Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali

Kim, Yangmi; Bang, Hyoweon; Gnatenco, Carmen; Kim, Dong‐Hee

doi:10.1007/s004240000496

Cited by 106 publications

(118 citation statements)

References 38 publications

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“…Whereas TREK1 and TREK2 homodimers are activated by intracellular acidification (32), TRAAK is activated by intracellular alkalinization (27). We find that TREK1-TRAAK heterodimers are activated by both increases and decreases in pH i .…”

Section: Discussionmentioning

confidence: 69%

“…To visualize how extracellular His within the first loop of TREK channels may control the sensitivity to pH o , we used crystal structures of TREK2 (27) and TREK1 to build a model of the TREK1-TREK2 heterodimer. The model shows that charged residues within the second extracellular loop (negatively charged E265 and D263 in TREK1 and positively charged R293 in TREK2), which were previously identified as potential electrostatic interaction partners (11), are indeed positioned to interact with the His, and that these interactions occur within a subunit (Fig.…”

Section: Trek1 and Trek2 Coassemble And Are Targeted To The Plasmamentioning

confidence: 99%

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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: 69%

Section: Trek1 and Trek2 Coassemble And Are Targeted To The Plasmamentioning

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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“…TRAAK (K2P4.1) and TREK channels are members of the two-pore domain K + (K2P) ion channels. Their gating is regulated by mechanical perturbation of the cell membrane as well as polyunsaturated fatty acids, other lipids, and temperature (18)(19)(20)(21)(22)(23). TRAAK/TREK knockout mice exhibit mechanical and temperature allodynia (24).…”

mentioning

confidence: 99%

Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K ⁺ channels

Brohawn

MacKinnon

2014

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

359

327

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Mechanosensitive ion channels underlie neuronal responses to physical forces in the sensation of touch, hearing, and other mechanical stimuli. The fundamental basis of force transduction in eukaryotic mechanosensitive ion channels is unknown. Are mechanical forces transmitted directly from membrane to channel as in prokaryotic mechanosensors or are they mediated through macromolecular tethers attached to the channel? Here we show in cells that the K + channel TRAAK (K2P4.1) is responsive to mechanical forces similar to the ion channel Piezo1 and that mechanical activation of TRAAK can electrically counter Piezo1 activation. We then show that the biophysical origins of force transduction in TRAAK and TREK1 (K2P2.1) two-pore domain K + (K2P) channels come from the lipid membrane, not from attached tethers. These findings extend the "force-from-lipid" principle established for prokaryotic mechanosensitive channels MscL and MscS to these eukaryotic mechanosensitive K + channels.mechanosensation | potassium channel | gating | tension | reconstitution

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“…The TREK/TRAAK Subunit Family Is Up-regulated by Intracellular LPA-TREK-2 and TRAAK are, similar to TREK-1, stimulated by membrane stretch and polyunsaturated fatty acids (21,29,31,48,50). Both channels are also reversibly activated by intracellular LPA at atmospheric pressure (Fig.…”

Section: Resultsmentioning

confidence: 85%

“…At atmospheric pressure, their open probability is low but is dose dependent and reversibly increased by membrane stretch (17,19,21,28). Furthermore, TREK-1 and TREK-2 are stimulated by intracellular acidosis, whereas TRAAK opens upon intracellular alkalosis (19,20,28,29). TREK-1 is additionally opened by heat, whereas it closes upon cooling (18).…”

mentioning

confidence: 99%

Lysophosphatidic Acid-operated K+ Channels

Chemin¹,

Patel²,

Duprat

et al. 2005

Journal of Biological Chemistry

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Lysophosphatidic acid (LPA) is an abundant cellular lipid with a myriad of biological effects. It plays an important role in both inter-and intracellular signaling. Activation of the LPA 1-3 G-protein-coupled receptors explains many of the extracellular effects of LPA, including cell growth, differentiation, survival, and motility. However, LPA also acts intracellularly, activating the nuclear hormone receptor peroxisome proliferator-activated receptor-␥ that regulates gene transcription. This study shows that the novel subfamily of mechano-gated K 2P channels comprising TREK-1, TREK-2, and TRAAK is strongly activated by intracellular LPA. The LPA-activated 2P domain K ؉ channels are intracellular ligandgated K ؉ channels such as the Ca 2؉ -or the ATP-sensitive K ؉ channels. LPA reversibly converts these mechano-gated, pH-and voltage-sensitive channels into leak conductances. Gating conversion of the 2P domain K ؉ channels by intracellular LPA represents a novel form of ion channel regulation. Thus, the TREK and TRAAK channels should be included in the LPA-associated physiological and disease states.

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Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali

Cited by 106 publications

References 38 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

Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K ⁺ channels

Lysophosphatidic Acid-operated K+ Channels

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Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali

Cited by 106 publications

References 38 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

Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K + channels

Lysophosphatidic Acid-operated K+ Channels

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Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K ⁺ channels