Electrophysiology and pharmacology of tandem domain potassium channel TREK-1 related BDNF synthesis in rat astrocytes

Lü, Li; Wang, Weiping; Peng, Ying; Li, Jiang; Wang, Xiaoliang

doi:10.1007/s00210-013-0952-2

Cited by 17 publications

(7 citation statements)

References 41 publications

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“…Another key role of astrocytes is the maintenance and survival of neurons through BDNF, and increased BDNF levels have been linked to treatment of astrocytes with certain TREK-1 antagonists (Lu et al, 2014). This could occur from an upregulation of PKA-CREB-BDNF signaling via TREK-1 to increase 5-HT transmission (Shirayama et al, 2002;Ye et al, 2015), or to increase cell viability and hippocampal neurogenesis to elicit an antidepressant-like response (Heurteaux et al, 2006;Zhou et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

Lee

Park

Han

et al. 2022

Preprint

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Background and Purpose: TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel’s potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects. Experimental Approach: We sought to find selective and potent inhibitors for TREK-1 related dimers both in vitro and in vivo. We synthesized and evaluated 2-hydroxy-3-phenoxypropyl piperidine derivatives yielding a library from which many TREK-1 targeting candidates emerged. Key Results: Hydroxyl-phenyl- (2a), piperidino- (2g), and pyrrolidino- (2h) piperidinyl substituted compounds showed high potencies to TREK-1 homodimers with significant antidepressant-like effects in forced swim test and tail suspension test. Interestingly, these compounds were found to have high potencies to TWIK-1/TREK-1 heterodimers, contrastingly, difluoropiperidinyl-4-fluorophenoxy (3e) and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy (3j) compounds had high potencies to TREK-1 homodimer but lower potency to TWIK-1/TREK-1 heterodimers without significant antidepressant-like effects. We observed positive correlation between inhibition potency to TWIK-1/TREK-1 and immobility time, and no correlation between inhibition potency to TREK-1 homodimer and immobility time. This was consistent with molecular docking simulations of selected compounds to TREK-1 homodimeric and TWIK-1/TREK-1 heterodimeric models. Existing antidepressant fluoxetine was also found to potently inhibit TWIK-1/TREK-1 heterodimers. Conclusion and Implications: Our study reveals novel potent TWIK-1/TREK-1 inhibitors 2a, 2g, and 2h as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.

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Section: Discussionmentioning

confidence: 99%

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

Lee

Park

Han

et al. 2022

Preprint

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“…One study reports that activation of the BDNF pathway controls the morphology of cytoskeletal changes in astrocytes [ 34 ]. Moreover, previous research demonstrates that the synthesis of BDNF is enhanced following the inhibition of TREK-1 [ 35 ]. In the present study, we also found that the knockdown of TREK-1 increased the level of BDNF following isoflurane-induced astrocytic injury, and we thus inferred that BDNF participated in the protective effects associated with decreased TREK-1 levels following isoflurane-induced astrocytic cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

TREK-1 mediates isoflurane-induced cytotoxicity in astrocytes

et al. 2017

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BackgroundThere are growing concerns that anaesthetic exposure can cause extensive apoptotic degeneration of neurons and the impairment of normal synaptic development and remodelling. However, little attention has been paid to exploring the possible cytotoxicity of inhalation anaesthetics, such as isoflurane, in astrocytes. In this research, we determined that prolonged exposure to an inhalation anaesthetic caused cytotoxicity in astrocytes, and we identified the underlying molecular mechanism responsible for this process.MethodsAstrocytes were exposed to isoflurane, and astrocytic survival was then measured via LDH release assays, MTT assays, and TUNEL staining. TWIK-related potassium (K+) channel-1 (TREK-1) over-expression and knockdown models were also created using lentiviruses. The levels of TREK-1 and brain-derived neurotrophic factor (BDNF) were measured via Western blot and qRT-PCR.ResultsProlonged exposure to isoflurane decreased primary astrocytic viability in a dose- and time-dependent manner. Moreover, with prolonged exposure to isoflurane, the TREK-1 level increased, and the BDNF level was reduced. TREK-1 knockdown promoted the survival of astrocytes and increased BDNF expression following isoflurane exposure.ConclusionsOverdoses of and prolonged exposure to isoflurane induce cytotoxicity in primary astrocytes. TREK-1 plays an important role in isoflurane-induced cultured astrocytic cytotoxicity by down-regulating the expression of BDNF.

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“…This is of significance because astrocytes not only sense nutrients and hormones, but also are known to regulate action potential generation and pattern in neuronal circuits. 13,14 Historically, in vivo studies have predominantly used extracellular, single unit or intracellular sharp electrode recording configurations because movement of the brain in response to blood flow was less likely to disrupt the recording. In comparison, even the slightest movement can disrupt a patch clamp recording pipette seal.…”

Section: F I G U R E 1 Major Electrophysiological Recording Configurations Used To Investigate the Effects Of Glucose And Insulin On Neurmentioning

confidence: 99%

Insulin actions on hypothalamic glucose‐sensing neurones

Garcia

Hirschberg

Sarkar

et al. 2021

J Neuroendocrinology

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This aims to highlight the electrophysiological evidence supporting a critical role of insulin in regulating glucose-sensing neurones. Electrophysiological techniques have been used for over a half of a century to investigate the responses of neurones to extracellular glucose, as well as other nutrients and hormones. These techniques have evolved significantly over time, leading to a variety of different recording configurations. The distinctions between the different configurations are subtle and can be confusing to individuals who are not electrophysiologists. For this reason, we begin the discussion of glucose-sensing and insulin-responsive neurones with a brief

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Electrophysiology and pharmacology of tandem domain potassium channel TREK-1 related BDNF synthesis in rat astrocytes

Cited by 17 publications

References 41 publications

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

TREK-1 mediates isoflurane-induced cytotoxicity in astrocytes

Insulin actions on hypothalamic glucose‐sensing neurones

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