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Thomas C. Südhof - One of the best experts on this subject based on the ideXlab platform.
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deconstructing complexin function in activating and clamping ca2 triggered Exocytosis by comparing knockout and knockdown phenotypes
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Xiaofei Yang, Peng Cao, Thomas C. SüdhofAbstract:Complexin, a presynaptic protein that avidly binds to assembled SNARE complexes, is widely acknowledged to activate Ca2+-triggered Exocytosis. In addition, studies of invertebrate complexin mutants and of mouse neurons with a double knockdown (DKD) of complexin-1 and -2 suggested that complexin maintains the readily releasable pool (RRP) of vesicles and clamps spontaneous Exocytosis. In contrast, studies of mouse neurons with a double knockout (DKO) of complexin-1 and -2, largely carried out in hippocampal autapses, did not detect changes in the RRP size or in spontaneous Exocytosis. To clarify complexin function, we here directly compared in two different preparations, cultured cortical and olfactory bulb neurons, the phenotypes of complexin DKD and DKO neurons. We find that complexin-deficient DKD and DKO neurons invariably exhibit a ∼50% decrease in vesicle priming. Moreover, the DKD consistently increased spontaneous Exocytosis, but the DKO did so in cortical but not olfactory bulb neurons. Furthermore, the complexin DKD but not the complexin DKO caused a compensatory increase in complexin-3 and -4 mRNA levels; overexpression of complexin-3 but not complexin-1 increased spontaneous Exocytosis. Complexin-3 but not complexin-1 contains a C-terminal lipid anchor attaching it to the plasma membrane; addition of a similar lipid anchor to complexin-1 converted complexin-1 from a clamp into an activator of spontaneous Exocytosis. Viewed together, our data suggest that complexin generally functions in priming and Ca2+ triggering of Exocytosis, and additionally contributes to the control of spontaneous Exocytosis dependent on the developmental history of a neuron and on the subcellular localization of the complexin.
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postsynaptic complexin controls ampa receptor Exocytosis during ltp
Neuron, 2012Co-Authors: Mohiuddin Ahmad, Thomas C. Südhof, Jai S Polepalli, Debanjan Goswami, Xiaofei Yang, Yea Jin Kaeserwoo, Robert C MalenkaAbstract:Long-term potentiation (LTP) is a compelling synaptic correlate of learning and memory. LTP induction requires NMDA receptor (NMDAR) activation, which triggers SNARE-dependent Exocytosis of AMPA receptors (AMPARs). However, the molecular mechanisms mediating AMPAR Exocytosis induced by NMDAR activation remain largely unknown. Here, we show that complexin, a protein that regulates neurotransmitter release via binding to SNARE complexes, is essential for AMPAR Exocytosis during LTP but not for the constitutive AMPAR Exocytosis that maintains basal synaptic strength. The regulated postsynaptic AMPAR Exocytosis during LTP requires binding of complexin to SNARE complexes. In hippocampal neurons, presynaptic complexin acts together with synaptotagmin-1 to mediate neurotransmitter release. However, postsynaptic synaptotagmin-1 is not required for complexin-dependent AMPAR Exocytosis during LTP. These results suggest a complexin-dependent molecular mechanism for regulating AMPAR delivery to synapses, a mechanism that is surprisingly similar to presynaptic Exocytosis but controlled by regulators other than synaptotagmin-1.
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activity dependent igf 1 Exocytosis is controlled by the ca2 sensor synaptotagmin 10
Cell, 2011Co-Authors: Peng Cao, Thomas C. Südhof, Anton MaximovAbstract:Synaptotagmins Syt1, Syt2, Syt7, and Syt9 act as Ca(2+)-sensors for synaptic and neuroendocrine Exocytosis, but the function of other synaptotagmins remains unknown. Here, we show that olfactory bulb neurons secrete IGF-1 by an activity-dependent pathway of Exocytosis, and that Syt10 functions as the Ca(2+)-sensor that triggers IGF-1 Exocytosis in these neurons. Deletion of Syt10 impaired activity-dependent IGF-1 secretion in olfactory bulb neurons, resulting in smaller neurons and an overall decrease in synapse numbers. Exogenous IGF-1 completely reversed the Syt10 knockout phenotype. Syt10 colocalized with IGF-1 in somatodendritic vesicles of olfactory bulb neurons, and Ca(2+)-binding to Syt10 caused these vesicles to undergo Exocytosis, thereby secreting IGF-1. Thus, Syt10 controls a previously unrecognized pathway of Ca(2+)-dependent Exocytosis that is spatially and temporally distinct from Ca(2+)-dependent synaptic vesicle Exocytosis controlled by Syt1. Our findings thereby reveal that two different synaptotagmins can regulate functionally distinct Ca(2+)-dependent membrane fusion reactions in the same neuron.
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Cell Biology of Ca2+-Triggered Exocytosis
Current Opinion in Cell Biology, 2010Co-Authors: Zhiping P. Pang, Thomas C. SüdhofAbstract:Ca 2+ triggers many forms of Exocytosis in different types of eukaryotic cells, for example synaptic vesicle Exocytosis in neurons, granule Exocytosis in mast cells, and hormone Exocytosis in endocrine cells. Work over the past two decades has shown that synaptotagmins function as the primary Ca 2+ -sensors for most of these forms of Exocytosis, and that synaptotagmins act via Ca 2+ -dependent interactions with both the fusing phospholipid membranes and the membrane fusion machinery. However, some forms of Ca 2+ -induced Exocytosis may utilize other, as yet unidentified Ca 2+ -sensors, for example, slow synaptic Exocytosis mediating asynchronous neurotransmitter release. In the following overview, we will discuss the synaptotagmin-based mechanism of Ca 2+ -triggered Exocytosis in neurons and neuroendocrine cells, and its potential extension to other types of Ca 2+ -stimulated Exocytosis for which no synaptotagmin Ca 2+ -sensor has been identified.
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Cell biology of Ca 2+ -triggered Exocytosis
2010Co-Authors: Zhiping P. Pang, Thomas C. SüdhofAbstract:Ca triggers many forms of Exocytosis in different types of eukaryotic cells, for example synaptic vesicle Exocytosis in neurons, granule Exocytosis in mast cells, and hormone Exocytosis in endocrine cells. Work over the past two decades has shown that synaptotagmins function as the primary Ca-sensors for most of these forms of Exocytosis, and that synaptotagmins act via Ca-dependent interactions with both the fusing phospholipid membranes and the membrane fusion machinery. However, some forms of Ca-induced Exocytosis may utilize other, as yet unidentified Ca-sensors, for example, slow synaptic Exocytosis mediating asynchronous neurotransmitter release. In the following overview, we will discuss the synaptotagmin-based mechanism of Ca-triggered Exocytosis in neurons and neuroendocrine cells, and its potential extension to other types of Ca-stimulated Exocytosis for which no synaptotagmin Ca-sensor has been identified.
Thomas F. J. Martin - One of the best experts on this subject based on the ideXlab platform.
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Synaptotagmins I and IX function redundantly in regulated Exocytosis but not endocytosis in PC12 cells
Journal of Cell Science, 2007Co-Authors: Kara L. Lynch, Thomas F. J. MartinAbstract:Synaptotagmin I is considered to be a Ca2+ sensor for fast vesicle Exocytosis. Because Ca2+-dependent vesicle Exocytosis persists in synaptotagmin I mutants, there must be additional Ca2+ sensors. Multiple synaptotagmin isoforms co-reside on vesicles, which suggests that other isoforms complement synaptotagmin I function. We found that full downregulation of synaptotagmins I and IX, which co-reside on vesicles in PC12 cells, completely abolished Ca2+-dependent vesicle Exocytosis. By contrast, Ca2+-dependent Exocytosis persisted in cells expressing only synaptotagmin I or only synaptotagmin IX, which indicated a redundancy in function for these isoforms. Although either isoform was sufficient to confer Ca2+ regulation on vesicle Exocytosis, synaptotagmins I and IX conferred faster and slower release rates, respectively, indicating that individual isoforms impart distinct kinetic properties to vesicle Exocytosis. The downregulation of synaptotagmin I but not synaptotagmin IX impaired compensatory vesicle endocytosis, which revealed a lack of isoform redundancy and functional specialization of synaptotagmin I for endocytic retrieval.
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mechanisms of protein secretion in endocrine and exocrine cells
Vitamins and Hormones Series, 1998Co-Authors: Thomas F. J. MartinAbstract:Publisher Summary This chapter describes that dense core vesicles (DCVs) Exocytosis in exocrine cells proceeds by mechanisms that are less clearly understood and involves proteins or protein isoforms different from those employed in neural/endocrine secretion. Biochemical and molecular biological studies have resulted in the characterization of at least 25 types of synaptic vesicle (SV) membrane proteins that may mediate aspects of SV function including calcium-dependent Exocytosis, endocytosis, and neurotransmitter loading. In neuronal cells, there are important physiological differences between the Exocytosis of SVs that contain neurotransmitters such as glutamate and the Exocytosis of larger DCVs that contain neuropeptides, including calcium sensitivity and speed. Microinjection and genetic studies have documented the importance of SNARE proteins and synaptotagmin in neurosecretion without revealing their sites of action and mechanisms. Of the other isoforms of synaptotagmin characterized, synaptotagmin III has the most appealing characteristics as a calcium sensor for DCV Exocytosis. Expression of synaptotagmin isoforms in the acinar pancreas has not been reported, so it is uncertain whether this protein family plays a role in calcium sensing for zymogen granule Exocytosis.
Abigail G Garrity - One of the best experts on this subject based on the ideXlab platform.
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a trp channel in the lysosome regulates large particle phagocytosis via focal Exocytosis
Developmental Cell, 2013Co-Authors: Mohammad Samie, Xiang Wang, Xiaoli Zhang, Andrew Goschka, Xinran Li, Xiping Cheng, Evan Gregg, Marlene Azar, Yue Zhuo, Abigail G GarrityAbstract:Summary Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca 2+ channel regulating focal Exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal Exocytosis are inhibited by synthetic TRPML1 blockers and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal Exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P 2 elevation to trigger TRPML1-mediated lysosomal Ca 2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal Exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca 2+ -dependent Exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.
Yuko Koyanagi - One of the best experts on this subject based on the ideXlab platform.
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role of specific presynaptic calcium channel subtypes in isoflurane inhibition of synaptic vesicle Exocytosis in rat hippocampal neurones
BJA: British Journal of Anaesthesia, 2019Co-Authors: Yuko Koyanagi, Christina L Torturo, Daniel C Cook, Zhenyu Zhou, Hugh C HemmingsAbstract:Abstract Background P/Q- and N-type voltage-gated calcium channels (VGCC) are the principal subtypes mediating synaptic vesicle (SV) Exocytosis. Both the degree of isoflurane inhibition of SV Exocytosis and VGCC subtype expression vary between brain regions and neurotransmitter phenotype. We hypothesised that differences in VGCC subtype expression contribute to synapse-selective presynaptic effects of isoflurane. Methods We used quantitative live-cell imaging to measure Exocytosis in cultured rat hippocampal neurones after transfection of the fluorescent biosensor vGlut1-pHluorin. Selective inhibitors of P/Q- and N-type VGCCs were used to isolate subtype-specific effects of isoflurane. Results Inhibition of N-type channels by 1 μM ω-conotoxin GVIA reduced SV Exocytosis to 81±5% of control (n=10). Residual Exocytosis mediated by P/Q-type channels was further inhibited by isoflurane to 42±4% of control (n=10). The P/Q-type channel inhibitor ω-agatoxin IVA at 0.4 μM inhibited SV Exocytosis to 29±3% of control (n=10). Residual Exocytosis mediated by N-type channels was further inhibited by isoflurane to 17±3% of control (n=10). Analysis of isoflurane effects at the level of individual boutons revealed no difference in sensitivity to isoflurane between P/Q- or N-type channel-mediated SV Exocytosis (P=0.35). There was no correlation between the effect of agatoxin (P=0.91) or conotoxin (P=0.15) and the effect of isoflurane on Exocytosis. Conclusions Sensitivity of SV Exocytosis to isoflurane in rat hippocampal neurones is independent of the specific VGCC subtype coupled to Exocytosis. The differential sensitivity of VGCC subtypes to isoflurane does not explain the observed neurotransmitter-selective effects of isoflurane in hippocampus.
Wei Guo - One of the best experts on this subject based on the ideXlab platform.
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Polarized Exocytosis.
Cold Spring Harbor perspectives in biology, 2017Co-Authors: Jingwen Zeng, Shanshan Feng, Wei GuoAbstract:Polarized Exocytosis is generally considered as the multistep vesicular trafficking process in which membrane-bounded carriers are transported from the Golgi or endosomal compartments to specific sites of the plasma membrane. Polarized Exocytosis in cells is achieved through the coordinated actions of membrane trafficking machinery and cytoskeleton orchestrated by signaling molecules such as the Rho family of small GTPases. Elucidating the molecular mechanisms of polarized Exocytosis is essential to our understanding of a wide range of pathophysiological processes from neuronal development to tumor invasion.
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The exocyst complex in Exocytosis and cell migration
Protoplasma, 2011Co-Authors: Jianglan Liu, Wei GuoAbstract:Exocytosis is a fundamental membrane trafficking event in eukaryotic cells in which membrane proteins or lipids are incorporated into the plasma membrane and vesicle contents are secreted to the exterior of the cell. The exocyst, an evolutionarily conserved octameric protein complex, plays a crucial role in the targeting of secretory vesicles to the plasma membrane during Exocytosis. The exocyst has been shown to be involved in diverse cellular processes requiring polarized Exocytosis such as yeast budding, epithelial polarity establishment, and neurite outgrowth. Recently, the exocyst has also been implicated in cell migration through mechanisms independent of its role in Exocytosis. In this review, we will first summarize our knowledge on the exocyst complex at a molecular and structural level. Then, we will discuss the specific functions of the exocyst in Exocytosis in various cell types. Finally, we will review the emerging roles of the exocyst during cell migration and tumor cell invasion.
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The Exocyst Complex in Polarized Exocytosis
International Review of Cytology-a Survey of Cell Biology, 2004Co-Authors: Shu-chan Hsu, Daniel Terbush, Mathew Abraham, Wei GuoAbstract:Abstract Exocytosis is an essential membrane traffic event mediating the secretion of intracellular protein contents such as hormones and neurotransmitters as well as the incorporation of membrane proteins and lipids to specific domains of the plasma membrane. As a fundamental cell biological process, Exocytosis is crucial for cell growth, cell–cell communication, and cell polarity establishment. For most eukaryotic cells Exocytosis is polarized. A multiprotein complex, named the exocyst, is required for polarized Exocytosis from yeast to mammals. The exocyst consists of eight components: Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84. They are localized to sites of active Exocytosis, where they mediate the targeting and tethering of post-Golgi secretory vesicles for subsequent membrane fusion. Here we review the progress made in the understanding of the exocyst and its role in polarized Exocytosis.
