Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Lengyel, M; Czirják, Gábor; Enyedi, Péter

doi:10.1074/jbc.m116.719039

Cited by 42 publications

(30 citation statements)

References 39 publications

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“…Despite the fact that K 2P channels share a similar architecture and global function, they share a low level of sequence identity, even between members of the same subfamily. Surprisingly, this low level of identity does not preclude heteromerization, as we and others recently showed within the TREK subfamily Hwang et al, 2014;Lengyel et al, 2016;Levitz et al, 2016). Based on this and the fact that TG neurons express many K 2P channels (TREK1, TREK2, TRAAK, TASK1, and TASK3; Bautista et al, 2008;Yamamoto et al, 2009), we hypothesized that the difference between TRESK mutants is due to their differential ability to modify the function of other K 2P chan-nels through heteromerization.…”

Section: Tresk Heteromerizes With Trek1 and Trek2mentioning

confidence: 80%

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Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Royal

Andrés‐Bilbé

Prado

et al. 2019

Neuron

113

135

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Section: Tresk Heteromerizes With Trek1 and Trek2mentioning

confidence: 80%

“…We and others Hwang et al, 2014;Lengyel et al, 2016;Levitz et al, 2016) have recently shown that K 2P channels are able to form both homodimeric and heterodimeric potassium channels. In this study, we show that TREK and TRESK readily assemble as heteromers.…”

Section: Discussionmentioning

confidence: 90%

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Royal

Andrés‐Bilbé

Prado

et al. 2019

Neuron

113

135

View full text Add to dashboard Cite

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“…For example, TREK-2 can heterodimerize with TREK-1 or TRAAK; thus, it will be important for future studies to determine how TREK-2 modulators influence TREK-1/TREK-2 or TRAAK/TREK-2 heterodimers. 40–42 While TREK-2 selective activators will be useful for uncovering the roles of TREK-2 in pain signaling, they may also be useful in identifying new strategies for reducing postoperative pain or neuropathic pain without the potential for addiction. Currently pain strategies are being developed to reduce CNS addictive properties such as μ – δ opioid receptor heteromer-biased agonists.…”

Section: Discussionmentioning

confidence: 99%

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

Dadi

Vierra

Days

et al. 2016

ACS Chem. Neurosci.

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The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl+) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC50 ≈ 0.294 µM), which was utilized to optimize the TREK-2 Tl+ flux assay (Z′ = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca2+ influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.

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“…Whole-cell patch-clamp experiments in the voltage-clamp configuration were performed as described previously (Lengyel et al, 2016). The resting membrane potential was recorded in the current-clamp mode with no current injection (I 5 0 mode).…”

Section: Methodsmentioning

confidence: 99%

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K_2P18.1) Background Potassium Channel

et al. 2019

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Cloxyquin has been reported as a specific activator of TRESK [TWIK-related spinal cord K 1 channel (also known as K 2P 18.1)] background potassium channel. In this study, we have synthetized chemically modified analogs of cloxyquin and tested their effects on TRESK and other K 2P channels. The currents of murine K 2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K 1 conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch-clamp method. Some of the analogs retained the activator character of the parent compound, but, more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogs (A2764 and A2793) exerted state-dependent effects. The degree of inhibition by 100 mM A2764 (77.8% 6 3.5%, n 5 6) was larger in the activated state of TRESK (i.e., after calcineurin-dependent stimulation) than in the resting state of the channel (42.8% 6 11.5% inhibition, n 5 7). The selectivity of the inhibitor compounds was tested on several K 2P channels. A2793 inhibited TWIKrelated acid-sensitive K 1 channel (TASK)-1 (100 mM, 53.4% 6 13, 5%, n 5 5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TWIK-related alkaline pH-activated K 1 channel. The effect of A2764 was also examined on the background K 1 currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K 1 currents sensitive to A2764, whereas the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine. SIGNIFICANCE STATEMENTTRESK background potassium channel is a potential pharmacological target in migraine and neuropathic pain. In this study, we have identified a selective inhibitor of TRESK, A2764. This compound can inhibit TRESK in native cells, leading to cell depolarization and increased excitability. This new inhibitor may be of use to probe the role of TRESK channel in migraine and nociception.

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Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Cited by 42 publications

References 39 publications

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K_2P18.1) Background Potassium Channel

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Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

Cited by 42 publications

References 39 publications

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel

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Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K_2P18.1) Background Potassium Channel