The TASK-1 Two-Pore Domain K<sup>+</sup> Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

Sirois, Jay E.; Lei, Qiubo; Talley, Edmund M.; Lynch, Carl; Bayliss, Douglas A.

doi:10.1523/jneurosci.20-17-06347.2000

Cited by 242 publications

(230 citation statements)

References 47 publications

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“…Of the possible TEA-insensitive yet pH-sensitive K ϩ channels expressed in LC neurons, TASK channels are probably the most likely candidates. Recent studies have shown high expression of TASK-1 and TASK-3 channels in LC neurons (52,57), and TASK channels are known to be highly sensitive to inhibition by extracellular acidification in the physiological pH range (22). To test whether TASK channels contribute to the HAinduced membrane depolarization, we exposed LC neurons to IH, which we have previously shown leads to a fall of pH i but is not accompanied by any change of pH o (26).…”

Section: Resultsmentioning

confidence: 99%

“…Of the potential pH-sensitive channels, these neurons are known to express K ir , K Ca , and TASK channels (3,5,13,34,39,52). We hypothesize that multiple channels, including various K ϩ and Ca 2ϩ channels, are involved in the increased firing rate induced by chemosensitive signals in LC neurons.…”

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confidence: 98%

“…For example, decreased pH i has been shown to inhibit K ir and K Ca channels, whereas decreased pH o has been shown to inhibit TASK channels (37,38,41,50,52,58). Thus it is likely that depending on the stimulus present at any given time, multiple channels rather than a single channel could be targeted by any given chemosensitive stimulus.…”

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Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels

Filosa

Putnam

2003

American Journal of Physiology-Cell Physiology

113

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Filosa, Jessica A., and Robert W. Putnam. Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K ϩ and Ca 2ϩ channels. Am J Physiol Cell Physiol 284: C145-C155, 2003. First published September 18, 2002 10.1152/ajpcell.00346.2002We studied chemosensitive signaling in locus coeruleus (LC) neurons using both perforated and whole cell patch techniques. Upon inhibition of fast Na ϩ spikes by tetrodotoxin (TTX), hypercapnic acidosis [HA; 15% CO 2, extracellular pH (pHo) 6.8] induced small, slow spikes. These spikes were inhibited by Co 2ϩ or nifedipine and were attributed to activation of L-type Ca 2ϩ channels by HA. Upon inhibition of both Na ϩ and Ca 2ϩ spikes, HA resulted in a membrane depolarization of 3.52 Ϯ 0.61 mV (n ϭ 17) that was reduced by tetraethylammonium (TEA) (1.49 Ϯ 0.70 mV, n ϭ 7; P Ͻ 0.05) and absent (Ϫ0.97 Ϯ 0.73 mV, n ϭ 7; P Ͻ 0.001) upon exposure to isohydric hypercapnia (IH; 15% CO2, 77 mM HCO 3 Ϫ , pHo 7.45). Either HA or IH, but not 50 mM Na-propionate, activated Ca 2ϩ channels. Inhibition of L-type Ca 2ϩ channels by nifedipine reduced HA-induced increased firing rate and eliminated IH-induced increased firing rate. We conclude that chemosensitive signals (e.g., HA or IH) have multiple targets in LC neurons, including TEA-sensitive K ϩ channels and TWIKrelated acid-sensitive K ϩ (TASK) channels. Furthermore, HA and IH activate L-type Ca 2ϩ channels, and this activation is part of chemosensitive signaling in LC neurons. acidosis; membrane potential; perforated patch clamp; respiration; whole cell patch clamp CENTRAL CHEMORECEPTION is fundamental for the understanding of cardiovascular and respiratory regulation. A number of different brain stem areas, including the ventrolateral medulla (VLM) (44,45,53), the nucleus tractus solitarii (NTS) (15,19), the rostral medullary raphe (33, 62), and the locus coeruleus (LC) (4, 35), have been shown to contain neurons that are sensitive to chemosensitive stimuli such as high CO 2 /H ϩ or hypercapnic acidosis (HA). These neurons share the common characteristic of, upon an acid challenge, increasing Na ϩ spike frequency. This is particularly true for the LC, in which Ͼ80% of neurons are found to be chemosensitive (26,36), making the LC an ideal nucleus for the study of the cellular basis of chemosensitivity.The current model of cellular chemosensitivity, based on chemosensitive cells located both in the brain stem and the carotid bodies, is that a chemosensitive signal such as high CO 2 /H ϩ results in a neuronal membrane depolarization, presumably through inhibition of a K ϩ channel, resulting in an increased spike frequency (17,35,36,42,63,64). A number of findings suggest that this model may be simplistic. When using hypercapnic stimuli without a change of extracellular pH (pH o ), an increase in spike frequency without an apparent membrane depolarization has been observed in both LC (26) and medullary raphe neurons (62). Furthermore, an increase in membrane input resistance, which should be associated with K ϩ channel closure...

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Section: Resultsmentioning

confidence: 99%

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Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels

Filosa

Putnam

2003

American Journal of Physiology-Cell Physiology

113

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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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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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“…These channels are the major determinants of the resting membrane potential, and exert control over neuronal excitability through their influence on the resting membrane potential. Enhanced leak channel activity hyperpolarizes neurons, leading to decreased action potential firing; in contrast, leak suppression results in membrane depolarization and excitation (Sirois et al, 2000). TREK-1 is an important member of this family, and is expressed through out the central nervous system (Fink et al, 1996;Lauritzen et al, 2000;Hervieu et al, 2001;Medhurst et al, 2001;Talley et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human TREK-1 channels by caffeine and theophylline

Harinath

Sikdar

2005

Epilepsy Research

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Caffeine (1,3,7-trimethylxanthine) and theophylline (1,3-dimethylxanthine) are used for therapeutic purposes and can cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. TWIK-related K + channels (TREK-1) are highly expressed in the human central nervous system and have a major role in the control of neuronal excitability by regulating the resting membrane potential. In view of their physiological significance, inhibition of TREK-1 channels may be implicated in caffeine-and theophylline-induced seizures. We thus investigated, using whole-cell patch-clamp technique, modulation of hTREK-1 channels expressed in Chinese hamster ovary (CHO) cells by caffeine and theophylline. Caffeine and theophylline produced reversible inhibition of TREK-1 channels in a concentration-dependent manner. The half-maximal inhibitory concentrations (IC 50 ) for caffeine and theophylline were 377 ± 54 M and 486 ± 76 M, respectively. Caffeine and theophylline depolarized the membrane potential of CHO TREK-1 cells in a reversible and concentrationdependent manner. Inhibition by caffeine (5 mM) and theophylline (2 mM) was attenuated in TREK-1 channels with mutation of the PKA consensus sequence at serine 348, suggesting the involvement of cAMP/PKA pathway in the inhibitory process. Inhibition of TREK-1 channels and consequent membrane depolarization may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline.

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The TASK-1 Two-Pore Domain K⁺ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

Cited by 242 publications

References 47 publications

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels

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

Inhibition of human TREK-1 channels by caffeine and theophylline

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The TASK-1 Two-Pore Domain K+ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

Cited by 242 publications

References 47 publications

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K+ and Ca2+channels

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K+ and Ca2+channels

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

Inhibition of human TREK-1 channels by caffeine and theophylline

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The TASK-1 Two-Pore Domain K⁺ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels

Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K⁺ and Ca²⁺channels