Cholesterol, regulated exocytosis and the physiological fusion machine

Churchward, Matthew A.; Coorssen, Jens R.

doi:10.1042/bj20090969

Cited by 60 publications

(61 citation statements)

References 252 publications

(333 reference statements)

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“…These results (Figs. 3, 4, and 5) are consistent with a dual role for CHOL in the fusion mechanism: (1) a physiological fusion site/PFM organizer, defining fusion efficiency; and (2) a negative curvature-promoting FFM component, defining the ability to fuse [21,[25][26][27]72].…”

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 53%

“…A squalene synthase inhibitor, Zara, blocks the first committed step in CHOL synthesis and should not adversely affect isoprenoid pathways. As CHOL reduction correlated with fusion inhibition, including pronounced inhibition of fusion efficiency, this suggests a more potent effect of Zara on the stability of CHOL-rich microdomains [25,27,72]. Overall, these data highlight critical roles for CHOL in membrane fusion rather than a more central role of isoprenoids.…”

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 80%

“…Well-characterized acute CV manipulations identified multiple roles for CHOL in triggered fusion [25][26][27]. The correlation between decreased CV membrane CHOL and fusion inhibition was tested here by suppressing CHOL biosynthesis.…”

Section: Resultsmentioning

confidence: 99%

“…As efficiency parameters are linked to integrity of CHOL-rich microdomains [26,27,38,72], yet PE does not actively support domain formation/stability, our data provide clues as to the physical nature of microdomains and the localized, functional domain composition at fusion sites [25]. Simply, (1) different negative curvature lipids may contribute to a given fusion site, and (2) highly localized and somewhat more fluid PE regions within the broader microdomain matrix may be critical to PFM/FFM (see [25], Fig. 3)-these areas (and thus global domain structure) would be stabilized by cinnamycin, preserving Ca 2+ sensitivity, but PE molecules could no longer contribute their negative curvature to promote fusion.…”

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 91%

“…The fundamental fusion mechanism (FFM) and the larger, integrated physiological fusion machine (PFM) are affected by membrane lipids [25]. The addition of exogenous high positive curvature lipids to interacting monolayers or removing endogenous high negative curvature lipids effectively inhibits formation of high curvature intermediates [20,26,27,86].…”

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 99%

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A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Rogasevskaia

Coorssen

2011

J Chem Biol

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Studies using isolated sea urchin cortical vesicles have proven invaluable in dissecting mechanisms of Ca 2+ -triggered membrane fusion. However, only acute molecular manipulations are possible in vitro. Here, using selective pharmacological manipulations of sea urchin eggs ex vivo, we test the hypothesis that specific lipidic components of the membrane matrix selectively affect defined late stages of exocytosis, particularly the Ca 2+ -triggered steps of fast membrane fusion. Egg treatments with cholesterol-lowering drugs resulted in the inhibition of vesicle fusion. Exogenous cholesterol recovered fusion extent and efficiency in cholesterol-depleted membranes; α-tocopherol, a structurally dissimilar curvature analogue, selectively restored fusion extent. Inhibition of phospholipase C reduced vesicle phosphatidylethanolamine and suppressed both the extent and kinetics of fusion. Although phosphatidylinositol-3-kinase inhibition altered levels of polyphosphoinositide species and reduced all fusion parameters, sequestering polyphosphoinositides selectively inhibited fusion kinetics. Thus, cholesterol and phosphatidylethanolamine play direct roles in the fusion pathway, contributing negative curvature. Cholesterol also organizes the physiological fusion site, defining fusion efficiency. A selective influence of phosphatidylethanolamine on fusion kinetics sheds light on the local microdomain structure at the site of docking/fusion. Polyphosphoinositides have modulatory upstream roles in priming: alterations in specific polyphosphoinositides likely represent the terminal priming steps defining fully docked, release-ready vesicles. Thus, this pharmacological approach has the potential to be a robust high-throughput platform to identify molecular components of the physiological fusion machine critical to docking, priming, and triggered fusion.

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Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 53%

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 91%

Section: Critical Roles For Chol In Triggered Membrane Fusionmentioning

confidence: 99%

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A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Rogasevskaia

Coorssen

2011

J Chem Biol

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From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

2017

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The emerging diverse roles of ether (phospho)lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of ether lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in ether lipid-deficient human patients and mice by linking individual functional properties of ether lipids with pathological features. Furthermore, recent publications have identified altered ether lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore ether lipids in peroxisomal disorders as well as AD are critically reviewed.

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Altered Lipid Composition of Secretory Cells Following Exposure to Zinc Can Be Correlated to Changes in Exocytosis

Ren

Pour

Malmberg

et al. 2019

Chemistry A European J

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Am icromolar concentrationo fz inc has been shown to significantly change the dynamics of exocytosis as well as the vesicle contentsi namodel cell line, providing direct evidencet hat zinc regulates neurotransmitter release.T op rovide insight into how zinc modulates these exocytotic processes, neurotransmitter releasea nd vesicle contentw erec ompared with single cell amperometry and intracellular impact vesicle cytometry with ar ange of zinc concentrations.A dditionally,t ime-of-flight secondary ion mass spectrometry (ToF-SIMS) images of lipid distributions in the cell membranea fter zinc treatment correlatet o changes in exocytosis. By combining electrochemical techniques andm ass spectrometry imaging, we proposed a mechanism by which zinc changes the fusion pore and the rate of neurotransmitter release by changing lipid distributions and results in the modulation of synaptic strength and plasticity.

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Cholesterol, regulated exocytosis and the physiological fusion machine

Cited by 60 publications

References 252 publications

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

Altered Lipid Composition of Secretory Cells Following Exposure to Zinc Can Be Correlated to Changes in Exocytosis

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