A Membrane Thickness Sensor in TREK-1 Channels Transduces Mechanical Force

Nayebosadri, Arman; Petersen, E. Nicolas; Cabanos, Cerrone; Hansen, Scott B.

doi:10.2139/ssrn.3155650

Cited by 12 publications

(12 citation statements)

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“…3d) as expected since PLD is known to bind directly to TREK-1 35 . TREK-1 localized minimally with GM1 domains, a result consistent with a proportion of TREK-1 preferring the disordered, bulk-like lipids when not bound to PLD 42 . Images of each individual channel for the abovementioned localizations are included in Supplemental Fig.…”

Section: The Trek-1 Force Transduction Pathwaysupporting

confidence: 63%

“…We also found that purified TREK-1 in liposomes show major regulation by the thickness of the membrane in which TREK-1 resides ( Fig. 2e) as well as by anionic lipid 42 . These results show in a purified system how PLD2 is the primary force transducer for TREK-1 activation in HEK cell membranes (see Fig.…”

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

confidence: 55%

“…In artificial membranes TREK-1 responds directly to membrane thinning 42 and stretch 41,50 , i.e. FFL appears to directly open and close the channel 17,51 .…”

Section: Discussionmentioning

confidence: 99%

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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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Section: The Trek-1 Force Transduction Pathwaysupporting

confidence: 63%

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

confidence: 55%

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

Gudheti

et al. 2019

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“…ACE2 association with PIP2 lipid domains is very similar to our previous finding with phospholipase D2. PIP2 opposes the function of GM1 clusters by trafficking the proteins away 32,58 . These results suggest that cholesterol is likely in balance with PIP2 in the membrane to regulate the trafficking of an ACE2 in or out of the GM1 cluster and this may change with age and disease.…”

Section: Discussionmentioning

confidence: 99%

The role of high cholesterol in age-related COVID19 lethality

Wang

Yuan

Pavel

et al. 2020

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Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan China in 2019. The disease in notably severe in elderly and those with underlying chronic conditions. The molecular mechanism as to why the elderly are vulnerable and why children are resistant is largely unknown. Understanding these differences is critical for safeguarding the vulnerable and guiding effective policy and treatments. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the endocytic entry of pseudotyped SARS-CoV-2. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol showed markedly increased apparent diameter (~10% to 100 nm) and almost twice the total number of viral entry points. The cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the viral entry site where SARS-CoV-2 docks to properly exploit entry into the cell. Furthermore, we show cholesterol enhances binding of SARS-CoV-2 to the cell surface which increases association with the endocytic pathway. Decreasing cellular cholesterol has the opposite effect. Based on these findings and known loading of cholesterol into peripheral tissue during aging and inflammation, we build a cholesterol dependent model for COVID19 lethality in elderly and the chronically ill. As cholesterol increases with age and inflammation (e.g. smoking and diabetes), the cell surface is coated with viral entry points and optimally assembled viral entry proteins. Importantly our model suggests high levels of cholesterol is most alarming in the tissue, not the blood. In fact, rapidly dropping cholesterol in the blood may indicate severe loading of cholesterol in peripheral tissue and a dangerous situation for escalated SARS-CoV-2 infectivity. Polyunsaturated fatty acids (PUFAs) oppose the effects of cholesterol and provide a molecular basis for eating healthy diets to avoid severe cases of COVID19.

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“…This result agrees with previous studies that showed the effect of anesthetics on bulk lipids is insufficient to activate a channel ( 42 ) at clinical concentrations despite the fact that anesthetics fluidize and thin membranes ( 43 ). TREK-1 is very sensitive to membrane thickness ( 44 ). It’s possible we failed to test an optimal thickness that is responsive in artificial systems, however, the fact that xPLD2 blocked all detectible anesthetic currents in whole cells suggests, in a biological membrane, domain disruption and TREK-1 and PLD2 translocation are the primary mechanism for anesthetic activation of TREK-1, not thinning of bulk lipids.…”

Section: Discussionmentioning

confidence: 99%

Studies on the mechanism of membrane mediated general anesthesia

Pavel

Petersen

Wang

et al. 2018

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12Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly 13 activate TWIK related K+ channels (TREK-1) and reversibly induce loss of consciousness. For a 14 hundred years anesthetics were speculated to target cellular membranes, yet no plausible 15 mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled 16 anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of palmitate-17 mediated localization of phospholipase D2 (PLD2) to lipid rafts and subsequent production of 18 signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-19 1 currents in cell patch-clamp. Localization of PLD2 renders the anesthetic-insensitive TRAAK 20 channel sensitive. General anesthetics chloroform, isoflurane, diethyl ether, xenon, and propofol 21 disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and 22 PLD null flies resist anesthesia. Our results establish a membrane mediated target of inhaled 23 anesthesia and suggest PA helps set anesthetic sensitivity in vivo. 24 25 12 chemical environment (10) ( Supplementary Fig. S1b-c). PLD2 actives Twik related potassium 13 channel-1 (TREK-1). If inhaled anesthetics can disrupt lipid domains to activate a channel, this 14 would constitute a mechanism distinct from the usual receptor-ligand interaction and establish a 15 definitive membrane mediated mechanism for an anesthetic. 16 17 TREK-1 is an anesthetic-sensitive two-pore-domain potassium (K2P) channel. Xenon, diethyl 18 ether, halothane, and chloroform robustly activate TREK-1 at concentrations relevant to their 19 clinical use (11, 12) and genetic deletion of TREK-1 decreases anesthesia sensitivity in mice (13).20 Here we show inhaled anesthetics disrupt palmitate-mediated localization in the membranes of 21 cultured neuronal, muscle cells, and in the whole brain of anesthetized flies. The disruption 22 releases PLD2 from muscle and neuronal cells which signal downstream to activate TREK-1 23 channels. This result establishes the membrane as a pertinent target of inhaled anesthetics.24 25 Anesthetics perturb nanoscale lipid heterogeneity (GM1 domains). 3The best studied lipid domains contain saturated lipids cholesterol and sphingomyelin (e.g.

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A Membrane Thickness Sensor in TREK-1 Channels Transduces Mechanical Force

Cited by 12 publications

References 11 publications

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

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

The role of high cholesterol in age-related COVID19 lethality

Studies on the mechanism of membrane mediated general anesthesia

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