Studies on the mechanism of general anesthesia

Pavel, Mahmud Arif; Petersen, Erling N.; Wang, Hao; Lerner, Richard A.; Hansen, Scott B.

doi:10.1073/pnas.2004259117

Cited by 166 publications

(200 citation statements)

References 67 publications

(86 reference statements)

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“…N2a cells exhibited the smallest rafts by far, on average only 100 nm in apparent diameter. All of the mammalian cells had domains larger than what we saw in intact fly brain which had an apparent diameter of ~90 nm 38 . Lipid rafts were also measured in neurons with the SREBP2 gene ablated in cocultured astrocytes.…”

Section: Characterization Of Lipid Raft Prevalence In Brain Tissuementioning

confidence: 60%

“…Investigating the effect of astrocyte cholesterol on channels will be important for studying AD since many of the palmitoylated channels have profound effects on neuronal excitability and learning and memory 68 . In a separate study we saw apoE and high cholesterol caused the potassium channel TREK-1 to traffic to lipid rafts similar to APP (Nayebosadri unpublished data) 69 and anesthetics 38 and mechanical force disrupts the localization 70 .…”

Section: Discussionmentioning

confidence: 93%

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Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Wang

Kulas

Ferris

et al. 2020

Preprint

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Alzheimer's Disease (AD), a common and burdensome neurodegenerative disorder, is characterized by the presence of β-Amyloid (Aβ) plaques, inflammation, and loss of cognitive function. A cholesteroldependent process sorts Aβ-producing enzymes into nanoscale lipid compartments (also called lipid rafts). Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. Evidence suggests apoE links to Aβ production through lipid rafts, but so far there has been little scientific validation of this link in vivo. Here we use super-resolution imaging to show apoE utilizes astrocyte-derived cholesterol to specifically traffic amyloid precursor protein (APP) into lipid rafts where it interacts with β-and g-secretases to generate Aβ-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with αsecretase and gives rise to soluble APPα (sAPPα), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and g-secretase trafficking, suggesting the ratio of Aβ to sAPPα is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1β, IL-6 and TNF-α upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is a signaling molecule kept low in neurons to inhibit raft function, decrease Aβ formation, and enable astrocyte regulation of APP by cholesterol control of substrate presentation. Highlights:ApoE regulates amyloid precursor protein localization to rafts and its exposure to α-vs. β-secretase. α-, β-, and g-Secretases are activated by substrate presentation. ApoE specifically transports astrocyte cholesterol to neurons. Astrocyte cholesterol synthesis disruption prevents Alzheimer's-associated amyloid pathology in mice.

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Section: Characterization Of Lipid Raft Prevalence In Brain Tissuementioning

confidence: 60%

Section: Discussionmentioning

confidence: 93%

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Wang

Kulas

Ferris

et al. 2020

Preprint

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“…Phospholipase D2 (PLD2) is an anesthetic sensitive enzyme that translocates out of GM1 rafts in response to general anesthetics xenon, chloroform, isoflurane, propofol, and diethyl ether. Furthermore, mutant flies lacking PLD2 are resistant to anesthesia 10,31 and thus provides a test for anesthetic like effects in the membrane.…”

Section: Hcq Acts In the Anesthetic Pathwaymentioning

confidence: 99%

“…S1A). In cellular membranes, local and general anesthetics, including propofol, disrupt GM1 rafts 10,14 .…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

Yuan

Pavel

Wang

et al. 2020

Preprint

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Background: SARS-coronavirus 2 (SARS-CoV-2) is currently causing a worldwide pandemic. Potential drugs identified for the treatment of SARS-CoV-2 infection include chloroquine (CQ), its derivative hydroxychloroquine (HCQ), and the anesthetic propofol. Their mechanism of action in SARS-CoV-2 infection is poorly understood. Recently, anesthetics, both general and local, were shown to disrupt ordered lipid domains. These same lipid domains recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to an endocytic entry point and their disruption by cholesterol depletion decreases ACE2 recruitment and viral entry. Methods: Viral entry was determined using a SARS-CoV-2 pseudovirus (SARS2-PV) and a luciferase reporter gene expressed by the virus after treatment of the cells with 50 micromolar propofol, tetracaine, HCQ, and erythromycin. HCQ disruption of monosialotetrahexosylganglioside1 (GM1) lipid rafts, phosphatidylinositol 4,5-bisphosphate (PIP2) domains, and ACE2 receptor at nanoscale distances was monitored by direct stochastic reconstruction microscopy (dSTORM). Cells were fixed, permeabilized, and then labeled with either fluorescent cholera toxin B (CTxB) or antibody and then fixed again prior to imaging. Cluster analysis of dSTORM images was used to determine size and number and cross pair correlation was used to determine trafficking of endogenously expressed ACE2 in and out of lipid domains. Results: Propofol, tetracaine, and HCQ inhibit SARS2-PV viral entry. HCQ directly perturbs both GM1 lipid rafts and PIP2 domains. GM1 rafts increased in size and number similar to anesthetic disruption of lipid rafts; PIP2 domains decreased in size and number. HCQ blocked both GM1 and PIP2 domains ability to attract and cluster ACE2. Conclusions: We conclude HCQ is an anesthetic-like compound that disrupts GM1 lipid rafts similar to propofol and other local or general anesthetics. Furthermore, we conclude disruption of GM1 raft function, and not the concentration of GM1 raft molecules, governs the antiviral properties of HCQ. HCQ disruption of the membrane appears to also disrupt the production of host defense peptide, hence an antimicrobial such as erythromycin could be an important combined treatment. Nonetheless erythromycin has anti-SARS-CoV-2 activity and may combine with HCQ to reduce infection.

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“…In particular, PIP 2 is essential for the intracellular localization of PLD2 [1,2,5,[7][8][9]. Furthermore, it has recently been suggested that PIP 2 cluster-PLD2 interaction plays a primary role in the action of general anesthetics (GAs) [16][17][18]. The mechanism of general anesthesia, 'a reversible, drug-induced loss of consciousness', is one of the unsolved problems of neuropharmacology [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

PLD2–PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations

2020

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Interaction of phospholipase D2 (PLD2) with phosphatidylinositol (4,5)-bisphosphate (PIP 2) is regarded as the critical step of numerous physiological processes. Here we build a fulllength model of human PLD2 (hPLD2) combining template-based and ab initio modeling techniques and use microsecond all-atom molecular dynamics (MD) simulations of the protein in contact with a complex membrane to determine hPLD2-PIP 2 interactions. MD simulations reveal that the intermolecular interactions preferentially occur between specific PIP 2 phosphate groups and hPLD2 residues; the most strongly interacting residues are arginine at the pbox consensus sequence (PX) and pleckstrin homology (PH) domain. Interaction networks indicate formation of clusters at the protein-membrane interface consisting of amino acids, PIP 2 , and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidic acid (POPA); the largest cluster was in the PH domain.

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Studies on the mechanism of general anesthesia

Cited by 166 publications

References 67 publications

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

PLD2–PI(4,5)P2 interactions in fluid phase membranes: Structural modeling and molecular dynamics simulations

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