The lateral pressure profile in membranes: a physical mechanism of general anesthesia

Cantor, Robert S.

doi:10.1016/s0378-4274(98)00220-3

Cited by 167 publications

(200 citation statements)

References 24 publications

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“…Alternatively, or in synergy with membrane rigidification, SHP-1 may act through nonspecific alterations of integral membrane protein stability/activity (28). For example, distortion of the lateral pressure profile, a mechanism that has been attributed to general anesthetics (29), may lead to increased lateral pressure, which in turn may physically inhibit transmembrane channels (30). Additionally, peptides corresponding to the Escherichia coli LamB signal peptide have been shown to affect the oligomerization of integral transmembrane proteins (31).…”

Section: Discussionmentioning

confidence: 99%

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Harrington

Widener

Stephens

et al. 2010

Journal of Biological Chemistry

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Trypanosoma brucei is the causative agent of both a veterinary wasting disease and human African trypanosomiasis, or sleeping sickness. The cell membrane of the developmental stage found within the mammalian host, the bloodstream form (BSF), is highly dynamic, exhibiting rapid rates of endocytosis and lateral flow of glycosylphosphatidylinositol-anchored proteins. Here, we show that the cell membrane of these organisms is a target for killing by small hydrophobic peptides that increase the rigidity of lipid bilayers. Specifically, we have derived trypanocidal peptides that are based upon the hydrophobic N-terminal signal sequences of human apolipoproteins. These peptides selectively partitioned into the plasma membrane of BSF trypanosomes, resulting in an increase in the rigidity of the bilayer, dramatic changes in cell motility, and subsequent cell death. No killing of the developmental stage found within the insect midgut, the procyclic form, was observed. Additionally, the peptides exhibited no toxicity toward mammalian cell lines and did not induce hemolysis. Studies with model liposomes indicated that bilayer fluidity dictates the susceptibility of membranes to manipulation by hydrophobic peptides. We suggest that the composition of the BSF trypanosome cell membrane confers a high degree of fluidity and unique susceptibility to killing by hydrophobic peptides and is therefore a target for the development of trypanocidal drugs.

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Section: Discussionmentioning

confidence: 99%

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Harrington

Widener

Stephens

et al. 2010

Journal of Biological Chemistry

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“…lipids which preferentially do not aggregate into a bilayer phase [64], may modulate the distribution of pressure across a bilayer and indirectly affect the function of membrane proteins [284]. Also small molecules, like alcohols or anesthetics, may regulate the activity of transmembrane proteins through a lipid mediated and purely mechanical interaction, via an anesthetic-induced redistribution of the lateral pressure across the bilayer-as proposed by Cantor [174,[285][286][287]. Although the mechanism of action of anesthetics is not yet fully understood [288], experimental findings [175,289] seem to confirm the importance of the lateral pressure in regulating the activity of mechanosensitive transmembrane proteins.…”

Section: A21 Pressure Profilementioning

confidence: 99%

Mesoscopic models of biological membranes

Venturoli¹,

et al. 2006

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Phospholipids are the main components of biological membranes and dissolved in water these molecules self-assemble into closed structures, of which bilayers are the most relevant from a biological point of view. Lipid bilayers are often used, both in experimental and by theoretical investigations, as model systems to understand the fundamental properties of biomembranes. The properties of lipid bilayers can be studied at different time and length scales. For some properties it is sufficient to envision a membrane as an elastic sheet, while for others it is important to take into account the details of the individual atoms. In this review, we focus on an intermediate level, where groups of atoms are lumped into pseudo-particles to arrive at a coarse-grained, or mesoscopic, description of a bilayer, which is subsequently studied using molecular simulation.The aim of this review is to compare various strategies to coarse grain a biological membrane. The conclusion of this comparison is that there can be many valid different strategies, but that the results obtained by the various mesoscopic models are surprisingly consistent. A second objective of this review is to illustrate how mesoscopic models can be used to obtain a better understanding of experimental systems. The advantage of coarse-grained models is that these can be simulated very efficiently, so that phenomena involving large systems, or requiring a large number of simulations, can be studied in detail. This is illustrated with the study of the relation between the phase behavior of a membrane and the structure of the phospholipids, and the membrane structural changes due to molecules (such as alcohols, cholesterol and anesthetics) adsorbed to the membrane. We then discuss the effect of transmembrane peptides on the local structure of a membrane and the mechanism of vesicle fusion and fission.

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“…It has been suggested that the solubility of anaesthetics in a lipid bilayer may cause a disturbance in membrane fluidity [12][13][14][15][16][17] that could affect the protein structure of sodium channel formation, and as a consequence of this perturbance, a conformational change in the ion channel could take place, resulting in the blockage of ion transduction. 18 Thus, rather than considering the cell membrane as a homogeneous entity, it should be considered as a structure with different domains formed by different components, in which lipid rafts of different composition are spread over the membrane, and certain protein functions might be moderated by specific lipids. 19 Thus, perturbations in a part of the membrane bilayer could affect other specific regions of membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Thermodynamic study of benzocaine insertion into different lipid bilayers

Cascales

Costa

Porasso

2011

The Journal of Chemical Physics

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Despite the general consensus concerning the role played by sodium channels in the molecular mechanism of local anesthetics, the potency of anaesthetic drugs also seems to be related with their solubility in lipid bilayers. In this respect, this work represents a thermodynamic study of benzocaine insertion into lipid bilayers of different compositions by means of molecular dynamics simulation. Thus, the free energy profiles associated with benzocaine insertion into symmetric lipid bilayers composed of different proportions of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylserine were studied. From the simulation results, a maximum in the free energy ( G) profile was measured in the region of the lipid/solution interface. This free energy barrier appears to be very much dependent on the lipid composition of the membrane. On the other hand, the minimum free energy ( G) within the bilayer remained almost independent of the lipid composition of the bilayer. By repeating the study at different temperatures, it was seen how the spontaneity of benzocaine insertion into the lipid bilayer is due to an increase in the entropy associated with the process.

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The lateral pressure profile in membranes: a physical mechanism of general anesthesia

Cited by 167 publications

References 24 publications

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Mesoscopic models of biological membranes

Thermodynamic study of benzocaine insertion into different lipid bilayers

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