TREK2 Expressed Selectively in IB4-Binding C-Fiber Nociceptors Hyperpolarizes Their Membrane Potentials and Limits Spontaneous Pain

Acosta, Cristian; Djouhri, Laiche; Watkins, Roger Holmes; Berry, Carol; Bromage, Kirsty; Lawson, Sally N.

doi:10.1523/jneurosci.4528-13.2014

Cited by 105 publications

(131 citation statements)

References 71 publications

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“…Interestingly, other members of the K2P channel family (TREK-1, TREK-2 and TRAAK) are very sensitive to temperature (Kang et al, 2005; Maingret et al, 2000) and have been shown to play important roles in modulating the excitability of sensory neurons, including nociceptors (Acosta et al, 2014; Noel et al, 2009). Relative to other K2P channels, TASK-3 shows low expression values in rat DRG at the level of the whole ganglia (Marsh et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

et al. 2014

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Summary Animals sense cold ambient temperatures through the activation of peripheral thermoreceptors that express TRPM8, a cold- and menthol-activated ion channel. These receptors can discriminate a very wide range of temperatures from innocuous to noxious. The molecular mechanism responsible for the variable sensitivity of individual cold receptors to temperature is unclear. To address this question, we performed a detailed ion channel expression analysis of cold sensitive neurons, combining BAC transgenesis with a molecular profiling approach in FACS purified TRPM8 neurons. We found that TASK-3 leak potassium channels are highly enriched in a subpopulation of these sensory neurons. The thermal threshold of TRPM8 cold neurons is decreased during TASK-3 blockade and in mice lacking TASK-3 and, most importantly, these mice display hypersensitivity to cold. Our results demonstrate a novel role of TASK-3 channels in thermosensation, showing that a channel-based combinatorial strategy in TRPM8 cold thermoreceptors leads to molecular specialization and functional diversity.

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Section: Discussionmentioning

confidence: 99%

Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

et al. 2014

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“…1–4 The importance of TREK-2 conductance in setting the resting membrane potential was demonstrated by siRNA knockdown of DRG neuron TREK-2, which caused a 10 mV depolarization of the membrane potential. 3 As DRG c-fiber hyperpolarization limits electrical excitability, when TREK-2 channels are inactive or removed the DRG neurons show enhanced electrical excitability and increased pain signaling in response to nonaversive stimuli. 3 TREK-2 channels are mechanosensitive and also activated by heat; therefore, these channels are responsible for limiting allodynia in response to nonaversive mechanical stimulation as well as heat.…”

mentioning

confidence: 99%

“…3 As DRG c-fiber hyperpolarization limits electrical excitability, when TREK-2 channels are inactive or removed the DRG neurons show enhanced electrical excitability and increased pain signaling in response to nonaversive stimuli. 3 TREK-2 channels are mechanosensitive and also activated by heat; therefore, these channels are responsible for limiting allodynia in response to nonaversive mechanical stimulation as well as heat. 4–6 Moreover, TREK-2 channels limit spontaneous pain, neuropathic pain, and hyperalgesia.…”

mentioning

confidence: 99%

“…4–6 Moreover, TREK-2 channels limit spontaneous pain, neuropathic pain, and hyperalgesia. 3,4 Consequently, ablation of TREK-2 leads to enhanced allodynia in response to mechanical and heat stimulation. 4 Interestingly, TREK-2 transcript levels are reduced under conditions of DRG damage that leads to chronic pain, which may result from DRG c-fiber electrical hyperexcitability.…”

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confidence: 99%

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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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“…1.13) (Brohawn, 2015). Whereas TRAAK is mainly found in neuronal cells, TREK1 and TREK2 are expressed in smooth muscle tissues and nociceptors, and have been implicated in pain sensation, as well as cancer, and side effects to fluoxetine, also known as Prozac© (Acosta et al, 2014;Brohawn, 2015;Dong et al, 2015;K. S. Park et al, 2013).…”

Section: Mechanosensitive Channels In Higher-order Organismsmentioning

confidence: 99%

Biophysical and Structural Studies of Escherichia coli Mechanosensitive Channel of Large Conductance in Lipid Bilayers

Chi¹

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A major challenge of drug development is maximising specificity and efficacy at the lowest possible dose to minimise toxic side effects (Basile et al., 2012). Not only are the pharmaceutical windows small for both drug candidates and approved drugs alike, but they can also vary between individuals, making a dose level safe for one individual potentially harmful for another. One strategy for overcoming this problem is to develop new drug delivery methods where the drug is preferentially concentrated at the site of disease (Basile et al., 2012). In this respect, liposomal drug delivery systems have been used with success in topical applications in skin cancer treatment, and there is significant research interest in engineering similar systems for intravenous administration (Al-Jamal & Kostarelos, 2011;Fan & Zhang, 2013). Incorporating nanovalves into liposomes with controllable gating properties would further enhance the usefulness of liposomal drug delivery systems, providing a method to further regulate the release of liposome-encapsulated drugs from liposomes at the target site (Martinac et al., 2014).The mechanosensitive channel of large conductance (MscL) has been identified as a major candidate for the development of a protein-based nanovalve (Martinac et al., 2014). More generally, MscL is a prototype for the class of ion channels primarily gated by membrane tension, which includes medically significant proteins such as Piezo channels and TRP-type sodium channels (Martinac, 2011). As a well-expressing protein from Escherichia coli, MscL has been extensively studied both structurally and biophysically (Martinac, 2011). However, the channel gating mechanism of MscL, and by extension of mechanosensitive channels in general, remains poorly understood at the molecular level.This thesis aims to investigate the relationship between E. coli MscL and phospholipids both in the context of its structure and its behaviour in a lipid bilayer environment. While much has been studied on the channel gating properties of MscL in various phospholipid environments (Anishkin et al., 2005;Iscla et al., 2004;Iscla et al., 2011;Powl et al., 2008b;Tsai et al., 2005;Yoshimura et al., 2004), there remains a limited understanding of the behaviour and distribution of MscL in the bilayer. These are not only important from academic perspective as well as in the context of nanovalve development, but also for example, to identify factors which may limit the functional studies on MscL. More specifically, this thesis has focused on the identification of phospholipids closely associating with MscL, the distribution of MscL in phospholipid bilayers, and the incorporation of MscL into liposomes with heterogeneous phospholipids.The first research chapter (Chapter 2) outlines the optimisation of MscL expression and purification system for biophysical and structural studies. The original MscL construct had problems of ii heterogeneous expression and being not well-suited to reliable quantification by routine methods.New constructs were suc...

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TREK2 Expressed Selectively in IB4-Binding C-Fiber Nociceptors Hyperpolarizes Their Membrane Potentials and Limits Spontaneous Pain

Cited by 105 publications

References 71 publications

Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

Ion Channel Profile of TRPM8 Cold Receptors Reveals a Role of TASK-3 Potassium Channels in Thermosensation

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

Biophysical and Structural Studies of Escherichia coli Mechanosensitive Channel of Large Conductance in Lipid Bilayers

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