Neuronal Conduction of Excitation without Action Potentials Based on Ceramide Production

Fasano, Caroline; Tercé, François; Niel, Jean-Pierre; Nguyen, Hang Thi Thu; Hiol, Abel; Bertrand‐Michel, Justine; Mallet, Nicole; Collet, Xavier; Miolan, Jean-Pierre

doi:10.1371/journal.pone.0000612

Cited by 15 publications

(7 citation statements)

References 45 publications

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“…Lipids were extracted in chloroform-methanol-water (1∶2∶0.9, v/v/v) in a Dounce homogenizer in the presence of standards and then analyzed by gas liquid chromatography for phosphatidylcholine and cholesterol mass content as already described [11] , [47] .…”

Section: Methodsmentioning

confidence: 99%

Exosomal Lipids Impact Notch Signaling and Induce Death of Human Pancreatic Tumoral SOJ-6 Cells

et al. 2012

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Exosomes are of increasing interest as alternative mode of cell-to-cell communication. We previously reported that exosomes secreted by human SOJ-6 pancreatic tumor cells induce (glyco)protein ligand-independent cell death and inhibit Notch-1 pathway, this latter being particularly active during carcinogenesis and in cancer stem cells. Therefore, we asked whether exosomal lipids were key-elements for cell death and hypothesized that cholesterol-rich membrane microdomains were privileged sites of exosome interactions with tumor cells. To address these questions and based on the lipid composition of exosomes from SOJ-6 cells (Ristorcelli et al. (2008) FASEB J. 22; 3358–3369) enriched in cholesterol and sphingomyelin (lipids forming liquid-ordered phase, Lo) and depleted in phospholipids (lipids forming liquid-disordered phase, Ld), we designed Synthetic Exosome-Like Nanoparticles (SELN) with ratios Lo/Ld from 3.0 to 6.0 framing that of SOJ-6 cell exosomes. SELN decreased tumor cell survival, the higher the Lo/Ld ratio, the lower the cell survival. This decreased survival was due to activation of cell death with inhibition of Notch pathway. FRET analyses indicated fusions/exchanges of SELN with cell membranes. Fluorescent SELN co-localized with the ganglioside GM1 then with Rab5A, markers of lipid microdomains and of early endosomes, respectively. These interactions occurred at lipid microdomains of plasma and/or endosome membranes where the Notch-1 pathway matures. We thus demonstrated a major role for lipids in interactions between SELN and tumor cells, and in the ensued cell death. To our knowledge this is the first report on such effects of lipidic nanoparticles on tumor cell behavior. This may have implications in tumor progression.

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Section: Methodsmentioning

confidence: 99%

Exosomal Lipids Impact Notch Signaling and Induce Death of Human Pancreatic Tumoral SOJ-6 Cells

et al. 2012

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“…Lipids were extracted in chloroform-methanol-water (1:2:0.9, v/v/v) in a Dounce homogenizer in the presence of standards and then analyzed by gas liquid chromatography for phospholipids, cholesterol, sphingomyelin, and ceramide mass content (18).…”

Section: Lipid Analysismentioning

confidence: 99%

Human tumor nanoparticles induce apoptosis of pancreatic cancer cells

et al. 2008

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Exosomes are vesicles secreted by most hematopoietic cells on fusion of multivesicular endosomes with the plasma membrane. Many studies have reported that exosomes may also be released by tumor cells. Exosomes are believed to play an antitumor role through immune cells. We asked whether tumor exosomes have biological activities on tumor cells. We report that human pancreatic tumor nanoparticles, exosome-like as characterized by proteomic analyses and rich in lipid rafts, decreased tumor cell proliferation. Nanoparticles increased Bax and decreased Bcl-2 expressions. Caspase-3 and -9 but not caspase-8 inhibitors impaired apoptosis, which implicates the mitochondria apoptotic pathway. The ceramide-sphingomyelin apoptotic pathway was inoperative. Moreover, nanoparticles induced phosphatase and tensin homolog (PTEN) and glycogen synthase kinase (GSK) -3beta activation and decreased pyruvate dehydrogenase activity. In nanoparticle-treated cells, PTEN formed complexes with actin, beta-catenin, and GSK-3beta. Thus, beta-catenin may no longer be available to activate the survival pathway. Nanoparticles triggered the down-regulation of cyclin D1 and poly(ADP-ribose) polymerase. Hence, nanoparticles counteracted the constitutively activated phosphatidylinositol 3-kinase/Akt survival pathway to drive tumor cells toward apoptosis. Our study provides the first evidence of an apoptotic function of tumor-derived nanoparticles on tumor cells. We propose a new role for nanoparticles, i.e., as signal carriers for interaction between cells, which may have implications in physiopathological situations.

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“… 34 Another study showed that synaptic excitation could be conducted along the nerve fiber without action potentials but via a production of ceramides in the membrane lipid rafts, which increased the intracellular calcium concentration and triggered the release of other secondary messengers including nitric oxide and cyclic guanosin monophosphate (cGMP). 35 In our study, the firing silencing in hippocampal neurons by TTX induces an elevation of ceramides possibly via an activation of the sphingomyelin signaling pathway. This could result in the increased concentrations of intracellular calcium, nitric oxide, and cGMP, which subsequently mediate the conduction of synaptic activation in the absence of firing caused by TTX.…”

Section: Results and Discussionmentioning

confidence: 49%

Secondary Ion Mass Spectrometry Imaging Reveals Changes in the Lipid Structure of the Plasma Membranes of Hippocampal Neurons following Drugs Affecting Neuronal Activity

Agüi‐Gonzalez

Bao

Castro

et al. 2021

ACS Chem. Neurosci.

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The cellular functions of lipids in the neuronal plasma membranes have been increasingly acknowledged, particularly their association to neuronal processes and synaptic plasticity. However, the knowledge of their regulatory mechanisms in neuronal cells remains sparse. To address this, we investigated the lipid organization of the plasma membranes of hippocampal neurons in relation to neuronal activity using secondary ion mass spectrometry imaging. The neurons were treated with drugs, particularly tetrodotoxin (TTX) and bicuculline (BIC), to induce chronic activation and silencing. Distinct lipid organization was found in the plasma membrane of the cell body and the neurites. Moreover, significant alterations of the levels of the membrane lipids, especially ceramides, phosphatidylserines, phosphatidic acids, and triacylglycerols, were observed under the TTX and BIC treatments. We suggest that many types of membrane lipids are affected by, and may be involved in, the regulation of neuronal function.

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Neuronal Conduction of Excitation without Action Potentials Based on Ceramide Production

Cited by 15 publications

References 45 publications

Exosomal Lipids Impact Notch Signaling and Induce Death of Human Pancreatic Tumoral SOJ-6 Cells

Exosomal Lipids Impact Notch Signaling and Induce Death of Human Pancreatic Tumoral SOJ-6 Cells

Human tumor nanoparticles induce apoptosis of pancreatic cancer cells

Secondary Ion Mass Spectrometry Imaging Reveals Changes in the Lipid Structure of the Plasma Membranes of Hippocampal Neurons following Drugs Affecting Neuronal Activity

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