Distinct yet overlapping roles of Rab GTPases on synaptic vesicles

Pavlos, Nathan J.; Jahn, Reinhard

doi:10.4161/sgtp.2.2.15201

Cited by 67 publications

(70 citation statements)

References 44 publications

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“…TI-VAMP localizes to the trans-Golgi network (Danglot et al, 2010) and to late endosomes and lysosomes (Chaineau et al, 2009). The absence of effect of the transfection of a dominant-negative form of Rab5 is likely due to redundancy of small GTPases involved in early endocytosis (Pavlos and Jahn, 2011). Our results thus favor a mechanism of endocytosis, including early and late endosomes, possibly a partial fusion with lysosomes and a recycling pathway by exocytosis.…”

Section: Discussionmentioning

confidence: 62%

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Cassé¹,

Bardou²,

Danglot³

et al. 2012

J. Neurosci.

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Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter.

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Section: Discussionmentioning

confidence: 62%

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Cassé¹,

Bardou²,

Danglot³

et al. 2012

J. Neurosci.

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“…The reason why rabphilin 3A specifically needs this conformational change upon Ca 2+ binding is not known but this protein is a Rab3/Rab27 effector in neurons and endocrine cells (reviewed in refs. 34,35), and is involved in vesicle docking and repriming (36,37). This implies it has to be present in scenarios with concomitant Ca 2+ influx that triggers vesicle fusion through its main target syt1.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into the Ca ²⁺ and PI(4,5)P ₂ binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1

Guillén

Ferrer-Orta

Buxaderas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Proteins containing C2 domains are the sensors for Ca 2+ and PI (4,5)P 2 in a myriad of secretory pathways. Here, the use of a freemounting system has enabled us to capture an intermediate state of Ca 2+ binding to the C2A domain of rabphilin 3A that suggests a different mechanism of ion interaction. We have also determined the structure of this domain in complex with PI(4,5)P 2 and IP 3 at resolutions of 1.75 and 1.9 Å, respectively, unveiling that the polybasic cluster formed by strands β3-β4 is involved in the interaction with the phosphoinositides. A comparative study demonstrates that the C2A domain is highly specific for PI(4,5)P 2 /PI (3,4,5)P 3 , whereas the C2B domain cannot discriminate among any of the diphosphorylated forms. Structural comparisons between C2A domains of rabphilin 3A and synaptotagmin 1 indicated the presence of a key glutamic residue in the polybasic cluster of synaptotagmin 1 that abolishes the interaction with PI (4,5)P 2 . Together, these results provide a structural explanation for the ability of different C2 domains to pull plasma and vesicle membranes close together in a Ca 2+ -dependent manner and reveal how this family of proteins can use subtle structural changes to modulate their sensitivity and specificity to various cellular signals.PIP2 | calcium | vesicle fusion C 2 modules are most commonly found in enzymes involved in lipid modifications and signal transduction and in proteins involved in membrane trafficking. They consist of 130 residues and share a common fold composed of two four-stranded β-sheets arranged in a compact β-sandwich connected by surface loops and helices (1-4). Many of these C2 domains have been demonstrated to function in a Ca 2+ -dependent membrane-binding manner and hence act as cellular Ca 2+ sensors. Calcium ions bind in a cupshaped invagination formed by three loops at one tip of the β-sandwich where the coordination spheres for the Ca 2+ ions are incomplete (5-7). This incomplete coordination sphere can be occupied by neutral and anionic (7-9) phospholipids, enabling the C2 domain to dock at the membrane.Previous work in our laboratory has shed light on the 3D structure of the C2 domain of PKCα in complex with both PS and PI(4,5)P 2 simultaneously (10). This revealed an additional lipidbinding site located in the polybasic region formed by β3-β4 strands that preferentially binds to PI(4,5)P 2 (11-15). This site is also conserved in a wide variety of C2 domains of topology I, for example synaptotagmins, rabphilin 3A, DOC2, and PI3KC2α (10,(16)(17)(18)(19). Given the importance of PI(4,5)P 2 for bringing the vesicle and plasma membranes together before exocytosis to ensure rapid and efficient fusion upon calcium influx (20-23), it is crucial to understand the molecular mechanisms beneath this event.Many studies have reported different and contradictory results about the membrane binding properties of C2A and C2B domains of synaptotagmin 1 and rabphilin 3A providing an unclear picture about how Ca 2+ and PI(4,5)P 2 combine to orchestrate the vesi...

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“…This role is further supported by several lines of evidence: First, nerve terminals of mice that lack all synapsins have a lower content of SVs and such vesicles are more disperse than at wild type synapses (Gitler et al, 2004). As clusters are not abolished, the action of synapsin is most likely overlapping with that of other proteins peripherally associated with their membranes, including synuclein (Vargas et al, 2017), Rab proteins and their interactors (Pavlos and Jahn, 2011). Second, anti-synapsin antibody injection in the giant axon of the lamprey results in dramatic loss of SV clusters (Figure 4A,B; Pieribone et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Synaptic Vesicle Clusters at Synapses: A Distinct Liquid Phase?

Milovanović

Camilli

2017

Neuron

107

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Phase separation in the cytoplasm is emerging as a major principle in intracellular organization. In this process, sets of macromolecules assemble themselves into liquid compartments that are distinct from the surrounding medium but are not delimited by membrane boundaries. Here, we discuss how phase separation, where a component of one of the two phases is vesicles rather than macromolecules, could underlie the formation of synaptic vesicle (SV) clusters in proximity of presynaptic sites. The organization of SVs into a liquid phase could explain how SVs remain tightly clustered without being stably bound to a scaffold so that they can be efficiently recruited to release site by active zone components.

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Distinct yet overlapping roles of Rab GTPases on synaptic vesicles

Cited by 67 publications

References 44 publications

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Structural insights into the Ca ²⁺ and PI(4,5)P ₂ binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1

Synaptic Vesicle Clusters at Synapses: A Distinct Liquid Phase?

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Distinct yet overlapping roles of Rab GTPases on synaptic vesicles

Cited by 67 publications

References 44 publications

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Glutamate Controls tPA Recycling by Astrocytes, Which in Turn Influences Glutamatergic Signals

Structural insights into the Ca 2+ and PI(4,5)P 2 binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1

Synaptic Vesicle Clusters at Synapses: A Distinct Liquid Phase?

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Structural insights into the Ca ²⁺ and PI(4,5)P ₂ binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1