Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid

Comoglio, Yannick; Levitz, Joshua; Kienzler, Michael A.; Lesage, Florian; Isacoff, Ehud Y.; Sandoz, Guillaume

doi:10.1073/pnas.1407160111

Cited by 49 publications

(82 citation statements)

References 30 publications

(26 reference statements)

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“…PLD2 has been shown recently to regulate TREK1 and TREK2, but not TRAAK, with specificity defined by the ability of PLD2 to bind to the C termini of TREK1 and TREK2, but not TRAAK (5). We find that TREK1-TRAAK heterodimers are regulated by PLD2 with a similar potency to TREK1, indicating that a channel needs only one PLD2-compatible C-terminal domain to bind PLD2.…”

Section: Discussionmentioning

confidence: 47%

“…We recently described how, in both TREK1 and TREK2, interaction of the intracellular Ctd with the PA-producing enzyme PLD2 results in PA-dependent tonic activation (5). Despite its sensitivity to PA, TRAAK is not regulated by PLD2 because it does not form a channel-enzyme complex.…”

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

confidence: 99%

“…They are not very active under basal conditions but can be dynamically stimulated by a wide range of stimuli, including mechanical stretch (1), heat (2,3), phospholipids (4)(5)(6), and polyunsaturated fatty acids (1,7). pH is an especially prominent regulator of these channels.…”

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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: 47%

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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“…To further confirm that PLD2 is responsible for stretch activation of TREK-1 currents in cellular membranes, we truncated the C-terminus of TREK-1 (truncated TREK-1) and compared its pressure activation to wildtype-PLD2 binds to the C-terminus of TREK 35 (Supplemental Fig. S3c).…”

Section: Consistent With Previous Experiments Overexpression Of Trek-1mentioning

confidence: 99%

Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling

Gudheti

et al. 2019

Preprint

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The transduction of force into a biological signal is critical to all living organisms. Recently, disruption of ordered lipids has emerged as an 'atypical' force sensor in biological membranes; however, disruption has yet to link with canonical channel mechanosensation. Here we show that forceinduced disruption and lipid mixing activates TWIKrelated K + channel (TREK-1), and that this activation is dependent on phospholipase D2 (PLD2). PLD2 transduces the force into a chemical signal phosphatidic acid (PA) that is then sensed by TREK-1 with a latency of <3 ms. TREK-1 then produces a mechanically induced change in membrane potential. Hence, in a biological membrane, we show the ordered lipid is the force sensor, PLD2 is a chemical transducer, and the 'mechanosensitive' ion channel TREK-1 is a downstream effector of mechanical transduction. Confirming this central role for PA singling in force transduction, genetic deletion of PLD decreases mechanosensitivity and pain thresholds in D. melanogaster.

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“…PLC functionally colocalized with NMDA receptors [78] and the IP3 receptor co-localizes with PLC to regulate calcium release [107]. PLD lipases directly localize to ion channels, including TRPM8 [108] and TREK-1 [109]. There are many subtypes of lipases; their diverse regulation and specific localization satisfies cells with the needed diversity for signaling.…”

Section: Cellular Regulation Of Pip2 Agonismmentioning

confidence: 99%

Lipid agonism: The PIP2 paradigm of ligand-gated ion channels

Hansen

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

127

138

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The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid-ligand bind to a membrane protein in the plasma membrane and what does it mean for a lipid to activate or regulate an ion channel? How does lipid-binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.

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Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid

Cited by 49 publications

References 30 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

Mechanical activation of TWIK-related potassium channel by nanoscopic movement and rapid second messenger signaling

Lipid agonism: The PIP2 paradigm of ligand-gated ion channels

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