Role of TREK-1 in Health and Disease, Focus on the Central Nervous System

Djillani, Alaeddine; Mazella, Jean; Heurteaux, Catherine; Borsotto, Marc

doi:10.3389/fphar.2019.00379

Cited by 75 publications

(68 citation statements)

References 117 publications

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“…TREK-1 is a background potassium channel, the protagonist in multiple key physiological functions and pathophysiological conditions in nervous and cardiovascular tissue including neuroprotection, depression, epilepsy, pain, ischemia, and atrial fibrillation (Djillani et al, 2019). We have previously shown pharmacological evidence that implicates TREK-1 as a major potassium conductance regulating gastrointestinal smooth muscle contractility (Ma et al, 2018), providing a potential therapeutic target for motility disorders.…”

Section: Discussionmentioning

confidence: 99%

Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Lewis

2020

Front. Pharmacol.

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TREK-1 channel activity is a critical regulator of neuronal, cardiac, and smooth muscle physiology and pathology. The antidepressant peptide, spadin, has been proposed to be a TREK-1-specific blocker. Here we sought to examine the mechanism of action underlying spadin inhibition of TREK-1 channels. Heterologous expression in Xenopus laevis oocytes and electrophysiological analysis using two-electrode voltage clamp in standard bath solutions was used to characterize the pharmacological profile of wild-type and mutant murine TREK-1 and TREK-2 channels using previously established human K 2P activators; arachidonic acid (AA), cis-4,7,10,13,16,19-docosahexaenoic acid (DHA), BL-1249, and cinnamyl-3,4-dihydroxy-a-cyanocinnamate (CDC) and inhibitors; spadin and barium (Ba 2+). Mouse TREK-1 and TREK-2 channel currents were both significantly increased by AA, BL-1249, and CDC, similar to their human homologs. Under basal conditions, both TREK-1 and TREK-2 currents were insensitive to application of spadin, but could be blocked by Ba 2+. Spadin did not significantly inhibit either TREK-1 or TREK-2 currents either chemically activated by AA, BL-1249, or CDC, or structurally activated via a gating mutation. However, pre-exposure to spadin significantly perturbed the subsequent activation of TREK-1 currents by AA, but not TREK-2. Furthermore, spadin was unable to prevent activation of TREK-1 by BL-1249, CDC, or the related bioactive lipid, DHA. Spadin specifically antagonizes the activation of TREK-1 channels by AA, likely via an allosteric mechanism. Lack of intrinsic activity may explain the absence of clinical side effects during antidepressant therapy.

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Section: Discussionmentioning

confidence: 99%

Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Lewis

2020

Front. Pharmacol.

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“…Researches have demonstrated that the two pore potassium channel TREK-1 plays the protective role in central nervous disorders (Djillani et al 2019). However, to our best knowledge, no ndings concerned about the role of TREK-1 in AD.…”

Section: Discussionmentioning

confidence: 96%

Activation of TREK-1 Potassium Channel Improved Cognitive Deficits in Alzheimer's Disease Model Mice by Modulation of Glutamate Metabolic Pathway

Zhou

Zeng

et al. 2021

Preprint

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Alzheimerʼs disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction. Glutamate (Glu) metabolism pathway mediated neurotoxicity is one of main factors causing memory impairment in AD. TWIK-related potassium channel-1 (TREK-1) exerts protective effect in brain ischemia, but the role of it in AD is unknown. In this study, the SAMP8 mice were used as an AD model, the age-matched SAMR1 mice as a control, we investigated the change trend of TREK-1 channel as well as AD related molecules in brains of SAMP8 mice and showed the expression levels of TREK-1 compensatory arose before 3 months of age, then began to decline. Meanwhile the levels of Tau and Glu increased with age while Ach level decreased over age. Next, using α-Linolenic acid (ALA) as an activator of TREK-1 channel, we showed that activation of TREK-1 channel improved the learning and memory deficits of SAMP8 mice aged in 6 months. Furthermore, we explored the possible mechanisms and found that the levels of molecules were closely related to the glutamate metabolism pathway. After the activation of TREK-1 channel, the damaged neurons and astrocyte were rescued, the levels of Glu and NMDAR were down-regulated, while the level of GLT-1 was up-regulated. These findings suggested that TREK-1 played the crucial role in the pathological progression of AD and activation of TREK-1 channel improved the cognitive deficits in SAMP8 mice which is mediated by Glu metabolism pathway. The TREK-1 potassium channel may be expected to be a new potential therapeutic target for AD.

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“…Differential DNA methylation in PMG cases with 1q trisomy affected not only regions on the long arm of chromosome 1, but also was seen in other autosomes and mapped to several genes associated with brain function, malformation, epilepsy, developmental delay, and autism (Supplement Fig. 4, online source) [ 1 , 22 , 24 , 29 , 31 , 32 , 40 , 56 , 64 , 67 ]. Our observation suggests, that the DNA methylation signature did not only result from the 1q duplication, but represented a complex pattern including the development of the structural lesion, chronic seizures, and co-morbidities [ 11 , 36 , 37 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

et al. 2020

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Polymicrogyria (PMG) is a developmental cortical malformation characterized by an excess of small and frustrane gyration and abnormal cortical lamination. PMG frequently associates with seizures. The molecular pathomechanisms underlying PMG development are not yet understood. About 40 genes have been associated with PMG, and small copy number variations have also been described in selected patients. We recently provided evidence that epilepsy-associated structural brain lesions can be classified based on genomic DNA methylation patterns. Here, we analyzed 26 PMG patients employing array-based DNA methylation profiling on formalin-fixed paraffin-embedded material. A series of 62 well-characterized non-PMG cortical malformations (focal cortical dysplasia type 2a/b and hemimegalencephaly), temporal lobe epilepsy, and non-epilepsy autopsy controls was used as reference cohort. Unsupervised dimensionality reduction and hierarchical cluster analysis of DNA methylation profiles showed that PMG formed a distinct DNA methylation class. Copy number profiling from DNA methylation data identified a uniform duplication spanning the entire long arm of chromosome 1 in 7 out of 26 PMG patients, which was verified by additional fluorescence in situ hybridization analysis. In respective cases, about 50% of nuclei in the center of the PMG lesion were 1q triploid. No chromosomal imbalance was seen in adjacent, architecturally normal-appearing tissue indicating mosaicism. Clinically, PMG 1q patients presented with a unilateral frontal or hemispheric PMG without hemimegalencephaly, a severe form of intractable epilepsy with seizure onset in the first months of life, and severe developmental delay. Our results show that PMG can be classified among other structural brain lesions according to their DNA methylation profile. One subset of PMG with distinct clinical features exhibits a duplication of chromosomal arm 1q.

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Role of TREK-1 in Health and Disease, Focus on the Central Nervous System

Cited by 75 publications

References 117 publications

Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Spadin Selectively Antagonizes Arachidonic Acid Activation of TREK-1 Channels

Activation of TREK-1 Potassium Channel Improved Cognitive Deficits in Alzheimer's Disease Model Mice by Modulation of Glutamate Metabolic Pathway

Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay

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