The Lateral Pressure Profile in Membranes:  A Physical Mechanism of General Anesthesia

Cantor, Robert S.

doi:10.1021/bi9627323

Cited by 442 publications

(290 citation statements)

References 20 publications

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“…This implies the absence of nonspecific perturbations of lipid membranes by minocycline. However, it can not be excluded that minocycline acts at the protein-lipid interface causing redistribution of membrane lateral pressure sensed by specific membrane proteins [57].…”

Section: Discussionmentioning

confidence: 99%

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

García-Martínez

Sanz-Blasco

Karachitos

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Garcia-Martinez EM et al., 2 AbstractMinocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura-2/AM and mitochondria-targeted aequorin revealed that minocycline, at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death, inhibited NMDA-induced cytosolic and mitochondrial rises in Ca 2+ concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca 2+ intracellular levels, but not when induced by depolarization with a high K + medium. We also found that minocycline, at the same concentrations, partially depolarized mitochondria by about 5-30 mV, prevented mitochondrial Ca 2+ uptake under conditions of environmental stress, and abrogated NMDAinduced reactive oxygen species (ROS) formation. Consistently, minocycline also abrogates the rise in ROS induced by 75 M Ca 2+ in isolated brain mitochondria. In search for the mechanism of mitochondrial depolarization, we found that minocycline markedly inhibited state 3 respiration of rat brain mitochondria, although distinctly increased oxygen uptake in state 4. Minocycline inhibited NADH-cytochrome c reductase and cytochrome c oxidase activities, whereas the activity of succinate-cytochrome c reductase was not modified, suggesting selective inhibition of complex I and IV. Finally, minocycline affected activity of voltage-dependent anion channel (VDAC) as determined in the reconstituted system. Taken together, our results indicate that mitochondria are a critical factor in minocycline-mediated neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

García-Martínez

Sanz-Blasco

Karachitos

et al. 2010

Biochemical Pharmacology

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“…Such conductance increases could occur by the membrane acting on Na þ channels to stabilize the open state, or by the lipid membrane directly becoming leaky to Na þ ions. In support of the indirect pathway, it has been proposed (21), and supported by statistical thermodynamics (3,22) and coarse-grain modeling (23), that alcohol changes the lateral pressure within the membrane and that this increase can bias ion channels toward the closed state. In support of the direct pathway it has be shown that both ethanol (24) and other anesthetics (25) can change the permeability of lipid membranes.…”

Section: Introductionmentioning

confidence: 96%

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

Paxman

Hunt

Hallan

et al. 2017

Biophysical Journal

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Although the effects of ethanol on protein receptors and lipid membranes have been studied extensively, ethanol's effect on vesicles fusing to lipid bilayers is not known. To determine the effect of alcohols on fusion rates, we utilized the nystatin/ergosterol fusion assay to measure fusion of liposomes to a planar lipid bilayer (BLM). The addition of ethanol excited fusion when applied on the cis (vesicle) side, and inhibited fusion on the trans side. Other short-chain alcohols followed a similar pattern. In general, the inhibitory effect of alcohols (trans) occurs at lower doses than the excitatory (cis) effect, with a decrease of 29% in fusion rates at the legal driving limit of 0.08% (w/v) ethanol (IC 50 ¼ 0.2% v/v, 34 mM). Similar inhibitory effects were observed with methanol, propanol, and butanol, with ethanol being the most potent. Significant variability was observed with different alcohols when applied to the cis side. Ethanol and propanol enhanced fusion, butanol also enhanced fusion but was less potent, and low doses of methanol mildly inhibited fusion. The inhibition by trans addition of alcohols implies that they alter the planar membrane structure and thereby increase the activation energy required for fusion, likely through an increase in membrane fluidity. The cis data are likely a combination of the above effect and a proportionally greater lowering of the vesicle lysis tension and hydration repulsive pressure that combine to enhance fusion. Alternate hypotheses are also discussed. The inhibitory effect of ethanol on liposome-membrane fusion is large enough to provide a possible biophysical explanation of compromised neuronal behavior.

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“…Recently, interest has focused on distortions of the lipid bilayer caused by the presence of a membrane protein and on how these distortions could depend on elastic properties of the bulk lipid bilayer such as its spontaneous curvature (3)(4)(5)(6)(7). The spontaneous curvature of a lipid, C 0 , is the reciprocal of the spontaneous radius of curvature, R 0 , and is the curvature that one monolayer of a bilayer would adopt if it was allowed to bend freely, without the constraint imposed from being packed back to back with another monolayer in a bilayer (8).…”

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confidence: 99%

Importance of Direct Interactions with Lipids for the Function of the Mechanosensitive Channel MscL

2008

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We have studied the effects of lipid structure on the function of the mechanosensitive channel of large conductance (MscL) from Escherichia coli to determine whether effects follow from direct interaction between the lipids and protein or whether they follow indirectly from changes in the curvature stress in the membrane. The G22C mutant of MscL was reconstituted into sealed vesicles containing the fluorescent molecule calcein, and the release of calcein from the vesicles was measured following opening of the channel by reaction with [2-(triethylammonium)ethyl] methanethiosulfonate (MTSET), which introduces five positive charges into the region of the pore constriction. The presence of anionic lipids in the vesicle membrane changed the rates and amplitudes of calcein release, the effects not correlating with calculated changes in lipid spontaneous curvature. Mutation of charged residues in the Arg-104, Lys-105, Lys-106 cluster removed high-affinity binding of anionic lipids to MscL, and the presence of anionic lipid no longer affected calcein flux through MscL. Changing the zwitterionic lipid from phosphatidylcholine to phosphatidylethanolamine resulted in a large decrease in the rate of calcein release, the change in rate varying linearly with lipid composition, as expected if spontaneous curvature affected the rate of release. However, rates of release of calcein measured in the presence of phosphatidylethanolamine-N-methyl and phosphatidylethanolamine-N,N-dimethyl did not fit the correlation between rate and curvature established for the phosphatidylcholine/phosphatidylethanolamine mixtures. Rather, the effects of zwitterionic lipid headgroup on calcein flux suggested that what was important was the presence of a proton in the headgroup, able to take part in hydrogen bonding to MscL. We conclude that the function of MscL is likely to be modulated by direct interaction with the surrounding, annular phospholipids that contact the protein in the membrane.

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The Lateral Pressure Profile in Membranes: A Physical Mechanism of General Anesthesia

Cited by 442 publications

References 20 publications

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

Drunken Membranes: Short-Chain Alcohols Alter Fusion of Liposomes to Planar Lipid Bilayers

Importance of Direct Interactions with Lipids for the Function of the Mechanosensitive Channel MscL

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