Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception

Pereira, Vanessa; Busserolles, Jérôme; Christin, Marine; Devilliers, Maïly; Poupon, Laura; Legha, Wassim; Alloui, Abdelkrim; Aissouni, Youssef; Bourinet, Emmanuel; Lesage, Florian; Eschalier, Alain; Lazdunski, Michel; Noël, Jacques

doi:10.1016/j.pain.2014.09.013

Cited by 124 publications

(172 citation statements)

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“…Previous computational and theoretical studies of membrane tension have emphasized how stretch-induced changes in the lateral pressure profile might not be symmetrical between the two leaflets (i.e., inner and outer) of the lipid bilayer and explored how this may influence gating (16)(17)(18)(19)(20), but these studies were restricted mostly to prokaryotic MS channels. More tractable and better-defined experimental systems for the study of eukaryotic MS channels are needed.TREK-2 is a eukaryotic MS ion channel that belongs to the twopore domain (K2P) family of K + -selective channels and is important for mechanical and thermal nociception in many sensory neurons (21,22). Other members of this subgroup of MS K2P channels include TREK-1 and TRAAK.…”

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confidence: 99%

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Asymmetric mechanosensitivity in a eukaryotic ion channel

Clausen

Jarerattanachat

Carpenter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian twopore domain (K2P) K + channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.any forms of sensory perception in higher organisms depend on the rapid conversion of mechanical and physical stimuli into the electrochemical language of nerve and muscle cells (1). These transduction mechanisms often involve "mechanosensitive" (MS) ion channels that are able to rapidly convert physicomechanical stimuli into the electrical signals required for complex physiological responses (e.g., touch, pain, hearing, proprioception), as well those mechanical signals that play key roles in development and cell-cell communication (2). The enormous complexity and diversity of these sensory responses suggests that a variety of molecular mechanisms are likely responsible; for example, while some channels are regulated via physical coupling to proteins of the cytoskeleton and/or cell matrix, others respond directly to changes in lipid membrane tension (3). The precise structural and physical mechanisms underlying these processes remain poorly understood, however (4-6).Our current understanding of how membrane tension directly regulates ion channel gating is largely derived from studies of prokaryotic MS ion channels involved in the control of bacterial turgor pressure (7,8). The open state of these MS channels has a larger cross-sectional area than the closed state within the membrane, and stretch-induced changes in the forces within the bilayer stabilize the expanded open-state conformation. This is commonly referred to as the force-from-lipid principle of mechanosensitivity (9). Similar physical principles are thought to regulate many eukaryotic MS channels (5, 10).Typically, the functional activity of MS ion channels is examined in pipette-based patch-clamp recordings in which negative or positive pressures are used to alter bilayer tension. These pressure changes stretch the membrane to alter the lateral pressure profile, the complex profile of forces that vary with location acro...

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“…TREK-2 is a eukaryotic MS ion channel that belongs to the twopore domain (K2P) family of K + -selective channels and is important for mechanical and thermal nociception in many sensory neurons (21,22). Other members of this subgroup of MS K2P channels include TREK-1 and TRAAK.…”

mentioning

confidence: 99%

Asymmetric mechanosensitivity in a eukaryotic ion channel

Clausen

Jarerattanachat

Carpenter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus. All of the subunits are coexpressed in the cortex, hippocampus, hypothalamus, amygdala, and olfactory system (12), and in the spinal cord (16,17). K 2P channels are dimers of subunits (18)(19)(20).…”

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confidence: 99%

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Blin

Soussia

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The tandem of pore domain in a weak inwardly rectifying K + channel (Twik)-related acid-arachidonic activated K + channel (TRAAK) and Twikrelated K + channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K 2P ) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K 2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs. + channels (TREK) 1, TREK2, and Twik-related acid-arachidonic activated K + channel (TRAAK) channels produce inhibitory background K + currents (1-3). These channels respond to neuroprotective fatty acids, mechanical stretch, temperature, pH, and neurotransmitters through G proteincoupled receptors (GPCRs) (for a recent review, see ref. 4). TREK1 is activated by volatile anesthetics and plays a role in general anesthesia. These channels have emerged as promising targets for the development of other classes of clinical compounds. TREK1 is activated by opioid receptors and contributes to morphine-induced analgesia, but is not involved in morphine-induced constipation, respiratory depression, and dependence (5). TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7). Also, activation of TREK1 by GABA B receptors in the hippocampus (8), and inhibition of TREK2 by neurotensin receptors in the entorhinal cortex (9), suggests that specific modulators of these channels might also have beneficial actions against drug abuse, and against learning slow down and memory deficits in Alzheimer's disease. Finally, inhibition of TREK1 by spadin (10), an endogenous peptide, or by the antidepressant fluoxetine (Prozac) (11), pinpoints it as a valuable target for the treatment of depression. TREK/TRAAK channels are broadly expressed in the nervous system (12-15). TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus. All...

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“…122,123 Voltage-gated sodium channels (Nav), in particular Nav1. 8, also play a significant role in thermoreception (Fig.…”

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Molecular sensors and modulators of thermoreception

Zhang

2015

Channels

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Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception

Cited by 124 publications

References 70 publications

Asymmetric mechanosensitivity in a eukaryotic ion channel

Asymmetric mechanosensitivity in a eukaryotic ion channel

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Molecular sensors and modulators of thermoreception

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Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception

Cited by 124 publications

References 70 publications

Asymmetric mechanosensitivity in a eukaryotic ion channel

Asymmetric mechanosensitivity in a eukaryotic ion channel

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

Molecular sensors and modulators of thermoreception

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Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties