Localization of Multidrug Transporter Substrates within Model Membranes

Siarheyeva, Alena; Lopez, Jakob J.; Glaubitz, Clemens

doi:10.1021/bi0524870

Cited by 75 publications

(60 citation statements)

References 74 publications

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“…4). Maximum peak intensities for all aromatic resonances are found between positions C-3 and G-3 of the lipid chain, in agreement with similar studies of aromatic molecules in lipid membranes (3,9,10).…”

Section: Mas-noesy Measurements On Dopc Membranes Doped Withsupporting

confidence: 90%

“…However, it has been demonstrated numerous times that aromatic ring structures do not penetrate into the chain region of lipid membranes (3,9,21). This has been attributed to numerous factors, including the entropic cost associated with intercalating a rigid ring structure into the mobile chain region (3), the fact that asymmetric aromatic molecules have dipole moments that cannot easily be accommodated in the nonpolar chain region of the lipid membrane (25), and the enthalpic requirements of hydroxy, carbonyl, and other substitutions on the ring to fulfill their hydrogen bonding potential (26,27) (which cannot be achieved in the lipid chain region).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, 1 H NMR and specifically magic angle spinning-assisted nuclear Overhauser enhancement spectroscopy (MAS-NOESY) 2 experiments have proved to be an ideal tool for investigating the location of small molecules embedded in lipid membranes, with atomic resolution (3,9,10).…”

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confidence: 99%

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Location and Orientation of Serotonin Receptor 1a Agonists in Model and Complex Lipid Membranes

Lopez

Lorch

2008

Journal of Biological Chemistry

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Magic angle spinning (MAS) NMR has been used to investigate the location and orientation of five serotonin receptor 1a agonists (serotonin, buspirone, quipazine, 8-OH-DPAT, and LY-163,165) in single component model lipid and brain lipid membranes. The agonist locations are probed by monitoring changes in the lipid proton chemical shifts and by MAS-assisted nuclear Overhauser enhancement spectroscopy, which indicates the orientation of the agonists with respect to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipids. In the single component bilayer, the membrane agonists are found predominantly in the top of the hydrophobic chain or in the glycerol region of the membrane. Most of the agonists orient approximately parallel to the membrane plane, with the exception of quipazine, whose piperazine ring is found in the glycerol region, whereas its benzene ring is located within the lipid hydrophobic chain. The location of the agonist in brain lipid membranes is similar to the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers; however, many of the agonists appear to locate close to the cholesterol in the membrane in preference to the phospholipids.Drug molecule interaction with lipid membranes is a critical factor governing its final activity, because it needs to negotiate its way through several membranes on the way to its receptor protein. In an effort to facilitate the design of drugs, water/ octanol partitioning coefficients are often used. However, this simple two-phase model falls short of adequately describing the complexity of lipid/drug interactions. A lipid membrane is a chemically very diverse environment. Lipid headgroups are often charged and highly hydrated, and the interface between the headgroup and hydrophobic core of a membrane is typified by the presence of glycerol, carbonyl groups, and lower concentrations of water. It is only the very center of the membrane that is nonpolar and excludes water (1, 2).Drug molecules tend to contain substituted aromatic groups that add further complications; steric effects exclude aromatic groups from the lipid chain region (3), whereas other attractive forces between the ring and lipid carbonyls draw the molecule to the interface between the chain and headgroup regions of the membrane (4, 5). Furthermore, any charged chemical groups will be excluded from the low dielectric environment at the center of the bilayer (2). Consequently, the mechanism by which a molecule partitions into lipid bilayers or crosses a biological membrane will be a complex interplay of many factors.The majority of drug targets are membrane proteins. Hence the interaction of a drug with the membrane is crucial for its efficacy and involves several interesting aspects, such as its location probability profile across the membrane bilayer, its orientation, and its structure. A high location probability in a particular part of a membrane and its orientation with respect to the membrane normal could well be important to how the drug is presented to the binding site of the target protein (6).Fin...

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Section: Mas-noesy Measurements On Dopc Membranes Doped Withsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Location and Orientation of Serotonin Receptor 1a Agonists in Model and Complex Lipid Membranes

Lopez

Lorch

2008

Journal of Biological Chemistry

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“…The most affected were the signals of protons associated with the lipid glycerol backbone and a few upper groups of lipid acyl chains. A similar localization was reported for genistein in DMPC membranes [70]. Additionally, it was shown that the spatial orientation in the bilayer depended on the position of the polar centre of the flavonoid molecule [69].…”

Section: Discussionsupporting

confidence: 80%

Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Wesołowska

Hendrich

Łania-Pietrzak

et al. 2009

Cellular and Molecular Biology Letters

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The expression of transmembrane transporter multidrug resistance-associated protein 1 (MRP1) confers the multidrug-resistant phenotype (MDR) on cancer cells. Since the activity of the other MDR transporter, P-glycoprotein, is sensitive to membrane perturbation, we aimed to check whether the changes in lipid bilayer properties induced by flavones (apigenin, acacetin) and flavonols (morin, myricetin) were related to their MRP1 inhibitory activity. All the flavonoids inhibited the efflux of MRP1 fluorescent substrate from human erythrocytes and breast cancer cells. Morin was also found to stimulate the ATPase activity of erythrocyte ghosts. All flavonoids intercalated into phosphatidylcholine bilayers as judged by differential scanning calorimetry and fluorescence spectroscopy with the use of two carbocyanine dyes. The model of an intramembrane localization for flavones and flavonols was proposed. No clear relationship was found between the membrane-perturbing activity of flavonoids and their potency to inhibit MRP1. We concluded that mechanisms other than perturbation of the lipid phase of membranes were responsible for inhibition of MRP1 by the flavonoids.

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“…Cholesterol, in addition to stabilizing membrane structures, may further increase lipid insertion of hydrophobic drugs or xenobiotics. In addition, amphiphilic, positively charged drug compounds, e.g., doxorubicin, mitoxantrone, or verapamil, interact with negatively charged lipid headgroups, while the hydrophobic parts of these drugs interact with apolar membrane regions (Siarheyeva, Lopez, & Glaubitz, 2006;Speelmans, Staffhorst, De Wolf, & De Kruijff, 1995). Therefore, membrane lipids might significantly affect the plasma membrane concentrations and availability of ABCB1 or ABCG2 substrates.…”

Section: P0135mentioning

confidence: 99%