• bioactive peptides
• cholesterol
• cholesterol–peptide interactions
• membrane fluidity

• (CODI Grant 2024-66871) University of Antioquia
• (INV-2023-162-2782) Faculty of Sciences of the Universidad de los Andes

• APTT
• MPS
• apoptotic cells
• biomimetic
• blood coagulation

• JP19H04476 JSPS KAKENHI Grant-in-Aid for Scientific Research (B)
• JP20H05877 JSPS KAKENHI Grant-in-Aid for Transformative Research Areas (A)

• ANO10
• ANO3
• ANO4
• ANO5
• ANO7
• ANO8
• ANO9
• Calcium signaling
• Chronic kidney disease
• Dystonia
• TMEM16C
• TMEM16D
• TMEM16E
• TMEM16G
• TMEM16H
• TMEM16J
• TMEM16K

• Humans
• Anoctamins/metabolism
• Anoctamins/chemistry
• Animals
• Cell Membrane/metabolism
• Structure-Activity Relationship

• atomic force microscopy
• cell-free expression
• hERG
• ion channel
• kv11.1
• supported lipid bilayer

• JP20H02690 Japan Society for the Promotion of Science
• JPMJCR14F3 Japan Science and Technology Agency

• Antimicrobial peptides
• Bacterial membranes
• Fluorescence microscopy
• Giant unilamellar vesicles
• Model cell membranes
• Phase separation

• Daptomycin/pharmacology
• Daptomycin/metabolism
• Biomimetics
• Cell Membrane/metabolism
• Phosphatidylglycerols/chemistry
• Anti-Bacterial Agents/pharmacology
• Anti-Bacterial Agents/metabolism
• Bacteria/metabolism

• charged lipids
• cholesterol
• ergosterol
• liposomes
• signal transduction

• Atomic force microscopy
• Cholesterol
• Force spectroscopy
• Lipid bilayer
• Polyunsaturated lipid
• Raft

• Alkali
• Lipid asymmetry
• Plasma membrane
• Rim101 pathway
• Stress response
• Yeast

• TMEM16K
• endoplasmic reticulum
• nuclear membrane
• phosphatidylserine
• scramblase

• Animals
• Anoctamins/metabolism
• Calcimycin/pharmacology
• Calcium/metabolism
• Calcium Ionophores/pharmacology
• Endoplasmic Reticulum/metabolism
• Fibroblasts/metabolism
• Gene Knockout Techniques
• Intracellular Membranes/metabolism
• Mice
• Nuclear Envelope/metabolism
• Phosphatidylserines/metabolism

The β₂ adrenergic receptor (β₂AR) signals through both G_s and G_i in cardiac myocytes, and the G_i pathway counteracts the G_s pathway. However, G_i coupling is much less efficient than G_s coupling in most cell-based and biochemical assays, making it difficult to study β₂AR−G_i interactions. Here we investigate the role of phospholipid composition on G_s and G_i coupling. While negatively charged phospholipids are known to enhance agonist affinity and stabilize an active state of the β₂AR, we find that they impair coupling to G_i3 and facilitate coupling to G_s. Positively charged Ca²⁺ and Mg²⁺, known to interact with the negative charge on phospholipids, facilitates G_i3 coupling. Mutational analysis suggests that Ca²⁺ coordinates an interaction between phospholipid and the negatively charged EDGE motif on the amino terminal helix of G_i3. Taken together, our observations suggest that local membrane charge modulates the interaction between β₂AR and competing G protein subtypes.

In the healthy heart, the β₂ adrenergic receptor (β₂AR) signals through G_s and G_i proteins but the mechanism underlying G protein selectivity is not fully understood. Here, the authors show that membrane charge and intracellular cations modulate the β₂AR−G_i3 interaction.

Lipotoxicity is a pathophysiological process triggered by lipid overload. In metazoans, lipotoxicity is characterised by the ectopic deposition of lipids on organs other than adipose tissue. This leads to organ dysfunction, cell death, and is intimately linked to lipid-associated diseases such as cardiac dysfunction, atherosclerosis, stroke, hepatosteatosis, cancer and the metabolic syndrome. The molecules involved in eliciting lipotoxicity include FAs and their acyl-CoA derivatives, triacylglycerol (TG), diacylglycerol (DG), ceramides, acyl-carnitines and phospholipids. However, the cellular transport of toxic lipids through membrane contact sites (MCS) and vesicular mechanisms as well as lipid metabolism that progress lipotoxicity to the onset of disease are not entirely understood. Yeast has proven a useful model organism to study the molecular mechanisms of lipotoxicity. Recently, the Rim101 pathway, which senses alkaline pH and the lipid status at the plasmamembrane, has been connected to lipotoxicity. In this review article, we summarise recent research advances on the Rim101 pathway and MCS in the context of lipotoxicity in yeast and present a perspective for future research directions.

• Anti-Inflammatory Agents
• Apoptosis
• Biocompatible Materials
• Immunomodulation
• Phosphatidylserines

• Japan Society for the Promotion of Science

• Bending energy
• Depth-dependent membrane ordering
• Fusion peptide
• Membrane curvature
• Membrane fusion
• Void space

We previously demonstrated that the quinovose-containing hexaoside stichoposide C (STC) is a more potent anti-leukemic agent than the glucose-containing stichoposide D (STD), and that these substances have different molecular mechanisms of action. In the present study, we investigated the novel marine triterpene glycoside cladoloside C₂ from Cladolabes schmeltzii, which has the same carbohydrate moiety as STC. We assessed whether cladoloside C₂ could induce apoptosis in K562 and HL-60 cells. We also evaluated whether it showed antitumor action in mouse leukemia xenograft models, and its molecular mechanisms of action. We investigated the molecular mechanism behind cladoloside C₂-induced apoptosis of human leukemia cells, and examined the antitumor effect of cladoloside C₂ in a HL-60 and K562 leukemia xenograft model.

Cladoloside C₂ dose- and time-dependently induced apoptosis in the analyzed cells, and led to the activation of Fas/ceramide synthase 6 (CerS6)/p38 kinase/JNK/caspase-8. This cladoloside C₂-induced apoptosis was partially blocked by specific inhibition by Fas, CerS6, and p38 siRNA transfection, and by specific inhibition of JNK by SP600125 or dominant negative-JNK transfection. Cladoloside C₂ exerted antitumor activity through the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 without showing any toxicity in xenograft mouse models. The antitumor effect of cladoloside C₂ was reversed in CerS6 shRNA-silenced xenograft models. Our results suggest that cladoloside C2 has in vitro and in vivo anti-leukemic effects due to the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 in lipid rafts. These findings support the therapeutic relevance of cladoloside C₂ in the treatment of human leukemia.

• JNK
• anti-leukemic activity
• caspase-8
• ceramide synthase 6
• marine triterpene glycoside

Stichoposide D (STD) is a marine triterpene glycoside isolated from sea cucumbers. We examined the molecular mechanisms underlying the antitumor activity of STD in human leukemia cells. The role of Fas (CD95), ceramide synthase 6 (CerS6) and p38 kinase during STD-induced apoptosis was examined in human leukemia cells. In addition, the antitumor effects of STD in K562 and HL-60 leukemia xenograft models were investigated. We found that STD induces Fas translocation to lipid rafts, and thus mediates cell apoptosis. We also observed the activation of CerS6 and p38 kinase during STD-induced apoptosis. The use of methyl-β-cyclodextrin and nystatin to disrupt lipid rafts prevents the clustering of Fas and the activation of CerS6 and p38 kinase, and also inhibits STD-induced apoptosis. Specific inhibition by Fas, CerS6, and p38 kinase siRNA transfection partially blocked STD-induced apoptosis. In addition, STD has antitumor activity through the activation of CerS6 and p38 kinase without displaying any toxicity in HL-60 and K562 xenograft models. We observed that the anti-tumor effect of STD is partially prevented in CerS6 shRNA-silenced xenograft models. We first report that Fas/CerS6/p38 kinase activation in lipid rafts by STD is involved in its anti-leukemic activity. We also established that STD is able to enhance the chemosensitivity of K562 cells to etoposide or Ara-C. These data suggest that STD may be used alone or in combination with other chemotherapeutic agents to treat leukemia.

• apoptosis
• ceramide synthase 6
• lipid rafts
• p38 kinase
• triterpene glycoside

Cisplatin, a DNA crosslinking agent, is widely used for the treatment of a variety of solid tumors. Numerous studies have demonstrated that sphingolipid metabolism, which acts as a target for cisplatin treatment, is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes. Ceramide (Cer), which is the central molecule of this network, has been established to induce apoptosis. However, another molecule, sphingosine-1-phosphate (S1P), exerts the opposite function, i.e., serves as a regulator of pro-survival. Other sphingolipid molecules, including dihydroceramide, ceramide-1-phosphate, glucosylceramide (GluCer), and sphingosine (Sph), or sphingolipid catalytic enzymes such as Sph kinase (SphK), Cer synthase (CerS), and S1P lyase, have also attracted considerable attention, particularly Cer, GluCer, SphK, CerS, and S1P lyase, which have been implicated in cisplatin resistance. This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin, particularly in relation to induction of apoptosis and drug resistance.

• Apoptosis
• Sphingolipid metabolism
• Drug resistance
• Cisplatin
• Anticancer

• Lysophosphatidic
• PLRP2
• Phosphoinositides
• Phospholipase B
• Phospholipid asymmetry
• Platelet-activating factor

• Biomedical Research/history
• Blood Platelets/metabolism
• History, 20th Century
• History, 21st Century
• Lipase/history
• Lipase/metabolism
• Lysophospholipase/history
• Lysophospholipase/metabolism
• Phospholipids/history
• Phospholipids/metabolism
• Signal Transduction/physiology

• Biomedical application
• Cell adhesion
• LbL assembly
• Mammalian and bacterial cells
• Surface modification

• Rim21
• alkaline response
• lipid asymmetry
• lipid bilayer
• phospholipid
• plasma membrane
• signal transduction
• yeast

Lipid rafts are cholesterol and saturated lipid-rich, nanometer sized membrane domains that are hypothesized to play an important role in compartmentalization and spatiotemporal regulation of cellular signaling. Lipid rafts contribute to the plasma membrane order and to its spatial asymmetry, as well. The raft nanodomains on the surface of CD4⁺ T lymphocytes coalesce during their interaction with antigen presenting cells (APCs). Sensing of foreign antigen by the antigen receptor on CD4⁺ T cells occurs during these cell-cell interactions. In response to foreign antigen the CD4⁺ T cells proliferate, allowing the expansion of few antigen-specific primary CD4⁺ T cell clones. Proliferating CD4⁺ T cells specialize in their function by undergoing differentiation into appropriate effectors tailored to mount an effective adaptive immune response against the invading pathogen.

To investigate the role of lipid raft-based membrane order in the clonal expansion phase of primary CD4⁺ T cells, we have disrupted membrane order by incorporating an oxysterol, 7-ketocholesterol (7-KC), into the plasma membrane of primary CD4⁺ T cells expressing a T cell receptor specific to chicken ovalbumin_323–339 peptide sequence and tested their antigen-specific response. We report that 7-KC, at concentrations that disrupt lipid rafts, significantly diminish the c-Ovalbumin_323–339 peptide-specific clonal expansion of primary CD4⁺ T cells.

Our findings suggest that lipid raft-based membrane order is important for clonal expansion of CD4⁺ T cells in response to a model peptide.

The online version of this article (doi:10.1186/s12865-014-0058-8) contains supplementary material, which is available to authorized users.

• Lipid asymmetry
• Phospholipid
• Plasma membrane
• Yeast

The central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was blocked by acidic lipids and competed by other basic proteins. Further studies revealed that MBP induced damage to neuronal membrane integrity and function by depolarizing the resting membrane potential, increasing the permeability to cations and other molecules, and decreasing the membrane fluidity. At last, artificial liposome vesicle assay showed that MBP directly disturbed acidic lipid bilayer and resulted in increased membrane permeability. These results revealed that MBP induces neurotoxicity through its direct interaction with acidic components on the extracellular surface of neuronal membrane, which may suggest a possible contribution of MBP to the pathogenesis in the CNS disorders with myelin damage.

• Animals
• Cations/metabolism
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Cell Membrane Permeability/drug effects
• Female
• Lipid Bilayers/chemistry
• Lipid Bilayers/metabolism
• Male
• Membrane Potentials/drug effects
• Myelin Basic Protein/metabolism
• Myelin Basic Protein/toxicity
• Neurons/drug effects
• Neurons/physiology
• Protein Binding
• Pyramidal Cells/drug effects
• Pyramidal Cells/physiology
• Rats

• Animals
• Antineoplastic Agents/therapeutic use
• Ceramidases/metabolism
• Drug Design
• Drug Resistance, Neoplasm
• Glucosyltransferases/metabolism
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Oxidoreductases/metabolism
• Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors
• Phosphotransferases (Alcohol Group Acceptor)/metabolism
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction/drug effects
• Sphingolipids/metabolism
• Sphingomyelin Phosphodiesterase/metabolism

• Arabidopsis/enzymology
• Arabidopsis/metabolism
• Arabidopsis Proteins/metabolism
• Cell Membrane/metabolism
• Microscopy, Confocal
• Phospholipid Transfer Proteins/metabolism

• Animals
• Cell Membrane/enzymology
• Cell Membrane/genetics
• Cell Membrane/immunology
• Chemotaxis/genetics
• Chemotaxis/immunology
• Lipid Metabolism/genetics
• Lipid Metabolism/immunology
• Mice
• Neuropeptides/genetics
• Neuropeptides/immunology
• Neuropeptides/metabolism
• Neutrophils/enzymology
• Neutrophils/immunology
• Phagocytosis/immunology
• Phospholipids/genetics
• Phospholipids/immunology
• Phospholipids/metabolism
• Protein Structure, Tertiary
• Protein Transport/genetics
• Protein Transport/immunology
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/immunology
• Proto-Oncogene Proteins p21(ras)/metabolism
• Pseudopodia/enzymology
• Pseudopodia/genetics
• Pseudopodia/immunology
• Signal Transduction/genetics
• Signal Transduction/immunology
• Transfection
• rac GTP-Binding Proteins/genetics
• rac GTP-Binding Proteins/immunology
• rac GTP-Binding Proteins/metabolism
• rac1 GTP-Binding Protein
• RAC2 GTP-Binding Protein

• Canadian Institutes of Health Research

• Animals
• Cell Membrane/metabolism
• Humans
• Membrane Lipids/metabolism
• Phagocytes/metabolism
• Phagocytosis/immunology
• Phagosomes
• Signal Transduction
• Surface Properties

• Animals
• Calmodulin
• Cattle
• Factor V/physiology
• Hemostasis/drug effects
• Hemostasis/physiology
• Humans
• Liposomes/chemical synthesis
• Liposomes/pharmacology
• Lysophosphatidylcholines/pharmacology
• Phosphatidylcholines/pharmacology
• Phosphatidylethanolamines/pharmacology
• Phospholipids/chemistry
• Protein C/analysis
• Protein C/antagonists & inhibitors
• Protein C/drug effects
• Protein S/analysis
• Protein S/antagonists & inhibitors
• Protein S/drug effects

• ATP-Binding Cassette Transporters/metabolism
• Adenosine Triphosphatases/deficiency
• Adenosine Triphosphatases/metabolism
• Animals
• Biological Transport
• Cell Membrane/metabolism
• Disease
• Humans
• Lipid Metabolism

• Animals
• Cell Line
• Enzyme Activation/physiology
• Osteoblasts/enzymology
• Parathyroid Hormone/physiology
• Phorbol 12,13-Dibutyrate
• Phosphatidylethanolamines/metabolism
• Phospholipase D/physiology
• Rats
• Substrate Specificity

• R01 AR011262 NIAMS NIH HHS
• AR11262 NIAMS NIH HHS