Involvement of intracellular transport in TREK-1c current run-up in 293T cells

Andharia, Naaz; Joseph, Ancy; Hayashi, Mikio; Okada, Masayoshi; Matsuda, Hiroko

doi:10.1080/19336950.2017.1279368

Cited by 7 publications

(10 citation statements)

References 37 publications

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“…Immediately after whole-cell access, small outward currents were recorded in response to depolarizing step pulses ( Fig 1A , 0 min). As reported previously [ 21 ], the channel current exhibited a gradual and spontaneous increase, which is called run-up, and reached a maximum level 3 min after establishing the whole-cell access. After the end of run-up (5 min), the current amplitude was the same as at 3 min ( Fig 1A and 1C ).…”

Section: Resultssupporting

confidence: 71%

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Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

et al. 2018

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We screened a library of botanical compounds purified from plants of Vietnam for modulators of the activity of a two-pore domain K+ channel, TREK-1, and we identified a hydroxycoumarin-related compound, ostruthin, as an activator of this channel. Ostruthin increased whole-cell TREK-1 channel currents in 293T cells at a low concentration (EC50 = 5.3 μM), and also activity of the TREK-2 channel (EC50 = 3.7 mM). In contrast, ostruthin inhibited other K+ channels, e.g. human ether-à-go-go-related gene (HERG1), inward-rectifier (Kir2.1), voltage-gated (Kv1.4), and two-pore domain (TASK-1) at higher concentrations, without affecting voltage-gated potassium channel (KCNQ1 and 3). We tested the effect of this compound on mouse anxiety- and depression-like behaviors and found anxiolytic activity in the open-field, elevated plus maze, and light/dark box tests. Of note, ostruthin also showed antidepressive effects in the forced swim and tail suspension tests, although previous studies reported that inhibition of TREK-1 channels resulted in an antidepressive effect. The anxiolytic and antidepressive effect was diminished by co-administration of a TREK-1 blocker, amlodipine, indicating the involvement of TREK-1 channels. Administration of ostruthin suppressed the stress-induced increase in anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in other mood disorder-related nuclei, e.g. the amygdala, paraventricular nuclei, and dorsal raphe nucleus. Ostruthin may exert its anxiolytic and antidepressive effects through a different mechanism from current drugs.

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Section: Resultssupporting

confidence: 71%

“…We previously prepared a lentiviral vector that expressed the TREK-1 channel [ 16 ] and using this vector we established a cell line, TR-1, which stably expressed the channel [ 21 ]. First, we confirmed the expression of the channel current in this cell line with whole cell patch-clamp recordings.…”

Section: Resultsmentioning

confidence: 99%

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

et al. 2018

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“…Over recovery from inhibition was also lost in the shortest isoform of TREK-2 suggesting that the N terminus of the channel is also important for recovery of channel activity following application of sipatrigine. In TREK-1 channels, the N terminus interacts with the protein EBP50 in the plasma membrane which stabilises the structure of proteins and leads to a gradual run-up of current in the whole-cell configuration [ 30 ]. Therefore, loss of this interaction in the short form of TREK channels, may lead to a change in compound effects on the channel.…”

Section: Resultsmentioning

confidence: 99%

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092

Walsh

Leach

Veale

et al. 2021

Biochemistry and Biophysics Reports

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TREK and TRESK K2P channels are widely expressed in the nervous system, particularly in sensory neurons, where they regulate neuronal excitability. In this study, using whole-cell patch-clamp electrophysiology, we characterise the inhibitory effect of the anticonvulsant lamotrigine and two derivatives, sipatrigine and 3,5-diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine (CEN-092) on these channels. Sipatrigine was found to be a more effective inhibitor than lamotrigine of TREK-1, TREK-2 and TRESK channels. Sipatrigine was slightly more potent on TREK-1 channels (EC 50 = 16 μM) than TRESK (EC 50 = 34 μM) whereas lamotrigine was equally effective on TREK-1 and TRESK. Sipatrigine was less effective on a short isoform of TREK-2, suggesting the N terminus of the channel is important for both inhibition and subsequent over-recovery. Inhibition of TREK-1 and TREK-2 channels by sipatrigine was reduced by mutation of a leucine residue associated with the norfluoxetine binding site on these channels (L289A and L320A on TREK-1 and TREK-2, respectively) but these did not affect inhibition by lamotrigine. Inhibition of TRESK by sipatrigine and lamotrigine was attenuated by mutation of bulky phenylalanine residues (F145A and F352A) in the inner pore helix. However, phosphorylation mutations did not alter the effect of sipatrigine. CEN-092 was a more effective inhibitor of TRESK channels than TREK-1 channels. It is concluded that lamotrigine, sipatrigine and CEN-092 are all inhibitors of TREK and TRESK channels but do not greatly discriminate between them. The actions of these compounds may contribute to their current and potential use in the treatment of pain and depression.

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“…The membrane localization of several adhesion receptors, such as ICAMs, CD43, and CD44, were regulated by cytoskeleton through one or more members of the ezrin, radixin, and moesin (ERM) family of proteins [47]. The TREK-1 channel was previously found to co-localize with ezrin and induce the formation of actin-rich protrusions [48]. Bittner et al have found these adhesion molecules play a role in the TREK-1 deficiency-mediated immune infiltration in mice EAE model [18].…”

Section: Discussionmentioning

confidence: 99%

Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice

Fang

Tian

Huang

et al. 2019

J Neuroinflammation

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Background Intracerebral hemorrhage (ICH) is a devastating medical emergency with high mortality and severe neurological deficit. ICH-related poor outcomes are due to a combination of pathological processes that could be complicated by secondary insults. TWIK-related K+ channel 1 (TREK-1) is a two-pore-domain potassium channel that is highly expressed in the mammalian nervous system. Previous studies have shown that TREK-1 channels play important roles in various central nervous system diseases. However, its role in the secondary injuries after intracerebral hemorrhage remains unknown. In this study, we explored the function of TREK-1 in secondary blood-brain barrier injuries and neuroinflammation after intracerebral hemorrhage in mice. Methods Adult male TREK-1 −/− mice and WT mice were subjected to a collagenase-induced ICH model. Immunostaining, western blot, and enzyme-linked immunosorbent assay were used to assess inflammatory infiltration and neuronal death. Blood-brain barrier compromise was assessed using electron microscopy and Evans Blue dye injection on days 1 and 3 after intracerebral hemorrhage. Magnetic resonance imaging and behavioral assessments were conducted to evaluate the neurologic damage and recovery after intracerebral hemorrhage. Results Genetic deficiency of TREK-1 channel exacerbated blood-brain barrier impairment and promoted cerebral edema after intracerebral hemorrhage. Meanwhile, TREK-1 deficiency aggravated focal inflammatory featured by the increased recruitment of microglia and neutrophils, the enhanced secretion of proinflammatory factors interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and cell adhesion molecules (CAMs). Furthermore, TREK-1 deficiency promoted neuronal injury and neurological impairment. Conclusions These results establish the first in vivo evidence for the protective role of TREK-1 in blood-brain barrier injury and neuroinflammation after intracerebral hemorrhage. TREK-1 may thereby be harnessed to a potential therapeutical target for the treatment of intracerebral hemorrhage. Electronic supplementary material The online version of this article (10.1186/s12974-019-1485-5) contains supplementary material, which is available to authorized users.

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Involvement of intracellular transport in TREK-1c current run-up in 293T cells

Cited by 7 publications

References 37 publications

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

Antidepressive and anxiolytic effects of ostruthin, a TREK-1 channel activator

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092

Deficiency of TREK-1 potassium channel exacerbates blood-brain barrier damage and neuroinflammation after intracerebral hemorrhage in mice

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