Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: Insights from vesicle recycling in nerve terminals

Wenk, Markus R.; Camilli, Pietro De

doi:10.1073/pnas.0401874101

Cited by 292 publications

(247 citation statements)

References 156 publications

(188 reference statements)

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“…Note that the lengths of the arrows do not represent the time needed to complete these reactions. Nature Reviews | Neuroscience Clathrin coat phosphatidylinositol 4,5-bisphosphate (PIP2)-rich membranes 56 . Membrane bending mechanistically occurs by the insertion of amphipathic helices into the cytoplasmic leaflet of the plasma membrane and involves crescent-shaped F-BAR (FCH domain-binamphiphysin-rvs; FCH-BAR)-containing proteins such as FCHo proteins, amphiphysin, endophilin, syndapin as well as the EnTH domain of epsin 57 .…”

Section: Box 1 | Presynaptic Organization -Exocytic and Endocytic Zonesmentioning

confidence: 99%

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

2011

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Communication between nerve cells largely occurs at chemical synapses -specialized sites of cell-cell contact where electrical signals trigger the exocytic release of neurotransmitter, which in turn activates postsynaptic receptor channels. The efficacy with which such chemical signals are transmitted is crucial for the functioning of the nervous system. Modulation of neurotransmission enables nerve cells to respond to a vast range of stimulus patterns. Synaptic activity can also be tremendously diverse; from the fast synapses of the hippocampus, to slow neuropeptide-containing synapses. Indeed, some signalling pathways are active in the absence of stimulation, such as those involved in the processing of sensory information, which transmit tonically at high rates of up to 100 Hz or more 1,2 .Intriguing questions arise from these facts, including how high rates of neurotransmission can be maintained over long periods of time, and what limits the ability of a given synapse to release neurotransmitter during sustained periods of activity. Recent data indicate that in many synapses, exocytosis of neurotransmitter is coupled to endocytosis, and that synapses have evolved a specialized apparatus of scaffolding proteins to comply with these demands. Such scaffolds aid the temporal and spatial coupling of exocytosis and endocytosis, and are crucial for maintaining rapid neurotransmission during sustained activity 3 .Exocytosis of neurotransmitter is triggered by stimulusinduced calcium influx into the nerve terminal 4,5 and the subsequent fusion of synaptic vesicles with the presynaptic plasma membrane at specialized regions called active zones (BOX 1). Exocytosed synaptic vesicle membrane proteins and lipids in turn are recycled at the endocytic or periactive zone (BOX 1) that surrounds the release site, to restore functional synaptic vesicle pools for reuse and to ensure long-term functionality of the synapse 6-8 (FIG. 1). Depending on the type of synapse and the stimulation frequency, several modes of endocytosis with different time constants -for example, fast and slow endocytosisseem to operate 7,9,10 . Clathrin-mediated endocytosis arguably represents the main pathway of synaptic vesicle endocytosis 6,8,11 , although other modes -for example, fast kiss-and-run exocytosis and endocytosis -could operate in parallel.Although the machineries for exocytic membrane fusion 12,13 and for endocytic retrieval of synaptic vesicle membranes have been studied separately in some detail 6,14 , comparatively little is known about the coupling between exocytosis and endocytosis. Here we synthesize recent data from physiological, morphological and biochemical studies in several model systems into hypothetical models for scaffold-based mechanisms underlying exocytic-endocytic coupling.The synaptic vesicle cycle Synaptic vesicle pools. Some defining features of chemical synapses are the presence of one or several clusters of synaptic vesicles in the presynaptic nerve terminal, and ultrastructural specializations at the pre-and postsy...

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Section: Box 1 | Presynaptic Organization -Exocytic and Endocytic Zonesmentioning

confidence: 99%

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

2011

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“…What is the functional significance of this transient PI(4,5)P 2 segregation? It has been proposed that membrane foci enriched in PI(4,5)P 2 may serve as anchoring points for intracellular proteins that bind to this phosphoinositide with high affinity 26,42 (Supplementary information S2 (box)). This recruitment to specific membrane sites is well suited to guide cellular events that require a high degree of membrane localization, including synaptic vesicle exocytosis 42 .…”

Section: Signalling On Demandmentioning

confidence: 99%

“…It has been proposed that membrane foci enriched in PI(4,5)P 2 may serve as anchoring points for intracellular proteins that bind to this phosphoinositide with high affinity 26,42 (Supplementary information S2 (box)). This recruitment to specific membrane sites is well suited to guide cellular events that require a high degree of membrane localization, including synaptic vesicle exocytosis 42 . experiments with permeabilized neuroendocrine cells have shown that two key proteins for PI(4,5)P 2 metabolism -phosphatidylinositol-transfer protein, which transports phosphatidylinositol across the cytosol, and PI(4)P 5 -kinase, which converts PI(4)P Box 1 | The docosahexaenoic acid puzzle Docosahexaenoic acid (fIG.…”

Section: Signalling On Demandmentioning

confidence: 99%

A neuroscientist's guide to lipidomics

2007

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| Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses.

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“…Thus, reduced PI(4,5)P2 levels are expected in vesicles at the fully docked, fusion-ready stage. In contrast, PI(4,5)P2 formation in the PM during or immediately after triggered release is critical for its subsequent roles in endocytosis [83,89]. This suggests that PI(3,4)P2, PI(3,4,5)P3, and their immediate precursors PI(4)P and PI(4,5)P2 are not essential to docking/fusion steps per se and are not directly involved in the mechanism.…”

Section: Roles For Polyphosphoinositides In Regulated Releasementioning

confidence: 99%

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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Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: Insights from vesicle recycling in nerve terminals

Cited by 292 publications

References 156 publications

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

A neuroscientist's guide to lipidomics

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

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