The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Thomas C Sudhof - One of the best experts on this subject based on the ideXlab platform.
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Synaptic vesicle exocytosis
Cold Spring Harbor Perspectives in Biology, 2011Co-Authors: Thomas C Sudhof, Josep RizoAbstract:PreSynaptic nerve terminals release neurotransmitters by Synaptic vesicle exocytosis. Membrane fusion mediating Synaptic exocytosis and other intracellular Membrane traffic is affected by a universal machinery that includes SNARE (for "soluble NSF-attachment protein receptor") and SM (for "Sec1/Munc18-like") proteins. During fusion, vesicular and target SNARE proteins assemble into an α-helical trans-SNARE complex that forces the two Membranes tightly together, and SM proteins likely wrap around assembling trans-SNARE complexes to catalyze Membrane fusion. After fusion, SNARE complexes are dissociated by the ATPase NSF (for "N-ethylmaleimide sensitive factor"). Fusion-competent conformations of SNARE proteins are maintained by chaperone complexes composed of CSPα, Hsc70, and SGT, and by nonenzymatically acting synuclein chaperones; dysfunction of these chaperones results in neurodegeneration. The Synaptic Membrane-fusion machinery is controlled by synaptotagmin, and additionally regulated by a preSynaptic protein matrix (the "active zone") that includes Munc13 and RIM proteins as central components.
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rab3 and synaptotagmin the yin and yang of Synaptic Membrane fusion
Annual Review of Neuroscience, 1998Co-Authors: Martin Geppert, Thomas C SudhofAbstract:▪ Abstract Synaptic vesicle exocytosis occurs in consecutive steps: docking, which specifically attaches vesicles to the active zone; priming, which makes the vesicles competent for Ca2+-triggered release and may involve a partial fusion reaction; and the final Ca2+-regulated step that completes fusion. Recent evidence suggests that the critical regulation of the last step in the reaction is mediated by two proteins with opposite actions: synaptotagmin, a Ca2+-binding protein that is essential for Ca2+-triggered release and probably serves as the Ca2+-sensor in fusion, and rab3, which limits the number of vesicles that can be fused as a function of Ca2+ in order to allow a temporally limited, repeatable signal.
Reed C Carroll - One of the best experts on this subject based on the ideXlab platform.
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ampar exocytosis through no modulation of pick1
Neuropharmacology, 2007Co-Authors: Kenneth G Sossa, Jennifer B Beattie, Reed C CarrollAbstract:The activation of NMDA receptors (NMDARs) triggers long-term changes in AMPA receptor-mediated Synaptic transmission in the CNS. These long-lasting changes occur via the addition or removal of AMPA receptors (AMPARs) at the Synaptic Membrane and are mediated by a number of regulatory proteins including the GluR2 AMPAR-interacting proteins n-ethylmaleimide sensitive factor (NSF) and Protein Interacting with C Kinase (PICK1). We have shown that the potent activation of NMDARs drives unclustering of PICK1 and PICK1-GluR2 dissociation in dendrites resulting in increased surface delivery of AMPARs. Here we show that the dispersal of PICK1 is mediated by the actions of NSF. We find that elevated NMDAR signaling leads to the S-nitrosylation of NSF and increased NSF-GluR2 association. Both NMDAR-dependent unclustering of PICK1 and the delivery of surface AMPARs are dependent on release of nitric oxide (NO). Our data suggest that NMDAR activation can drive the surface delivery of AMPARs from a pool of intracellular AMPARs retained by PICK1 through the NO-dependent modification of NSF.
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nmda receptor trafficking and targeting implications for Synaptic transmission and plasticity
Trends in Neurosciences, 2002Co-Authors: Reed C Carroll, Suzanne R ZukinAbstract:Abstract Dynamic regulation of Synaptic efficacy is thought to play a crucial role in formation of neuronal connections and in experience-dependent modification of neural circuitry. The molecular and cellular mechanisms by which Synaptic changes are triggered and expressed are the focus of intense interest. This articles reviews recent evidence that NMDA receptors undergo dynamically regulated targeting and trafficking, and that the physical transport of NMDA receptors in and out of the Synaptic Membrane contributes to several forms of long-lasting Synaptic plasticity. The identification of targeting and internalization sequences in NMDA-receptor subunits has begun the unraveling of some mechanisms that underlie activity-dependent redistribution of NMDA receptors. Given that NMDA receptors are widely expressed throughout the CNS, regulation of NMDA-receptor trafficking provides a potentially important way to modulate efficacy of Synaptic transmission.
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role of ampa receptor endocytosis in Synaptic plasticity
Nature Reviews Neuroscience, 2001Co-Authors: Reed C Carroll, Eric C Beattie, M Von Zastrow, Robert C MalenkaAbstract:Activity-mediated changes in the strength of Synaptic communication are important for the establishment of proper neuronal connections during development and for the experience-dependent modification of neural circuitry that is believed to underlie all forms of behavioural plasticity. Owing to the wide-ranging significance of Synaptic plasticity, considerable efforts have been made to identify the mechanisms by which Synaptic changes are triggered and expressed. New evidence indicates that one important expression mechanism of several long-lasting forms of Synaptic plasticity might involve the physical transport of AMPA-type glutamate receptors in and out of the Synaptic Membrane. Here, we focus on the rapidly accumulating evidence that AMPA receptors undergo regulated endocytosis, which is important for long-term depression.
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role of ampa receptor cycling in Synaptic transmission and plasticity
Neuron, 1999Co-Authors: Christian Luscher, Reed C Carroll, Houhui Xia, Eric C Beattie, Mark Von Zastrow, Robert C Malenka, Roger A NicollAbstract:Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postSynaptic currents (EPSCs). Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the subsequent induction of LTD. These results suggest that AMPARs, but not NMDARs, cycle into and out of the Synaptic Membrane at a rapid rate and that certain forms of Synaptic plasticity may utilize this dynamic process.
Qi Zhang - One of the best experts on this subject based on the ideXlab platform.
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reciprocal modulation between amyloid precursor protein and Synaptic Membrane cholesterol revealed by live cell imaging
Neurobiology of Disease, 2019Co-Authors: Claire E Delbove, Claire E Strothman, Roman M Lazarenko, Hui Huang, Charles R Sanders, Qi ZhangAbstract:The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer's disease (AD). However, APP distribution across different subcellular Membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APP's distribution, subcellular trafficking, and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between Synaptic activities and APP trafficking. However, the Synaptic surface fraction of APP was increased by a reduction in Membrane cholesterol levels, a phenomenon that involves APP's cholesterol-binding motif. Mutations at or near binding sites not only reduced both the surface fraction of APP and Membrane cholesterol levels in a dominant negative manner, but also increased Synaptic vulnerability to moderate Membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and Membrane cholesterol levels at Synaptic boutons.
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reciprocal modulation between amyloid precursor protein and Synaptic Membrane cholesterol revealed by live cell imaging
bioRxiv, 2018Co-Authors: Claire E Delbove, Claire E Strothman, Roman M Lazarenko, Hui Huang, Charles R Sanders, Qi ZhangAbstract:The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer9s disease (AD). However, APP distribution across different subcellular Membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APP9s distribution, subcellular trafficking and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between Synaptic activities and APP trafficking. However, the Synaptic surface distribution of APP was inversely correlated to Membrane cholesterol levels, a phenomenon that involves APP9s cholesterol-binding site. Mutations within this site not only altered surface APP and cholesterol levels in a dominant negative manner, but also increased Synaptic vulnerability to moderate Membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and Membrane cholesterol levels at Synaptic boutons.
Jose A Esteban - One of the best experts on this subject based on the ideXlab platform.
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local control of ampa receptor trafficking at the postSynaptic terminal by a small gtpase of the rab family
Journal of Biological Chemistry, 2004Co-Authors: Nashaat Z Gerges, Donald S Backos, Jose A EstebanAbstract:Abstract The delivery of neurotransmitter receptors into the Synaptic Membrane is essential for Synaptic function and plasticity. However, the molecular mechanisms of these specialized trafficking events and their integration with the intracellular Membrane transport machinery are virtually unknown. Here, we have investigated the role of the Rab family of Membrane sorting proteins in the late stages of receptor trafficking into the postSynaptic Membrane. We have identified Rab8, a vesicular transport protein associated with trans-Golgi network Membranes, as a critical component of the cellular machinery that delivers AMPA-type glutamatergic receptors (AMPARs) into synapses. Using electron microscopic techniques, we have found that Rab8 is localized in close proximity to the Synaptic Membrane, including the postSynaptic density. Electrophysiological studies indicated that Rab8 is necessary for the Synaptic delivery of AMPARs during plasticity (long-term potentiation) and during constitutive receptor cycling. In addition, Rab8 is required for AMPAR delivery into the spine surface, but not for receptor transport from the dendritic shaft into the spine compartment or for delivery into the dendritic surface. Therefore, Rab8 specifically drives the local delivery of AMPARs into synapses. These results demonstrate a new role for the cellular secretory machinery in the control of Synaptic function and plasticity directly at the postSynaptic Membrane.
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local control of ampa receptor trafficking at the postSynaptic terminal by a small gtpase of the rab family
Journal of Biological Chemistry, 2004Co-Authors: Nashaat Z Gerges, Donald S Backos, Jose A EstebanAbstract:Abstract The delivery of neurotransmitter receptors into the Synaptic Membrane is essential for Synaptic function and plasticity. However, the molecular mechanisms of these specialized trafficking events and their integration with the intracellular Membrane transport machinery are virtually unknown. Here, we have investigated the role of the Rab family of Membrane sorting proteins in the late stages of receptor trafficking into the postSynaptic Membrane. We have identified Rab8, a vesicular transport protein associated with trans-Golgi network Membranes, as a critical component of the cellular machinery that delivers AMPA-type glutamatergic receptors (AMPARs) into synapses. Using electron microscopic techniques, we have found that Rab8 is localized in close proximity to the Synaptic Membrane, including the postSynaptic density. Electrophysiological studies indicated that Rab8 is necessary for the Synaptic delivery of AMPARs during plasticity (long-term potentiation) and during constitutive receptor cycling. In addition, Rab8 is required for AMPAR delivery into the spine surface, but not for receptor transport from the dendritic shaft into the spine compartment or for delivery into the dendritic surface. Therefore, Rab8 specifically drives the local delivery of AMPARs into synapses. These results demonstrate a new role for the cellular secretory machinery in the control of Synaptic function and plasticity directly at the postSynaptic Membrane.
Mark A Breidenbach - One of the best experts on this subject based on the ideXlab platform.
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highly specific interactions between botulinum neurotoxins and Synaptic vesicle proteins
Cellular and Molecular Life Sciences, 2008Co-Authors: Axel T Brunger, Mark A BreidenbachAbstract:Despite its extreme toxicity, botulinum neurotoxin is widely utilized in low doses as a treatment for several neurological disorders; higher doses cause the neuroparalytic syndrome botulism. The toxin blocks neurotransmitter release by preferentially attaching to pre-Synaptic Membrane receptors at neuromuscular junctions and subsequently delivering a Zn 2+-dependent protease component to preSynaptic neuronal cytosol. These highly specialized enzymes exclusively hydrolyze peptide bonds within SNARE (soluble N-ethylmaleiamide sensitive factor attachment protein receptor) proteins. In this review we discuss the structural basis for botulinum toxin’s exquisite specificity for its neuronal cell-surface receptors and intracellular SNARE targets.
