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Thomas C Sudhof - One of the best experts on this subject based on the ideXlab platform.
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Towards Understanding the Molecular Mechanism of Synchronous Neurotransmitter Release
Biophysical Journal, 2017Co-Authors: Qiangjun Zhou, Thomas C Sudhof, Axel T. BrungerAbstract:Most communication between neurons is achieved at synapses by the process of Neurotransmitter Release. Neurotransmitter Release is initiated by depolarization of a neuron, which in turn activates voltage-gated Ca2+ channels. The resulting Ca2+ influx then triggers the fusion of the synaptic vesicles with the plasma membrane. Synaptic vesicle fusion is mediated by a core fusion machinery SNARE complex, a small regulatory factor complexin (Cpx), and Ca2+ sensor synaptotagmin (Syt). However, it was unknown how they cooperate to trigger synaptic vesicle fusion. Combining X-ray crystallography and electrophysiological recording techniques, we determined two atomic resolution crystal structures of the synaptic vesicle fusion machinery at different states, revealing a large, specific, Ca2+-independent interface which is essential for synchronous Neurotransmitter Release in mouse neuronal synapses. We propose a working model and further reveal the molecular mechanism of synchronous Neurotransmitter Release.
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rim bps mediate tight coupling of action potentials to ca 2 triggered Neurotransmitter Release
Neuron, 2015Co-Authors: Claudio Acuna, Aneysis Gonzalez, Thomas C SudhofAbstract:Summary Ultrafast Neurotransmitter Release requires tight colocalization of voltage-gated Ca 2+ channels with primed, Release-ready synaptic vesicles at the presynaptic active zone. RIM-binding proteins (RIM-BPs) are multidomain active zone proteins that bind to RIMs and to Ca 2+ channels. In Drosophila , deletion of RIM-BPs dramatically reduces Neurotransmitter Release, but little is known about RIM-BP function in mammalian synapses. Here, we generated double conditional knockout mice for RIM-BP1 and RIM-BP2, and analyzed RIM-BP-deficient synapses in cultured hippocampal neurons and the calyx of Held. Surprisingly, we find that in murine synapses, RIM-BPs are not essential for Neurotransmitter Release as such, but are selectively required for high-fidelity coupling of action potential-induced Ca 2+ influx to Ca 2+ -stimulated synaptic vesicle exocytosis. Deletion of RIM-BPs decelerated action-potential-triggered Neurotransmitter Release and rendered it unreliable, thereby impairing the fidelity of synaptic transmission. Thus, RIM-BPs ensure optimal organization of the machinery for fast Release in mammalian synapses without being a central component of the machinery itself.
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The Molecular Machinery of Neurotransmitter Release (Nobel Lecture)
Angewandte Chemie (International ed. in English), 2014Co-Authors: Thomas C SudhofAbstract:The most important property of synaptic transmission is its speed, which is crucial for the overall workings of the brain. In his Nobel Lecture, T. C. Sudhof explains how the synaptic vesicle and the plasma membrane undergo rapid fusion during Neurotransmitter Release and how this process is spatially organized, such that opening of Ca(2+) -channels allows rapid translation of the entering Ca(2+) signal into a fusion event.
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calcium control of Neurotransmitter Release
Cold Spring Harbor Perspectives in Biology, 2012Co-Authors: Thomas C SudhofAbstract:Synaptic transmission is initiated when an action potential invades a nerve terminal, opening Ca2+ channels, which gate a highly localized, transient increase in intracellular Ca2+ at the active zone (Fig. 1A). Ca2+ triggers synaptic vesicle exocytosis, thereby releasing the Neurotransmitters contained in the vesicles and initiating synaptic transmission. This fundamental mechanism was discovered in pioneering work on the neuromuscular junction by Katz and Miledi (1967). Its precise time course was studied in many “model” synapses, including giant squid axon synapses (Augustine et al. 1985) and rat cerebellar parallel fiber synapses (Sabatini and Regehr 1996), but characterized in greatest detail in the calyx of Held synapses in the brainstem (Fig. 1B; reviewed in Meinrenken et al. 2003). Overall, these high-resolution electrophysiological studies on Neurotransmitter Release revealed that a presynaptic action potential is tightly coupled to Ca2+ influx and synaptic vesicle fusion, such that under physiological conditions, Ca2+ triggers fusion in a few hundred microseconds, or possibly even in less than 100 microseconds (Sabatini and Regehr 1996). Figure 1. Principle and time course of Ca2+-triggered synaptic transmission. (A) Schematic diagram of a synapse illustrating the localized influx of Ca2+ at the active zone (red = secreted Neurotransmitters). (B) Schematic illustration of the sequence and time ... The amazing speed and precision of Ca2+-triggered Neurotransmitter Release raised the question of how such speed might be possible—how can Ca2+ induce exocytosis in a few hundred microseconds, on the same timescale as the gating of an ion channel? As we will describe in this review, the speed and precision of Release are mediated, at least in part, by the properties of the Ca2+ sensor synaptotagmin (Syt) and its cofactor complexin. Moreover, increasing evidence indicates that the principal mechanism of Ca2+-triggered exocytosis, although not the organization of this mechanism, is conserved in other, slower forms of Ca2+-induced exocytosis. Thus, the Syt-based fusion apparatus emerges as a general paradigm that accounts for most Ca2+-regulated exocytosis in eukaryotic cells. In addition to normal action potential-evoked Neurotransmitter Release, synapses exhibit two additional forms of Ca2+-dependent synaptic exocytosis: spontaneous “mini” Release and asynchronous Release (Pang and Sudhof 2010). Spontaneous mini Release was discovered by Katz (Fatt and Katz 1952), and is thought to represent the background activity of a nerve terminal that is triggered by spontaneous Ca2+ fluctuations. Although the biological significance of spontaneous Release remains debated, its presence can be observed in all neurons. When calculated on a per-synapse basis, spontaneous Release occurs only once every 2–3 hours at an individual excitatory synapse of a pyramidal neuron in the CA1 region of the hippocampus, and approximately once every 3 min at individual inhibitory synapses. Asynchronous Release is undetectable in most synapses under physiological conditions, but becomes apparent when the principal Syt Ca2+ sensor for regular Release is ablated (Geppert et al. 1994). Some inhibitory synapses exhibit a slow form of Release on repetitive stimulation (Hefft and Jonas 2005), which may represent either genuine physiological asynchronous Release or simply synaptotagmin-dependent delayed Release.
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presenilins are essential for regulating Neurotransmitter Release
Nature, 2009Co-Authors: Thomas C Sudhof, Chen Zhang, Bei Wu, Vassilios Beglopoulos, Mary Winessamuelson, Dawei Zhang, Ioannis Dragatsis, Jie ShenAbstract:The presenilin genes have been genetically associated with familial cases of Alzheimer's disease but where they operate and what they do in neurons has been unclear. Zhang et al. demonstrate in mouse models that presinilins act in the presynaptic compartment to control activity-dependent Neurotransmitter Release, a process essential to neuronal computation, learning and memory. These findings suggest that presynaptic dysfunction might be an early cause of dementia in neurodegenerative disorders. Mutations in the presenilin genes are associated with familial cases of Alzheimer's disease, but the precise site and nature of the synaptic dysfunction remain unknown. Using a genetic approach to selectively inactivate presenilins in a mouse model, it has been possible to demonstrate that they act in the presynaptic compartment to control the activity-dependent efficacy of Neurotransmitter Release, a process essential for neuronal computation, learning and memory. Mutations in the presenilin genes are the main cause of familial Alzheimer’s disease. Loss of presenilin activity and/or accumulation of amyloid-β peptides have been proposed to mediate the pathogenesis of Alzheimer’s disease by impairing synaptic function1,2,3,4,5. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We show that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, we found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate Release, measured with the open-channel NMDA (N-methyl-d-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca2+ stores by thapsigargin, or blockade of Ca2+ Release from these stores by ryanodine receptor inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results indicate a selective role for presenilins in the activity-dependent regulation of Neurotransmitter Release and long-term potentiation induction by modulation of intracellular Ca2+ Release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer’s disease.
Bernard Poulain - One of the best experts on this subject based on the ideXlab platform.
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A role for phospholipase D1 in Neurotransmitter Release
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Yann Humeau, Nicolas Vitale, Sylvette Chasserot-golaz, Jean-luc Dupont, Michael A. Frohman, Marie-france Bader, Bernard PoulainAbstract:Phosphatidic acid produced by phospholipase D (PLD) as a result of signaling activity is thought to play a role in membrane vesicle trafficking, either as an intracellular messenger or as a cone-shaped lipid that promotes membrane fusion. We recently described that, in neuroendocrine cells, plasma membrane-associated PLD1 operates at a stage of Ca2+-dependent exocytosis subsequent to cytoskeletal-mediated recruitment of secretory granules to exocytotic sites. We show here that PLD1 also plays a crucial role in Neurotransmitter Release. Using purified rat brain synaptosomes subjected to hypotonic lysis and centrifugation, we found that PLD1 is associated with the particulate fraction containing the plasma membrane. Immunostaining of rat cerebellar granule cells confirmed localization of PLD1 at the neuronal plasma membrane in zones specialized for Neurotransmitter Release (axonal neurites, varicosities, and growth cone-like structures). To determine the potential involvement of PLD1 in Neurotransmitter Release, we microinjected catalytically inactive PLD1(K898R) into Aplysia neurons and analyzed its effects on evoked acetylcholine (ACh) Release. PLD1(K898R) produced a fast and potent dose-dependent inhibition of ACh Release. By analyzing paired-pulse facilitation and postsynaptic responses evoked by high-frequency stimulations, we found that the exocytotic inhibition caused by PLD1(K898R) was not the result of an alteration in stimulus-secretion coupling or in vesicular trafficking. Analysis of the fluctuations in amplitude of the postsynaptic responses revealed that the PLD1(K898R) blocked ACh Release by reducing the number of active presynaptic-releasing sites. Our results provide evidence that PLD1 plays a major role in neurotransmission, most likely by controlling the fusogenic status of presynaptic Release sites.
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how botulinum and tetanus neurotoxins block Neurotransmitter Release
Biochimie, 2000Co-Authors: Yann Humeau, Frédéric Doussau, Nancy J. Grant, Bernard PoulainAbstract:Abstract Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT) are bacterial proteins that comprise a light chain ( M r ≈50) disulfide linked to a heavy chain ( M r ≈100). By inhibiting Neurotransmitter Release at distinct synapses, these toxins cause two severe neuroparalytic diseases, tetanus and botulism. The cellular and molecular modes of action of these toxins have almost been deciphered. After binding to specific membrane acceptors, BoNTs and TeNT are internalized via endocytosis into nerve terminals. Subsequently, their light chain (a zinc-dependent endopeptidase) is translocated into the cytosolic compartment where it cleaves one of three essential proteins involved in the exocytotic machinery: vesicle associated membrane protein (also termed synaptobrevin), syntaxin, and synaptosomal associated protein of 25 kDa. The aim of this review is to explain how the proteolytic attack at specific sites of the targets for BoNTs and TeNT induces perturbations of the fusogenic SNARE complex dynamics and how these alterations can account for the inhibition of spontaneous and evoked quantal Neurotransmitter Release by the neurotoxins.
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How botulinum and tetanus neurotoxins block Neurotransmitter Release.
Biochimie, 2000Co-Authors: Yann Humeau, Frédéric Doussau, Nancy J. Grant, Bernard PoulainAbstract:Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT) are bacterial proteins that comprise a light chain (M(r) approximately 50) disulfide linked to a heavy chain (M(r) approximately 100). By inhibiting Neurotransmitter Release at distinct synapses, these toxins cause two severe neuroparalytic diseases, tetanus and botulism. The cellular and molecular modes of action of these toxins have almost been deciphered. After binding to specific membrane acceptors, BoNTs and TeNT are internalized via endocytosis into nerve terminals. Subsequently, their light chain (a zinc-dependent endopeptidase) is translocated into the cytosolic compartment where it cleaves one of three essential proteins involved in the exocytotic machinery: vesicle associated membrane protein (also termed synaptobrevin), syntaxin, and synaptosomal associated protein of 25 kDa. The aim of this review is to explain how the proteolytic attack at specific sites of the targets for BoNTs and TeNT induces perturbations of the fusogenic SNARE complex dynamics and how these alterations can account for the inhibition of spontaneous and evoked quantal Neurotransmitter Release by the neurotoxins.
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Tetanus and botulinum-B neurotoxins block Neurotransmitter Release by proteolytic cleavage of synaptobrevin
Nature, 1992Co-Authors: Giampietro G. Schiavo, Bibhuti R. Dasgupta, Ornella Rossetto, Bernard Poulain, Patrizia Polverino De Laureto, Fabio Benfenati, Cesare MontecuccoAbstract:CLOSTRIDIAL neurotoxins, including tetanus toxin and the seven serotypes of botulinum toxin (A–G), are produced as single chains and cleaved to generate toxins with two chains joined by a single disulphide bond (Fig. 1). The heavy chain (M_r 100,000 (100K)) is responsible for specific binding to neuronal cells and cell penetration of the light chain (50K), which blocks Neurotransmitter Release^1–9. Several lines of evidence have recently suggested that clostridial neurotoxins could be zinc endopeptidases^2,10–14. Here we show that tetanus and botulinum toxins serotype B are zinc endopeptidases, the activation of which requires reduction of the interchain disulphide bond. The protease activity is localized on the light chain and is specific for synaptobrevin, an integral membrane protein of small synaptic vesicles. The rat synaptobrevin-2 isoform is cleaved by both neurotoxins at the same single site, the peptide bond Gln76-Phe77, but the isoform synaptobrevin-1, which has a valine at the corresponding position, is not cleaved. The blocking of Neurotransmitter Release of Aplysia neurons injected with tetanus toxin or botulinum toxin serotype B is substantially delayed by peptides containing the synaptobrevin-2 cleavage site. These results indicate that tetanus and botulinum B neurotoxins block Neurotransmitter Release by cleaving synaptobrevin-2, a protein that, on the basis of our results, seems to play a key part in Neurotransmitter Release.
George J Augustine - One of the best experts on this subject based on the ideXlab platform.
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how does calcium trigger Neurotransmitter Release
Current Opinion in Neurobiology, 2001Co-Authors: George J AugustineAbstract:Abstract Recent work has established that different geometric arrangements of calcium channels are found at different presynaptic terminals, leading to a wide spectrum of calcium signals for triggering Neurotransmitter Release. These calcium signals are apparently transduced by synaptotagmins — calcium-binding proteins found in synaptic vesicles. New biochemical results indicate that all synaptotagmins undergo calcium-dependent interactions with membrane lipids and a number of other presynaptic proteins, but which of these interactions is responsible for calcium-triggered transmitter Release remains unclear.
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The actin cytoskeleton and Neurotransmitter Release: an overview.
Biochimie, 2000Co-Authors: Frédéric Doussau, George J AugustineAbstract:Here we review evidence that actin and its binding partners are involved in the Release of Neurotransmitters at synapses. The spatial and temporal characteristics of Neurotransmitter Release are determined by the distribution of synaptic vesicles at the active zones, presynaptic sites of secretion. Synaptic vesicles accumulate near active zones in a readily releasable pool that is docked at the plasma membrane and ready to fuse in response to calcium entry and a secondary, reserve pool that is in the interior of the presynaptic terminal. A network of actin filaments associated with synaptic vesicles might play an important role in maintaining synaptic vesicles within the reserve pool. Actin and myosin also have been implicated in the translocation of vesicles from the reserve pool to the presynaptic plasma membrane. Refilling of the readily releasable vesicle pool during intense stimulation of Neurotransmitter Release also implicates synapsins as reversible links between synaptic vesicles and actin filaments. The diversity of actin binding partners in nerve terminals suggests that actin might have presynaptic functions beyond synaptic vesicle tethering or movement. Because most of these actin-binding proteins are regulated by calcium, actin might be a pivotal participant in calcium signaling inside presynaptic nerve terminals. However, there is no evidence that actin participates in fusion of synaptic vesicles.
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SNARE proteins and the timing of Neurotransmitter Release
Molecular psychiatry, 1998Co-Authors: Felix E. Schweizer, George J AugustineAbstract:The SNARE complex proteins have been implicated in exocytotic Neurotransmitter Release and other forms of membrane fusion. Recent work shows that NSF, the ATPase of the SNARE complex, regulates the kinetics of Neurotransmitter Release and can thereby control the integrative properties of synapses.
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Two sites of action for synapsin domain E in regulating Neurotransmitter Release.
Nature neuroscience, 1998Co-Authors: Sabine Hilfiker, Felix E. Schweizer, Andrew J Czernik, Paul Greengard, Hung-teh Kao, George J AugustineAbstract:Synapsins, a family of synaptic vesicle proteins, have been shown to regulate Neurotransmitter Release; the mechanism(s) by which they act are not fully understood. Here we have studied the role of domain E of synapsins in Neurotransmitter Release at the squid giant synapse. Two squid synapsin isoforms were cloned and found to contain a carboxy (C)-terminal domain homologous to domain E of the vertebrate a-type synapsin isoforms. Presynaptic injection of a peptide fragment of domain E greatly reduced the number of synaptic vesicles in the periphery of the active zone, and increased the rate and extent of synaptic depression, suggesting that domain E is essential for synapsins to regulate a reserve pool of synaptic vesicles. Domain E peptide had no effect on the number of docked synaptic vesicles, yet reversibly inhibited and slowed the kinetics of Neurotransmitter Release, indicating a second role for synapsins that is more intimately associated with the Release process itself. Thus, synapsin domain E is involved in at least two distinct reactions that are crucial for exocytosis in presynaptic terminals.
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Regulation of Neurotransmitter Release Kinetics by NSF
Science (New York N.Y.), 1998Co-Authors: Felix E. Schweizer, George J Augustine, Thomas Dresbach, William M. Debello, Vincent O'connor, Heinrich BetzAbstract:NSF (N-ethylmaleimide-sensitive factor) is an adenosine triphosphatase (ATPase) that contributes to a protein complex essential for membrane fusion. The synaptic function of this protein was investigated by injecting, into the giant presynaptic terminal of squid, peptides that inhibit the ATPase activity of NSF stimulated by the soluble NSF attachment protein (SNAP). These peptides reduced the amount and slowed the kinetics of Neurotransmitter Release as a result of actions that required vesicle turnover and occurred at a step subsequent to vesicle docking. These results define NSF as an essential participant in synaptic vesicle exocytosis that regulates the kinetics of Neurotransmitter Release and, thereby, the integrative properties of synapses.
Yann Humeau - One of the best experts on this subject based on the ideXlab platform.
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A role for phospholipase D1 in Neurotransmitter Release
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Yann Humeau, Nicolas Vitale, Sylvette Chasserot-golaz, Jean-luc Dupont, Michael A. Frohman, Marie-france Bader, Bernard PoulainAbstract:Phosphatidic acid produced by phospholipase D (PLD) as a result of signaling activity is thought to play a role in membrane vesicle trafficking, either as an intracellular messenger or as a cone-shaped lipid that promotes membrane fusion. We recently described that, in neuroendocrine cells, plasma membrane-associated PLD1 operates at a stage of Ca2+-dependent exocytosis subsequent to cytoskeletal-mediated recruitment of secretory granules to exocytotic sites. We show here that PLD1 also plays a crucial role in Neurotransmitter Release. Using purified rat brain synaptosomes subjected to hypotonic lysis and centrifugation, we found that PLD1 is associated with the particulate fraction containing the plasma membrane. Immunostaining of rat cerebellar granule cells confirmed localization of PLD1 at the neuronal plasma membrane in zones specialized for Neurotransmitter Release (axonal neurites, varicosities, and growth cone-like structures). To determine the potential involvement of PLD1 in Neurotransmitter Release, we microinjected catalytically inactive PLD1(K898R) into Aplysia neurons and analyzed its effects on evoked acetylcholine (ACh) Release. PLD1(K898R) produced a fast and potent dose-dependent inhibition of ACh Release. By analyzing paired-pulse facilitation and postsynaptic responses evoked by high-frequency stimulations, we found that the exocytotic inhibition caused by PLD1(K898R) was not the result of an alteration in stimulus-secretion coupling or in vesicular trafficking. Analysis of the fluctuations in amplitude of the postsynaptic responses revealed that the PLD1(K898R) blocked ACh Release by reducing the number of active presynaptic-releasing sites. Our results provide evidence that PLD1 plays a major role in neurotransmission, most likely by controlling the fusogenic status of presynaptic Release sites.
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how botulinum and tetanus neurotoxins block Neurotransmitter Release
Biochimie, 2000Co-Authors: Yann Humeau, Frédéric Doussau, Nancy J. Grant, Bernard PoulainAbstract:Abstract Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT) are bacterial proteins that comprise a light chain ( M r ≈50) disulfide linked to a heavy chain ( M r ≈100). By inhibiting Neurotransmitter Release at distinct synapses, these toxins cause two severe neuroparalytic diseases, tetanus and botulism. The cellular and molecular modes of action of these toxins have almost been deciphered. After binding to specific membrane acceptors, BoNTs and TeNT are internalized via endocytosis into nerve terminals. Subsequently, their light chain (a zinc-dependent endopeptidase) is translocated into the cytosolic compartment where it cleaves one of three essential proteins involved in the exocytotic machinery: vesicle associated membrane protein (also termed synaptobrevin), syntaxin, and synaptosomal associated protein of 25 kDa. The aim of this review is to explain how the proteolytic attack at specific sites of the targets for BoNTs and TeNT induces perturbations of the fusogenic SNARE complex dynamics and how these alterations can account for the inhibition of spontaneous and evoked quantal Neurotransmitter Release by the neurotoxins.
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How botulinum and tetanus neurotoxins block Neurotransmitter Release.
Biochimie, 2000Co-Authors: Yann Humeau, Frédéric Doussau, Nancy J. Grant, Bernard PoulainAbstract:Botulinum neurotoxins (BoNT, serotypes A-G) and tetanus neurotoxin (TeNT) are bacterial proteins that comprise a light chain (M(r) approximately 50) disulfide linked to a heavy chain (M(r) approximately 100). By inhibiting Neurotransmitter Release at distinct synapses, these toxins cause two severe neuroparalytic diseases, tetanus and botulism. The cellular and molecular modes of action of these toxins have almost been deciphered. After binding to specific membrane acceptors, BoNTs and TeNT are internalized via endocytosis into nerve terminals. Subsequently, their light chain (a zinc-dependent endopeptidase) is translocated into the cytosolic compartment where it cleaves one of three essential proteins involved in the exocytotic machinery: vesicle associated membrane protein (also termed synaptobrevin), syntaxin, and synaptosomal associated protein of 25 kDa. The aim of this review is to explain how the proteolytic attack at specific sites of the targets for BoNTs and TeNT induces perturbations of the fusogenic SNARE complex dynamics and how these alterations can account for the inhibition of spontaneous and evoked quantal Neurotransmitter Release by the neurotoxins.
Ege T. Kavalali - One of the best experts on this subject based on the ideXlab platform.
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Presynaptic origins of distinct modes of Neurotransmitter Release
Current opinion in neurobiology, 2018Co-Authors: Natali L. Chanaday, Ege T. KavalaliAbstract:Presynaptic nerve terminals Release Neurotransmitter synchronously, asynchronously or spontaneously. During synchronous neurotransmission Release is precisely coupled to action potentials, in contrast, asynchronous Release events show only loose temporal coupling to presynaptic activity whereas spontaneous neurotransmission occurs independent of presynaptic activity. The mechanisms that give rise to this diversity in Neurotransmitter Release modes are poorly understood. Recent studies have described several presynaptic molecular pathways controlling synaptic vesicle pool segregation and recycling, which in turn may dictate distinct modes of Neurotransmitter Release. In this article, we review this recent work regarding Neurotransmitter Release modes and their relationship to synaptic vesicle pool dynamics as well as the molecular machinery that establishes synaptic vesicle pool identity.
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the mechanisms and functions of spontaneous Neurotransmitter Release
Nature Reviews Neuroscience, 2015Co-Authors: Ege T. KavalaliAbstract:It was traditionally assumed that the spontaneous Release of Neurotransmitter-containing vesicles at neuronal synapses results from the random activation of the vesicle fusion machinery that underlies action potential-driven evoked Release. However, the recent evidence described by Kavalali in this Review now suggests that the mechanisms, regulation and functions of spontaneous Neurotransmitter Release are distinct from those of evoked neurotransmission.
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Differential regulation of spontaneous and evoked Neurotransmitter Release at central synapses
Current opinion in neurobiology, 2011Co-Authors: Denise M.o. Ramirez, Ege T. KavalaliAbstract:Recent studies have begun to scrutinize the presynaptic machinery and vesicle populations that give rise to action potential evoked and spontaneous forms of Neurotransmitter Release. In several cases this work produced unexpected results which lend support to the notion that regulation, mechanisms, postsynaptic targets and possibly presynaptic origins of evoked and spontaneous Neurotransmitter Release differ. Furthermore, the list of regulatory pathways that impact spontaneous and evoked Release in a divergent manner is rapidly growing. These findings challenge our classical views on the relationship between evoked and spontaneous neurotransmission. In contrast to the well-characterized neuromodulatory pathways that equally suppress or augment all forms of Neurotransmitter Release, molecular substrates specifically controlling spontaneous Release remain unclear. In this review, we outline possible mechanisms that may underlie the differential regulation of distinct forms of neurotransmission and help demultiplex complex neuronal signals and generate parallel signaling events at their postsynaptic targets.
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Pharmacology of Neurotransmitter Release: Measuring Exocytosis
Handbook of experimental pharmacology, 2008Co-Authors: Mikhail Khvotchev, Ege T. KavalaliAbstract:Neurotransmission in the nervous system is initiated at presynaptic terminals by fusion of synaptic vesicles with the plasma membrane and subsequent exocytic Release of chemical transmitters. Currently, there are multiple methods to detect Neurotransmitter Release from nerve terminals, each with their own particular advantages and disadvantages. For instance, most commonly employed methods monitor actions of Released chemical substances on postsynaptic receptors or artificial substrates such as carbon fibers. These methods are closest to the physiological setting because they have a rapid time resolution and they measure the action of the endogenous Neurotransmitters rather than the signals emitted by exogenous probes. However, postsynaptic receptors only indirectly report Neurotransmitter Release in a form modified by the properties of receptors themselves, which are often nonlinear detectors of Released substances. Alternatively, Released chemical substances can be detected biochemically, albeit on a time scale slower than electrophysiological methods. In addition, in certain preparations, where presynaptic terminals are accessible to whole cell recording electrodes, fusion of vesicles with the plasma membrane can be monitored using capacitance measurements, In the last decade, in addition to electrophysiological and biochemical methods, several fluorescence imaging modalities have been introduced which report synaptic vesicle fusion, endocytosis, and recycling. These methods either take advantage of styryl dyes that can be loaded into recycling vesicles or exogenous expression of synaptic vesicle proteins tagged with a pH-sensitive GFP variant at regions facing the vesicle lumen. In this chapter, we will provide an overview of these methods with particular emphasis on their relative strengths and weaknesses and discuss the types of information one can obtain from them.