Interactions of drugs and amphiphiles with membranes: modulation of lipid bilayer elastic properties by changes in acyl chain unsaturation and protonation

Bruno, Michael J.; Rusinova, Radda; Gleason, Nicholas J.; Koeppe, Roger E.; Andersen, Olaf S.

doi:10.1039/c2fd20092a

Cited by 38 publications

(58 citation statements)

References 72 publications

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“…These data clearly demonstrate that modest changes to the plasma membrane can have significant biological effects. Similarly, DHA has been found to decrease the elastic coefficient of the plasma membrane by only 10%, yet this modest decrease is sufficient to alter protein structure, as detected by gramicidin channel function [68, 69]. Consistent with the observation that small perturbations to the plasma membrane can have significant biological effects, we observed modest changes in FRET signals (3 – 5%) at the plasma membrane enriched with n-3 PUFA, which was associated with the suppression of T cell lymphoproliferation.…”

Section: Discussionmentioning

confidence: 99%

n-3 polyunsaturated fatty acids suppress CD4+ T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization

Hou

Barhoumi

Yang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The mechanisms by which n-3 polyunsaturated fatty acids (n-3 PUFA), abundant in fish oil, exert their anti-inflammatory effects have not been rigorously defined. We have previously demonstrated that n-3 PUFA decrease the amount of phosphatidylinositol-(4,5)-bisphosphate, [PI(4,5)P2], in CD4+ T cells, leading to suppressed actin remodeling upon activation. Since discrete pools of PI(4,5)P2 exist in the plasma membrane, we determined whether n-3 PUFA modulate spatial organization of PI(4,5)P2 relative to raft and non-raft domains. We used Förster resonance energy transfer (FRET) to demonstrate that lipid raft mesodomains in the plasma membrane of CD4+ T cells enriched in n-3 PUFA display increased co-clustering of Lck(N10) and LAT(ΔCP), markers of lipid rafts. CD4+ T cells enriched in n-3 PUFA also exhibited a depleted plasma membrane non-raft PI(4,5)P2 pool as detected by decreased co-clustering of Src(N15), a non-raft marker, and PH(PLC-δ), a PI(4,5)P2 reporter. Incubation with exogenous PI(4,5)P2 rescued the effects on the non-raft PI(4,5)P2 pool, and reversed the suppression of T cell proliferation in CD4+ T cells enriched with n-3 PUFA. Furthermore, CD4+ T cells isolated from mice fed a 4% docosahexaenoic acid (DHA)-enriched diet exhibited a decrease in the non-raft pool of PI(4,5)P2, and exogenous PI(4,5)P2 reversed the suppression of T cell proliferation. Finally, these effects were not due to changes to post-translational lipidation, since n-3 PUFA did not alter the palmitoylation status of signaling proteins. These data demonstrate that n-3 PUFA suppress T cell proliferation by altering plasma membrane topography and the spatial organization of PI(4,5)P2.

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Section: Discussionmentioning

confidence: 99%

n-3 polyunsaturated fatty acids suppress CD4+ T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization

Hou

Barhoumi

Yang

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…DHA increased the appearance and lifetime of gramicidin channels, and decreased the free energy for channel formation. Oleic acid (OA, 18:1 Δ 9 ) that intercalated into the plasma membrane at a greater rate, had no effect on gramicidin channel formation, suggesting that the effect of DHA was due to changes in bilayer properties and not due to specific binding (Bruno et al, 2007; Bruno et al, 2013). EPA and DHA inhibit cardiac Na + and L-type Ca 2+ channels (Xiao et al, 1997; Xiao et al, 1995), activate TRAAK-1 and TRPV1 channels (Fink et al, 1998; Matta et al, 2007), and increase desensitization of nAChR and GABA a channels (Bouzat and Barrantes, 1993; Nabekura et al, 1998).…”

Section: N-3 Pufa and Lipid Rafts In The Cd4+ T Cell Plasma Membranementioning

confidence: 99%

Omega-3 fatty acids, lipid rafts, and T cell signaling

Hou

McMurray

Chapkin

2016

European Journal of Pharmacology

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n-3 PUFA have been shown in many clinical studies to attenuate inflammatory responses. Although inflammatory responses are orchestrated by a wide spectrum of cells, CD4+ T cells play an important role in the etiology of many chronic inflammatory diseases such as inflammatory bowel disease and obesity. In light of recent concerns over the safety profiles of non-steroidal anti-inflammatory drugs (NSAIDs), alternatives such as bioactive nutraceuticals are becoming more attractive. In order for these agents to be accepted into mainstream medicine, however, the mechanisms by which nutraceuticals such as n-3 polyunsaturated fatty acids (PUFA) exert their anti-inflammatory effects must be fully elucidated. Lipid rafts are nanoscale, dynamic domains in the plasma membrane that are formed through favorable lipid-lipid (cholesterol, sphingolipids, and saturated fatty acids) and lipid-protein (membrane-actin cytoskeleton) interactions. These domains optimize the clustering of signaling proteins at the membrane to facilitate efficient cell signaling which is required for CD4+ T cell activation and differentiation. This review summarizes novel emerging data documenting the ability of n-3 PUFA to perturb membrane-cytoskeletal structure and function in CD4+ T cells. An understanding of these underlying mechanisms will provide a rationale for the use of n-3 PUFA in the treatment of chronic inflammation.

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“…Other material quantities are the Gaussian curvature modulus K G , 7,8 important for membrane fusion, 9 and the isothermal area compressibility modulus K A . 10 Nevertheless, the centrality of the bending modulus is indicated, in the case of the Gaussian curvature, by the fact that it is the ratio K G / K C that is usually reported rather than K G alone, and the compressibility modulus K A is also often closely related to K C ( vide infra ). Also, there are relatively few measurements of K A and K G , so let’s focus on K C , without in any way disparaging the importance of K G and K A that are central to several papers in this Discussion .…”

Section: Bending Modulus: An Important Descriptor Of Biomembranesmentioning

confidence: 99%

Introductory Lecture: Basic quantities in model biomembranes

2013

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One of the many aspects of membrane biophysics dealt with in this Faraday Discussion regards the material moduli that describe energies at a supramolecular level. This introductory lecture first critically reviews differences in reported numerical values of the bending modulus KC, which is a central property for the biologically important flexibility of membranes. It is speculated that there may be a reason that the shape analysis method tends to give larger values of KC than the micromechanical manipulation method or the more recent X-ray method that agree very well with each other. Another theme of membrane biophysics is the use of simulations to provide exquisite detail of structures and processes. This lecture critically reviews the application of atomic level simulations to the quantitative structure of simple single component lipid bilayers and diagnostics are introduced to evaluate simulations. Another theme of this Faraday Discussion was lateral heterogeneity in biomembranes with many different lipids. Coarse grained simulations and analytical theories promise to synergistically enhance experimental studies when their interaction parameters are tuned to agree with experimental data, such as the slopes of experimental tie lines in ternary phase diagrams. Finally, attention is called to contributions that add relevant biological molecules to bilayers and to contributions that study the exciting shape changes and different non-bilayer structures with different lipids.

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Interactions of drugs and amphiphiles with membranes: modulation of lipid bilayer elastic properties by changes in acyl chain unsaturation and protonation

Cited by 38 publications

References 72 publications

n-3 polyunsaturated fatty acids suppress CD4+ T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization

n-3 polyunsaturated fatty acids suppress CD4+ T cell proliferation by altering phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] organization

Omega-3 fatty acids, lipid rafts, and T cell signaling

Introductory Lecture: Basic quantities in model biomembranes

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