Antipsychotics inhibit TREK but not TRAAK channels

Thümmler, Susanne; Duprat, Fabrice; Lazdunski, Michel

doi:10.1016/j.bbrc.2006.12.199

Cited by 50 publications

(42 citation statements)

References 26 publications

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“…Accordingly, it has been proposed that the clinical usefulness of SSRI antidepressants is complemented by the inhibition of TREK-1 channels (133, 317). This suggests that the blockers of this background K ϩ channel are of considerable therapeutic interest for the future management of psychiatric diseases (223,224,317). TREK-1 and TREK-2 (but not TRAAK) channels are also inhibited by several neuroleptic drugs, such as chlorpromazine (269), fluphenazine, haloperidol, and penfluridol (317).…”

Section: Depression and Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

“…This suggests that the blockers of this background K ϩ channel are of considerable therapeutic interest for the future management of psychiatric diseases (223,224,317). TREK-1 and TREK-2 (but not TRAAK) channels are also inhibited by several neuroleptic drugs, such as chlorpromazine (269), fluphenazine, haloperidol, and penfluridol (317). Further studies are needed to evaluate the significance of this effect in the therapeutic potential of neuroleptics.…”

Section: Depression and Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

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Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

760

769

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Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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Section: Depression and Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

Section: Depression and Selective Serotonin Reuptake Inhibitorsmentioning

confidence: 99%

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Enyedi

Czirják

2010

Physiological Reviews

760

769

View full text Add to dashboard Cite

show abstract

“…Moreover, TRAAK-family K2P channels are modulated by cellular lipids and pharmacological agents, including polyunsaturated fatty acids such as arachidonic acid and volatile general anesthetics [42] . Acidity and heat have also been suggested to activate the channel [43,44] , while antipsychotics such as fluphenazine have been shown to block TREK-1 but not the related TRAAK channels [45] .…”

Section: Traak-family Channelsmentioning

confidence: 99%

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

Buxton

Heyman

et al. 2011

Acta Pharmacol Sin

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Rates of premature birth are alarming and threaten societies and healthcare systems worldwide. Premature labor results in premature birth in over 50% of cases. Preterm birth accounts for three-quarters of infant morbidity and mortality. Children that survive birth before 34 weeks gestation often face life-long disability. Current treatments for preterm labor are wanting. No treatment has been found to be generally effective and none are systematically evaluated beyond 48 h. New approaches to the treatment of preterm labor are desperately needed. Recent studies from our laboratory suggest that the uterine muscle is a unique compartment with regulation of uterine relaxation unlike that of other smooth muscles. Here we discuss recent evidence that the mechanically activated 2-pore potassium channel, TREK-1, may contribute to contraction-relaxation signaling in uterine smooth muscle and that TREK-1 gene variants associated with human labor and preterm labor may lead to a better understanding of preterm labor and its possible prevention.

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“…[9][10][11] It has also been reported that paroxetine inhibits the G proteinactivated inwardly rectifying K + channel 12) and two P domain background K + channel, TREK. 13) These results suggest that paroxetine may have an effect on the cardiovascular system. However, the side effects of paroxetine on the cardiovascular system have not been thoroughly studied.…”

mentioning

confidence: 90%

Blockade of HERG Human K<sup>+</sup> Channels by the Antidepressant Drug Paroxetine

Lee

Sung

Lee

et al. 2014

Biological & Pharmaceutical Bulletin

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The effects of paroxetine, a selective serotonin reuptake inhibitor, on human ether-a-go-go-related gene (HERG) channels were investigated using the whole-cell patch-clamp technique. The HERG channels were stably expressed in human embryonic kidney cells. Paroxetine inhibited the peak tail currents of the HERG channel in a concentration-dependent manner, with an IC 50 value of 0.45 µM and a Hill coefficient of 0.85. These effects were reversible after wash-out of the drug. The paroxetine-induced inhibition of the HERG channels was voltage-dependent. There was a steep increase in inhibition over the voltage range of the channel opening. Also, a shallow voltage-dependent inhibition was detected over the voltage range in which the channels were fully activated. The fractional electrical distance was estimated to be 0.11. Paroxetine induced a leftward shift in the voltage-dependence of the steady-state activation of the HERG channels. Before and after application of the 1 µM paroxetine, the half-maximum activation was 14.21 mV and 27.04 mV, respectively, with no shift in the slope value. The HERG channel block was not use-dependent. The characteristics of the block were dependent on open and inactivated channel states rather than closed state. Paroxetine had no effect on activation and deactivation kinetics, steady-state inactivation. These results suggest that paroxetine blocks the HERG channels by binding to these channels in the open and inactivated states.

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Antipsychotics inhibit TREK but not TRAAK channels

Cited by 50 publications

References 26 publications

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

Blockade of HERG Human K<sup>+</sup> Channels by the Antidepressant Drug Paroxetine

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Antipsychotics inhibit TREK but not TRAAK channels

Cited by 50 publications

References 26 publications

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

Blockade of HERG Human K<sup>+</sup> Channels by the Antidepressant Drug Paroxetine

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Product

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Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels

Molecular Background of Leak K⁺Currents: Two-Pore Domain Potassium Channels