Changes of the membrane potential profile induced by verapamil and propranolol

Pohl, Elena E.; Krylov, Andrey V.; Block, Michael H.; Pohl, Peter

doi:10.1016/s0005-2736(98)00098-4

Cited by 44 publications

(30 citation statements)

References 40 publications

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“…According to MD simulations, the position of the RA-PE adduct in the lipid bilayer was responsible for the observed changes. Similar to the dipole potential modifier, phloretin [114], ONE-and HNE-PE adducts altered the boundary potential in the lipid membrane, and decreased the positive membrane energy barrier [115]. This resulted in increased valinomycin-mediated potassium transport and decreased proton transport mediated by CCCP.…”

Section: Modification Of Membrane Transporter Function In the Presencmentioning

confidence: 96%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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Reactive oxygen species (ROS) and their derivatives, reactive aldehydes (RAs), have been implicated in the pathogenesis of many diseases, including metabolic, cardiovascular, and inflammatory disease. Understanding how RAs can modify the function of membrane proteins is critical for the design of therapeutic approaches in the above-mentioned pathologies. Over the last few decades, direct interactions of RA with proteins have been extensively studied. Yet, few studies have been performed on the modifications of membrane lipids arising from the interaction of RAs with the lipid amino group that leads to the formation of adducts. It is even less well understood how various multiple adducts affect the properties of the lipid membrane and those of embedded membrane proteins. In this short review, we discuss a crucial role of phosphatidylethanolamine (PE) and PE-derived adducts as mediators of RA effects on membrane proteins. We propose potential PE-mediated mechanisms that explain the modulation of membrane properties and the functions of membrane transporters, channels, receptors, and enzymes. We aim to highlight this new area of research and to encourage a more nuanced investigation of the complex nature of the new lipid-mediated mechanism in the modification of membrane protein function under oxidative stress.

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Section: Modification Of Membrane Transporter Function In the Presencmentioning

confidence: 96%

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

Pohl

Jovanović

2019

Molecules

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“…Interestingly, although TPB behaves as a modulator of Pgp, tetraphenylphosphonium, a hydrophobic cation that is the counterpart of TPB, is a substrate for the transporter (51). Verapamil, a classic inhibitor of MDR1 Pgp, has also been shown to decrease the intramembranous dipole potential in lipid vesicles (52), which would directly enhance influx kinetics of hydrophobic cations like Tc-Sestamibi. Consistent with this model, the effects of TPB on dipole potential would be expected to affect the kinetics of transmembrane permeation, but not the final steady state (46).…”

Section: Mdr1 Pgp Affects Accumulation Of Tc-sestamibi Even In Thementioning

confidence: 99%

MDR1 P-glycoprotein Reduces Influx of Substrates without Affecting Membrane Potential

Luker

Flagg

Sha

et al. 2001

Journal of Biological Chemistry

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MDR1 (multidrug resistance) P-glycoprotein (Pgp; ABCB1) decreases intracellular concentrations of structurally diverse drugs. Although Pgp is generally thought to be an efflux transporter, the mechanism of action remains elusive. To determine whether Pgp confers drug resistance through changes in transmembrane potential (E m ) or ion conductance, we studied electrical currents and drug transport in Pgp-negative MCF-7 cells and MCF-7/MDR1 stable transfectants that were established and maintained without chemotherapeutic drugs. Although E m and total membrane conductance did not differ between MCF-7 and MCF-7/MDR1 cells, Pgp reduced unidirectional influx and steady-state cellular content of Tc-Sestamibi, a substrate for MDR1 Pgp, without affecting unidirectional efflux of substrate from cells. Depolarization of membrane potentials with various concentrations of extracellular K ؉ in the presence of valinomycin did not inhibit the ability of Pgp to reduce intracellular concentration of Tc-Sestamibi, strongly suggesting that the drug transport activity of MDR1 Pgp is independent of changes in E m or total ion conductance. Tetraphenyl borate, a lipophilic anion, enhanced unidirectional influx of Tc-Sestamibi to a greater extent in MCF-7/MDR1 cells than in control cells, suggesting that Pgp may, directly or indirectly, increase the positive dipole potential within the plasma membrane bilayer. Overall, these data demonstrate that changes in E m or macroscopic conductance are not coupled with function of Pgp in multidrug resistance. The dominant effect of MDR1 Pgp in this system is reduction of drug influx, possibly through an increase in intramembranous dipole potential.MDR1 P-glycoprotein (Pgp), 1 a member of the ATP-binding cassette family of membrane transporters, decreases intracellular concentrations of structurally diverse compounds, many of which are hydrophobic and cationic. Conventionally, Pgp is thought to function as an efflux transporter, although it is unclear whether any experiment has demonstrated unequivocally that Pgp mediates transport of a substrate across a membrane bilayer against its electrochemical gradient.Several models have been proposed to account for the apparent function and remarkable variety of compounds that are recognized by this protein. Pgp may be an efflux transporter that recognizes substrates within the lipid bilayer ("hydrophobic vacuum cleaner") (1). Pgp has been hypothesized to be a pump with multiple binding sites for different drugs (2), a translocase for lipids (3), or a modifier of vesicular trafficking (4). Another model suggests that MDR1 Pgp indirectly alters partitioning of substrates within cells through effects on transmembrane potential (E m ), intracellular pH, and/or surface potentials and does not directly transport drugs (5). These disparate hypotheses may result from comparisons of data from transfected cells that have not been exposed to chemotherapeutic agents with cell lines in which expression of MDR1 is induced or maintained through exposure to drugs in the M...

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“…Assuming that binding to the membrane obeys the Langmuir isotherm, it is possible to calculate the steady-state lipid binding constant (compare, e.g., Pohl et al, 1998) as well as z eff (Denisov et al, 1998) from the dependence of on c b . However, within reasonable limits of both parameters, a satisfactory fit to the data shown in Fig.…”

Section: Figurementioning

confidence: 99%

Photosensitizer Binding to Lipid Bilayers as a Precondition for the Photoinactivation of Membrane Channels

Rokitskaya

Block

Antonenko

et al. 2000

Biophysical Journal

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Changes of the membrane potential profile induced by verapamil and propranolol

Cited by 44 publications

References 40 publications

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

The Role of Phosphatidylethanolamine Adducts in Modification of the Activity of Membrane Proteins under Oxidative Stress

MDR1 P-glycoprotein Reduces Influx of Substrates without Affecting Membrane Potential

Photosensitizer Binding to Lipid Bilayers as a Precondition for the Photoinactivation of Membrane Channels

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