K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

Dong, Yin; Pike, A.C.W.; Mackenzie, Alexandra; McClenaghan, Conor; Aryal, Prafulla; Dong, Liang; Quigley, Andrew; Grieben, M.; Goubin, S.; Mukhopadhyay, Shubhashish M.M.; Ruda, G.F.; Clausen, Michael V.; Cao, Lishuang; Brennan, P.E.; Burgess-Brown, N.; Sansom, Mark S.P.; Tucker, Stephen J.; Carpenter, E.P.

doi:10.1126/science.1261512

Cited by 273 publications

(563 citation statements)

References 61 publications

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“…How could such interactions between the first and second external loops be communicated to the internal gate of the channel? An answer is suggested by the location of the charged residues in the second external loop just "above" the fourth transmembrane helix, which has been shown to serve as an intracellular gate in K 2P channels (29)(30)(31), implying an activation rearrangement that propagates through the helix to the intracellular gate.…”

Section: Discussionmentioning

confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

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

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Twik-related K + channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K + channel (TRAAK) form the TREK subfamily of two-pore-domain K + (K 2P ) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K 2P channels.potassium channels | single-molecule fluorescence | leak current | combinatorial diversity | heteromerization

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Section: Discussionmentioning

confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

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

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“…The family of mechanosensing channels are not confined to bacteria there are many examples from higher organisms, which do not share any sequence homology with the bacterial ones but fill important roles including K + transport [7,8] and mechanotransduction [9,10]. However, the bacterial systems are the most well studied.…”

Section: Bacterial Mechanosensors Mscs and Mscl: Open And Shut Storiesmentioning

confidence: 99%

“…The vanilloid agonist (resiniferatoxin, RTX) [10] and capsaicin [41] both have lyso-PC like acyl chains that bind within the TM region of the TRPV1 channel (akin to MscS [34]) activating it [10,41]. Norfluoxetine, the active metabolite of Prozac is very hydrophobic and binds within the Tm region modulating TREK-2 channel [7]. Yoda 1(2-[5-[[(2,6-dichlorophenyl)methyl]thio]-1,3,4-thiadiazol-2-yl]pyrazine), a molecule, which acts as an agonist for the Piezo1 eukaryotic mechanosensitive ion channel [42], binds to an unknown location.…”

Section: Linking Mechanosensing and Ligand-gatingmentioning

confidence: 99%

Spectator no more, the role of the membrane in regulating ion channel function

Pliotas

Naismith

2017

Current Opinion in Structural Biology

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A pressure gradient across a curved lipid bilayer leads to a lateral force within the bilayer. Following ground breaking work on eukaryotic ion channels, it is now known that many proteins sense this change in the lateral tension and alter their functions in response. It has been proposed that responding to pressure differentials may be one of the oldest signaling mechanisms in biology. The most well characterized mechanosensing ion channels are the bacterial ones which open when the pressure differential hits a threshold. Recent studies on one of these channels, MscS, have developed a simple molecular model for how they sense and adapt to pressure.Biochemical and structural studies on mechanosensitive channels from eukaryotes have disclosed pressure sensing mechanisms. In this review, we highlight these findings and discuss the potential for a general model for pressure sensing.3

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“…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). Heterodimerization has been shown to occur between the members of two subfamilies of K 2P channels: the TASK (21) and THIK (22) channels.…”

mentioning

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...

show abstract

K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

Cited by 273 publications

References 61 publications

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Spectator no more, the role of the membrane in regulating ion channel function

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

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K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac

Cited by 273 publications

References 61 publications

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Spectator no more, the role of the membrane in regulating ion channel function

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

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