheral chemoreceptors, mainly carotid bodies, and multiple chemoreceptive areas within the brainstem. Among the central chemoreceptive areas, two have attracted most attention: the raphe nuclei and the retrotrapezoid nucleus (RTN) (6, 7). The carotid bodies are the major sensors for acute O 2 changes. However, for longer periods of hypoxia, respiratory adaptation is substantially mediated by central mechanisms (8). The ventrolateral medullary surface comprising the RTN and the parafacial respiratory group (pFRG) has been proposed to contain intrinsically CO 2 -and O 2 -sensing neurons (9-12). Recently, a mouse model that carries a mutation of the transcription factor Phox2b, which causes congenital central hypoventilation syndrome in humans, was engineered. A specific loss of a population of Phox2b-expressing RTN/pFRG neurons ...

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confidence: 99%

Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Gestreau

Heitzmann

Thomas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

137

140

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“…Those K 2P channels that form functional K ϩ channels exhibit interesting electrophysiological and pharmacological properties. For example, TASK-1 and TASK-3 are active at rest, highly sensitive to extracellular pH and oxygen concentration (22), and activated by volatile anesthetics (23,24). TREK-1 and TREK-2 are activated by free fatty acids, protons, increased membrane tension, heat, and volatile anesthetics (25,26).…”

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confidence: 99%

Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

Kang¹,

Mariash

Kim

2004

Journal of Biological Chemistry

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A new member of the tandem-pore K ؉ (K 2P ) channel family has been isolated from mouse testis complementary DNA. The new K 2P channel was named TRESK-2, as its amino acid sequence shares 65% identity with that of TRESK-1. Mouse TRESK-2 is a 394-amino acid protein and possesses four putative transmembrane segments and two pore-forming domains. TRESK-2 has a long cytoplasmic domain joining the second and third transmembrane segments and a short carboxyl terminus. In the rat, TRESK-2 mRNA transcripts were expressed abundantly in the thymus and spleen and at low levels in many other tissues, including heart, small intestine, skeletal muscle, uterus, testis, and placenta, as judged by Northern blot analysis. TRESK-2 mRNA was also expressed in mouse and human tissues. In COS-7 cells transfected with TRESK-2 DNA, a time-independent and noninactivating K ؉ -selective current was recorded. TRESK-2 was insensitive to 1 mM tetraethylammonium, 100 nM apamin, 1 mM 4-aminopyridine, and 10 M glybenclamide. TRESK-2 was inhibited by 10 M quinidine, 20 M arachidonate and acid (pH 6.3) at 49, 43, and 23%, respectively. Single channel openings of TRESK-2 showed marked open channel noise. In symmetrical 150 mM KCl, the current-voltage relationship of TRESK-2 was slightly inwardly rectifying, with the single channel conductance 13 picosiemens (pS) at ؉60 mV and 16 pS at ؊60 mV. In inside-out patches, TRESK-2 was unaffected by the intracellular application of 10 M guanosine 5 -O-(thiotriphosphate). These results show that TRESK-2 is a functional member of the K 2P channel family and contributes to the background K ؉ conductance in many types of cells.Mammalian potassium channels are divided into three structural classes based on the number of predicted transmembrane (TM) 1 segments (two, four, or six) and pore-forming (P) domains (one or two). Searching the DNA data base for sequences homologous to previously cloned K ϩ channels led to identification of the class now referred to as tandem-pore or two-pore domain K ϩ (K 2P ) channels (1-4). Each subunit of a K 2P channel possesses four TM segments and two P domains, and therefore two subunits are thought to assemble to form a functional dimeric K ϩ channel (4, 5). K 2P channels can be divided into six subfamilies based on amino acid homology: TWIK-1 and TWIK-2 (6 -9); THIK-1 and THIK-2 (10); TASK-1, TASK-3, and TASK-5 (11-13); TALK-1, TASK-2, and TALK-2 (14 -16); TREK-1, TREK-2, and TRAAK (17-20); and TRESK-1 (21). Many of these K 2P channel are able to form functional K ϩ channels when expressed in oocytes or mammalian cells. Those K 2P channels that form functional K ϩ channels exhibit interesting electrophysiological and pharmacological properties. For example, TASK-1 and TASK-3 are active at rest, highly sensitive to extracellular pH and oxygen concentration (22), and activated by volatile anesthetics (23, 24). TREK-1 and TREK-2 are activated by free fatty acids, protons, increased membrane tension, heat, and volatile anesthetics (25, 26). These channels are functionally expressed...

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“…TASK3 is expressed at very low levels among the normal tissues except in the brain, where high levels expression of TASK3 were detected (7)(8)(9). The physiological functions of TASK channels are largely unknown, though their roles in the regulation of breathing (12,13), aldosterone secretion (5) and anesthetic-mediated neuronal activity (14) have been proposed. Recently, we showed that TASK3 is amplified in 10% of breast cancers and is overexpressed at a higher frequency of breast, lung, colon, and metastatic prostate cancers (15), suggesting that TASK3 may play a role in pathogenesis of some human carcinomas.…”

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confidence: 99%

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function

Pei¹,

Wiser²,

Slavin³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

161

124

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TASK3 gene (Kcnk9) is amplified and overexpressed in several types of human carcinomas. In this report, we demonstrate that a point mutation (G95E) within the consensus K ؉ filter of TASK3 not only abolished TASK3 potassium channel activity but also abrogated its oncogenic functions, including proliferation in low serum, resistance to apoptosis, and promotion of tumor growth. Furthermore, we provide evidence that TASK3 G95E is a dominant-negative mutation, because coexpression of the wild-type and the mutant TASK3 resulted in inhibition of K ؉ current of wild-type TASK3 and its tumorigenicity in nude mice. These results establish a direct link between the potassium channel activity of TASK3 and its oncogenic functions and imply that blockers for this potassium channel may have therapeutic potential for the treatment of cancers.T ASK (TWIK-related acid-sensitive K ϩ channels) channels are members of the two-pore domain family of potassium channels, whose structure consists of two-pore forming regions flanked by four transmembrane domains (1, 2). Like other two-pore domain members, these channels show little time or voltage dependence; thus, they have characteristics of leaky K ϩ channels, generating background currents that contribute to membrane potential and the regulation of cell excitability. The activity of TASK channels is modulated by volatile anesthetics (3, 4), neurotransmitters (5, 6), as well as extracellular pH in the physiological range (7-11). TASK3 is expressed at very low levels among the normal tissues except in the brain, where high levels expression of TASK3 were detected (7-9). The physiological functions of TASK channels are largely unknown, though their roles in the regulation of breathing (12, 13), aldosterone secretion (5) and anesthetic-mediated neuronal activity (14) have been proposed. Recently, we showed that TASK3 is amplified in 10% of breast cancers and is overexpressed at a higher frequency of breast, lung, colon, and metastatic prostate cancers (15), suggesting that TASK3 may play a role in pathogenesis of some human carcinomas.Is the dysregulated expression of TASK3 in tumor cells a consequence of their abnormal growth or is this K ϩ channel involved in promoting tumor growth? To begin to answer this question, we created an inactivating mutation of TASK3. We report here that TASK3 G95E is a dominant-negative mutation that abolishes not only TASK3 K ϩ channel activity but also its oncogenic functions. These results provide molecular basis for developing specific blockers for this K ϩ channel in the treatment of cancer. Materials and MethodsPlasmids and Mutagenesis. The coding region of TASK3 was cloned at BamHI and EcoRI sites of the pLPC retroviral expression vector (15) to generate pLPC-TASK3. Site-directed mutagenesis was performed to change Gly-95 to Glu to create pLPC-TASK3 G95E , by using QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. pTracer-TASK 3 G95E was generated by excising TASK3 G95E from pLPC vector and cloned at KpnI...

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An oxygen‐, acid‐ and anaesthetic‐sensitive TASK‐like background potassium channel in rat arterial chemoreceptor cells

Cited by 382 publications

References 28 publications

Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function

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An oxygen‐, acid‐ and anaesthetic‐sensitive TASK‐like background potassium channel in rat arterial chemoreceptor cells

Cited by 382 publications

References 28 publications

Task2 potassium channels set central respiratory CO 2 and O 2 sensitivity

Task2 potassium channels set central respiratory CO 2 and O 2 sensitivity

Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

Oncogenic potential of TASK3 (Kcnk9) depends on K+channel function

Contact Info

Product

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Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Task2 potassium channels set central respiratory CO ₂ and O ₂ sensitivity

Oncogenic potential of TASK3 (Kcnk9) depends on K⁺channel function