Glutamate-binding affinity of<i>Drosophila</i>metabotropic glutamate receptor is modulated by association with lipid rafts

Eroğlu, Çağla; Brügger, Britta; Wieland, Felix; Sinning, Irmgard

doi:10.1073/pnas.1737042100

Cited by 96 publications

(84 citation statements)

References 56 publications

(76 reference statements)

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“…A cholesterol gradient exists across the secretory pathway 41 (low in the endoplasmic reticulum (ER) and high in the plasma membrane), and would hence allow the formation of filaments at the plasma membrane, but not in the endomembrane system. To analyse the specific interactions of GP with cholesterol, we utilized a well-established photoaffinity-labelling assay [42][43][44][45] . Radioactively labelled (tritiated) photoactivatable cholesterol was fed to HeLa cells expressing either FLAG-GP 1,2 , FLAG-GP 2 or their respective variants.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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The high pathogenicity of the Ebola virus reflects multiple concurrent processes on infection. Among other important determinants, Ebola fusogenic glycoprotein (GP) has been associated with the detachment of infected cells and eventually leads to vascular leakage and haemorrhagic fever. Here we report that the membrane-anchored GP is sufficient to induce the detachment of adherent cells. The results show that the detachment induced through either full-length GP 1,2 or the subunit GP 2 depends on cholesterol and the structure of the transmembrane domain. These data reveal a novel molecular mechanism in which GP regulates Ebola virus assembly and suggest that cholesterol-reducing agents could be useful as therapeutics to counteract GP-mediated cell detachment.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

et al. 2015

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“…Drosophila lipid rafts are important for the light-induced recruitment of INADsignaling phototransduction complexes in photoreceptors (Sanxaridis et al, 2007) and also act as positive regulators of the Drosophila metabotropic glutamate receptor (DmGluRA) signaling between neurons (Eroglu et al, 2003). Drosophila lipid rafts also regulate voltage-gated ion channel signaling and the synaptic vesicle cycling underlying neurotransmission (Rohrbough et al, 2004;Gasque et al, 2005;Rohrbough and Broadie, 2005).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration

Phillips¹,

Woodruff²,

Liang³

et al. 2008

Journal of Neuroscience

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The mistrafficking and consequent cytoplasmic accumulation of cholesterol and sphingolipids is linked to multiple neurodegenerative diseases. One class of disease, the sphingolipid storage diseases, includes Niemann-Pick disease type C (NPC), caused predominantly (95%) by mutation of the NPC1 gene. A disease model has been established through mutation of Drosophila NPC1a (dnpc1a). Null mutants display early lethality attributable to loss of cholesterol-dependent ecdysone steroid hormone production. Null mutants rescued to adults by restoring ecdysone production mimic human NPC patients with progressive motor defects and reduced life spans. Analysis of dnpc1a null brains shows elevated overall cholesterol levels and progressive accumulation of filipin-positive cholesterol aggregates within brain and retina, as well as isolated cultured brain neurons. Ultrastructural imaging of dnpc1a mutant brains reveals ageprogressive accumulation of striking multilamellar and multivesicular organelles, preceding the onset of neurodegeneration. Consistently, electroretinogram recordings show age-progressive loss of phototransduction and photoreceptor synaptic transmission. Early lethality, movement impairments, neuronal cholesterol deposits, accumulation of multilamellar bodies, and age-dependent neurodegeneration are all rescued by targeted neuronal expression of a wild-type dnpc1a transgene. Interestingly, targeted expression of dnpc1a in glia also provides limited rescue of adult lethality. Generation of dnpc1a null mutant neuron clones in the brain reveals cellautonomous requirements for dNPC1a in cholesterol and membrane trafficking. These data demonstrate a requirement for dNPC1a in the maintenance of neuronal function and viability and show that loss of dNPC1a in neurons mimics the human neurodegenerative condition.

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“…Lipids are increasingly being recognized not only as constituents of cell membranes but also as key factors in intracellular trafficking, signaling, and diseases such as cancer, HIV infection, and Alzheimer's. Photoaffinity labeling using photoChol or [ 3 H]choline/10-ASA has been a very efficient tool for studying protein-cholesterol and protein-phosphatidylcholine interactions (5,(32)(33)(34)(35)). Now, [ 3 H]photoSph provides researchers with a novel tool to study protein-lipid interactions in vivo.…”

Section: Discussionmentioning

confidence: 99%

Protein-sphingolipid interactions within cellular membranes

Haberkant

Schmitt

Contreras

et al. 2008

Journal of Lipid Research

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Each intracellular organelle critically depends on maintaining its specific lipid composition that in turn contributes to the biophysical properties of the membrane. With our knowledge increasing about the organization of membranes with defined microdomains of different lipid compositions, questions arise regarding the molecular mechanisms that underlie the targeting to/segregation from microdomains of a given protein. In addition to specific lipid-transmembrane segment interactions as a basis for partitioning, the presence in a given microdomain may alter the conformation of proteins and, thus, the activity and availability for regulatory modifications. However, for most proteins, the specific lipid environment of transmembrane segments as well as its relevance to protein function and overall membrane organization are largely unknown. To help fill this gap, we have synthesized a novel photoactive sphingolipid precursor that, together with a precursor for phosphoglycerolipids and with photo-cholesterol, was investigated in vivo with regard to specific protein transmembrane spanlipid interactions. As a proof of principle, we show specific labeling of the ceramide transporter with the sphingolipid probe and describe specific in vivo interactions of lipids with caveolin-1, phosphatidylinositol transfer protein b, and the mature form of nicastrin. This novel photolabile sphingolipid probe allows the detection of proteinsphingolipid interactions within the membrane bilayer of living cells.-Haberkant,

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Glutamate-binding affinity ofDrosophilametabotropic glutamate receptor is modulated by association with lipid rafts

Cited by 96 publications

References 56 publications

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol

Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration

Protein-sphingolipid interactions within cellular membranes

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