The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K+ channels TREK-1 and TRAAK

Meadows, Helen; Chapman, C.G.; Duckworth, D. M.; Kelsell, Rosemary E.; Murdock, Paul R.; Nasir, Shabina; Rennie, Gillian; Randall, Andrew D.

doi:10.1016/s0006-8993(00)03239-x

Cited by 56 publications

(54 citation statements)

References 17 publications

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“…This study is the first description of the inhibition of TREK-1 by NBP, and this property may underlie its beneficial neuroprotective activity [31] . Moreover, the inhibition of TREK-1 currents by l-NBP was more significant than that by d-and dl-NBP.…”

Section: Discussionmentioning

confidence: 83%

“…This action on the part of lipids would be predicted to counteract the neuronal damage that arises from the increased membrane excitability that often accompanies CNS insults such as ischemia. A link between TREK-1 and neuroprotection, although a highly attractive hypothesis, has not been unequivocally demonstrated, mainly due to the lack of selective K2P antago nists [13,31] .…”

Section: Discussionmentioning

confidence: 99%

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Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

Zhao

Cao

et al. 2011

Acta Pharmacol Sin

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Aim:To study the effects of 3-n-butylphthalide (NBP) on the TREK-1 channel expressed in Chinese hamster ovary (CHO) cells. Methods: Whole-cell patch-clamp recording was used to record TREK-1 channel currents. The effects of varying doses of l-NBP on TREK-1 currents were also observed. Current-clamp recordings were performed to measure the resting membrane potential in TREK-1-transfected CHO (TREK-1/CHO) and wild-type CHO (Wt/CHO) cells. Results: l-NBP (0.01-10 μmol/L) showed concentration-dependent inhibition on TREK-1 currents (IC 50 =0.06±0.03 μmol/L), with a maximum current reduction of 70% at a concentration of 10 μmol/L. l-NBP showed a more potent inhibition on TREK-1 current than d-NBP or dl-NBP. This effect was partially reversed upon washout and was not voltage-dependent. l-NBP 10 μmol/L elevated the membrane potential in TREK-1/CHO cells from -55.3 mV to -42.9 mV. However, it had no effect on the membrane potential of Wt/CHO cells. Conclusion: l-NBP potently inhibited TREK-1 current and elevated the membrane potential, which may contribute to its neuroprotective activity.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

Zhao

Cao

et al. 2011

Acta Pharmacol Sin

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“…Further, suppression of bTREK-1 activity by a nonspecific TREK-1 antagonist, sipatrigine, or by over-expression of a dominant negative mutant of this channel restores proliferation to near normal levels [28]. Because curcumin is five times more potent than sipatrigine as a bTREK-1 antagonist [29], it is likely that curcumin may suppress prostate cancer cell growth by an action on bTREK-1 channels.…”

Section: Discussionmentioning

confidence: 99%

Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells

Enyeart

Liu

Enyeart

2008

Biochemical and Biophysical Research Communications

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Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 K + channels that set the resting membrane potential. Inhibition of these channels by adrenocorticotropic hormone (ACTH) is coupled to membrane depolarization and cortisol secretion. Curcumin, a phytochemical with medicinal properties extracted from the spice turmeric, was found to modulate both bTREK-1 K + currents and cortisol secretion from AZF cells. In whole-cell patch clamp experiments, curcumin inhibited bTREK-1 with an IC 50 of 0.93μM by a mechanism that was voltage-independent. bTREK-1 inhibition by curcumin occurred through interaction with an external binding site and was independent of ATP hydrolysis. Curcumin produced a concentration-dependent increase in cortisol secretion that persisted for up to 24 h. At a maximally effective concentration of 50 μM, curcumin increased secretion as much as10-fold. These results demonstrate that curcumin potently inhibits bTREK-1 K + channels and stimulates cortisol secretion from bovine AZF cells. The inhibition of bTREK-1 by curcumin may be linked to cortisol secretion through membrane depolarization. Since TREK-1 is widely expressed in a variety of cells, it is likely that some of the biological actions of curcumin, including its therapeutic effects, may be mediated through inhibition of these K + channels.

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“…그래서 많은 연구자들이 이 채널을 조 절하는 약제에 대한 검색을 시도하였다 [4,6,7]. 그 결과로 휘발성 마취제 뿐만 아니라 chloral hydrate, trichloroethanol 같은 비휘발성 마취제에 의해서도 활성화됨이 보고 되었고 [8], 근위축성 측삭경화증 (amyotrophic lateral sclerosis)의 치료제로 사용되면서 신경세포 손상보호제로 알려진 riluzole에 의해 활성화 됨을 확인 하였다 [9].…”

Section: 서론unclassified

“…그 결과로 휘발성 마취제 뿐만 아니라 chloral hydrate, trichloroethanol 같은 비휘발성 마취제에 의해서도 활성화됨이 보고 되었고 [8], 근위축성 측삭경화증 (amyotrophic lateral sclerosis)의 치료제로 사용되면서 신경세포 손상보호제로 알려진 riluzole에 의해 활성화 됨을 확인 하였다 [9]. 또한 신경세포 손상보호약물로 알려진 sipatragine과 lamotrigine, 그리고 항울제인 fluoxetin에 의해 억제됨이 보고되었다 [7]. 이처럼 TREK-1 채널의 생리학적 역할이 강조 되면서 다양한 물질 에서 이 채널을 표적으로 하는 활성제 또는 억제제를 찾는 연구가 시도되어 지고 있다 [10,11].…”

Section: 서론unclassified

The effect of flavonoids on the TREK-1 channel

Kim

Kim²

2011

Journal of the Korea Academia-Industrial cooperation Society

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TREK-1 channel is a member of the two-pore domain potassium (K2P) channel family that is regulated by intracellular pH, membrane stretch, polyunsaturated fatty acids, temperature, and some neuroprotectant agents. TREK-1 channel can influence neuronal excitability by regulating leakage of potassium ions and resting membrane potential. TREK-1 channel has been shown to be overexpressed in prostate cancer cells. Although the importance of these properties, relatively little is known about flavonoid effects in the regulations of TREK-1 channel. The purpose of the study was to screening of flavonoids as the TREK-1 channel modulator using one of electrophysiological techniques such as excised inside-out patch configuration. We demonstrated blocking effect on TREK-1 channel by flavonoids such as epigallocatechin-3-gallate (EGCG), curcumin and quercetin in CHO cells transiently expressing TREK-1 channel. The inhibition of TREK-1 channel by quercetin and curcumin was reversible, whereas EGCG was little reversible. Quercetin, EGCG and curcumin decreased the relative channel activity to 73%, 91% and 94%, respectively. The half-inhibitory concentration (IC50) of curcumin, quercetin and EGCG was 1.04 ± 0.19 μM, 1.13 ± 0.26 μM and 13.5 ± 2.20 μM in CHO cells expressing TREK-1 channel, respectively. These results indicate that flavonoids might regulate TREK-1 and this regulation might be one of the pharmacological actions of flavonoid in nervous systems and cancer cells.

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The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K+ channels TREK-1 and TRAAK

Cited by 56 publications

References 17 publications

Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells

The effect of flavonoids on the TREK-1 channel

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