Transport of oppositely charged lipophilic probe ions in lipid bilayer membranes having various structures

Pickar, Arnold D.; Benz, Roland

doi:10.1007/bf01944229

Cited by 174 publications

(164 citation statements)

References 27 publications

(83 reference statements)

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“…The difference in permeability of similar species carrying charges of opposite sign can reach several orders of magnitude, favoring anion permeation (51,52). This property of lipid membranes suggests that anionic protonophores must be more effective, which agrees with their lower acting concentrations.…”

Section: Discussionmentioning

confidence: 72%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C 12 R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H ؉ ions was generated in the presence of C 12 R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C 12 R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C 12 R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C 12 R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.Transport of electrons along the mitochondrial respiratory chain is accompanied by the formation of an electrochemical gradient of hydrogen ions (⌬ H ϩ) 3 at the inner mitochondrial membrane. ⌬ H ϩ is used for ATP production and other energyconsuming processes. However, high values of ⌬ H ϩ can increase the production of dangerous reactive oxygen species (ROS) (1, 2). Although mitochondria are able to control ⌬ H ϩ by adjusting the activity of natural uncoupling mechanisms (i.e. free fatty acids, anion carriers, and uncoupling proteins) (3), there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production (4 -7).Uncouplers, or protonophores, are small organic compounds capable of carrying hydrogen ions across artificial and biological membranes. The strategy of "mild uncoupling" (2) relies on the fact that partial decrease in ⌬ H ϩ can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. Apparently, such applications are hindered by high toxicity, as in the case of 2,4-dinitrophenol (DNP), which was temporarily used at the beg...

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Section: Discussionmentioning

confidence: 72%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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“…The most likely source of this attraction is the membrane dipole potential φ D . For GMO membranes φ D is about 100 mV (22)(23)(24) with an orientation such that the membrane interior is positive. For the hydroxyl anion, φ D corresponds to an energy barrier of ΔG D ¼ zFφ D ≈ 4 RT.…”

Section: Discussionmentioning

confidence: 99%

Protons migrate along interfacial water without significant contributions from jumps between ionizable groups on the membrane surface

Springer

Hagen²,

Cherepanov³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

101

140

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Kinetics of fluorescence changes on top of three different lipid bilayers due to lateral proton migration. The observation area was located at a distance of 70 μm from the area of proton release. Because all FPE molecules are surrounded by DPhPC or DPhPE molecules, they are anticipated to accept protons, which are released from these molecules. GMO does not possess ionizable moieties so that in case of two-dimensional diffusion, proton release from one FPE molecule seems to be required before the next FPE molecule may pick up the proton. Despite the huge differences in proton release rates from the different lipids, τ max for all three lipid bilayers was similar. That is, lateral proton diffusivity is independent of the choice of the lipid. The buffer contained 0.1 mM Capso (pH 9.0) and 100 mM NaCl. The F1 Wv/+ mice were then backcrossed to A/J mice for 10 generations, creating A/J N10 Wv/+ mice. These were then crossed to B6 Wv/+ mice to create F1 wildtype and F1 Wv/Wv mice for study. A/J mice had an increased airway resistance compared to B6 mice, and F1 mice had a naïve AHR phenotype equivalent to their parental A/J strain. F1 Wv/Wv mice displayed an airway resistance similar to normoresponsive B6 mice. Values represent mean ± SE, n = at least 10 in each group.

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“…Lipid bilayers usually are quite permeable to lipophilic compounds (15,41,44). However, the outer membrane (OM) of gram-negative bacteria forms a rather effective permeability barrier against various lipophilic substances, including antibiotics.…”

Section: ؉mentioning

confidence: 99%

Stages of Polymyxin B Interaction with the Escherichia coli Cell Envelope

Daugelavičius

Bakiene

Bamford

2000

Antimicrob Agents Chemother

144

164

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The effects of polymyxin B (PMB) on the Escherichia coli outer (OM) and cytoplasmic membrane (CM) permeabilities were studied by monitoring the fluxes of tetraphenylphosphonium, phenyldicarbaundecaborane, and K ؉ and H ؉ ions. At concentrations between 2 and 20 g/ml, PMB increased the OM permeability to lipophilic compounds and induced a leakage of K ؉ from the cytosol and an accumulation of lipophilic anions in the cellular membranes but did not cause the depolarization of the CM. At higher concentrations, PMB depolarized the CM, forming ion-permeable pores in the cell envelope. The permeability characteristics of PMB-induced pores mimic those of bacteriophage-and/or bacteriocin-induced channels. However, the bactericidal effect of PMB took place at concentrations below 20 g/ml, indicating that this effect is not caused by pore formation. Under conditions of increased ionic strength, PMB made the OM permeable to lipophilic compounds and decreased the K ؉ gradient but was not able to depolarize the cells. The OM-permeabilizing effect of PMB can be diminished by increasing the concentration of Mg 2؉. The major new findings of this work are as follows: (i) the OM-permeabilizing action of PMB was dissected from its depolarizing effect on the CM, (ii) the PMB-induced ion-permeable pores in bacterial envelope were registered, and (iii) the pore formation and depolarization of the CM are not obligatory for the bactericidal action of PMB and dissipation of the K ؉ gradient on the CM.Lipid bilayers usually are quite permeable to lipophilic compounds (15,41,44). However, the outer membrane (OM) of gram-negative bacteria forms a rather effective permeability barrier against various lipophilic substances, including antibiotics. At least 10-to 100-fold slower rates of lipophilic compound permeation through the OM bilayer compared to those through the cytoplasmic membrane (CM) are observed because of the highly charged lipopolysaccharide (LPS)-formed outer monolayer and the stabilization of this layer by divalent cations (20, 39). These compounds also cannot traverse the porins, the narrow channels for inorganic ions and small hydrophilic nutrients (19,38).Polymyxin B (PMB) is a decapeptide antibiotic characterized by a heptapeptide ring containing four 2,4-diaminobutyric acids. An additional peptide chain covalently bound to the ␥-amino group carries an aliphatic chain attached to the peptide through an amide bond. The molecule carries five positively charged residues of diaminobutyric acid (52). Due to its molecular mass (about 1,200 Da), charge, and amphiphilicity, PMB should be excluded by the OM. However, several polycationic compounds, including PMB, are known to penetrate the OM using pathways other than porins. Although the detailed mechanism of the OM permeability barrier disruption remains undetermined, complex formation by PMB with LPS is expected to be the first stage (26,50,56,60). Being bulkier than the inorganic divalent cations that it displaces, PMB changes the packing order of LPS and increases the permeabi...

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Transport of oppositely charged lipophilic probe ions in lipid bilayer membranes having various structures

Cited by 174 publications

References 27 publications

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Protons migrate along interfacial water without significant contributions from jumps between ionizable groups on the membrane surface

Stages of Polymyxin B Interaction with the Escherichia coli Cell Envelope

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