The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Joshua M Kaplan - One of the best experts on this subject based on the ideXlab platform.
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a hyperactive form of unc 13 enhances ca2 sensitivity and Synaptic Vesicle Release probability in c elegans
Cell Reports, 2019Co-Authors: Haowen Liu, Qi Hall, Wei Wang, Joshua M KaplanAbstract:Summary Munc13 proteins play several roles in regulating short-term Synaptic plasticity. However, the underlying molecular mechanisms remain largely unclear. Here we report that C. elegans UNC-13L, a Munc13-1 ortholog, has three domains that inhibit Synaptic Vesicle (SV) exocytosis. These include the X (sequence between C2A and C1), C1, and C2B domains. Deleting all three inhibitory domains produces a hyperactive UNC-13 (sUNC-13) that exhibits dramatically increased neurotransmitter Release, Ca2+ sensitivity of Release, and Release probability. The vesicular pool in unc-13 mutants rescued by sUNC-13 exhibits a faster Synaptic recovery and replenishment rate, demonstrating an important role of sUNC-13 in regulating Synaptic plasticity. Analysis of double mutants suggests that sUNC-13 enhances tonic Release by increasing the open probability of UNC-64/syntaxin-1A, whereas its effects on evoked Release appear to be mediated by additional functions, presumably by further regulating the activity of the assembled soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex.
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heterodimerization of unc 13 rim regulates Synaptic Vesicle Release probability but not priming in c elegans
eLife, 2019Co-Authors: Haowen Liu, Qi Hall, Daniel Nedelcu, Wei Wang, Lijun Zhou, Joshua M KaplanAbstract:UNC-13 proteins play an essential role in Synaptic transmission by recruiting Synaptic Vesicles (SVs) to become available for Release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L's C2A promotes Synaptic transmission by regulating a post-priming process. Stimulus-evoked Release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased Release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on Synaptic transmission, but fully restored the evoked Release and the Release probability of unc-10/RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A Releases UNC-13L from an autoinhibitory homodimeric complex to become fusion-competent by functioning as a switch only.
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heterodimerization of unc 13 rim regulates Synaptic Vesicle Release probability but not priming
bioRxiv, 2018Co-Authors: Joshua M Kaplan, Qi Hall, Haowen Liu, Daniel Nedelcu, Wei Wang, Lijun ZhouAbstract:UNC-13 proteins play an essential role in Synaptic transmission by recruiting Synaptic Vesicles (SVs) to become available for Release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L’s C2A promotes Synaptic transmission by regulating a post-priming process. Stimulus-evoked Release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased Release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on Synaptic transmission, but fully restored the evoked Release and the Release probability of unc-10 /RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A Releases UNC-13L from an autoinhibitory homodimeric complex to become fusion-competent by functioning as a switch only.
John F Wesseling - One of the best experts on this subject based on the ideXlab platform.
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elevated Synaptic Vesicle Release probability in synaptophysin gyrin family quadruple knockouts
eLife, 2019Co-Authors: Mathan K Raja, Reinhard Jahn, Julia Preobraschenski, Sergio Del Olmocabrera, Rebeca Martinezturrillas, Isabel Perezotano, John F WesselingAbstract:Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of Synaptic Vesicle membrane proteins. Unlike other widely expressed Synaptic Vesicle proteins such as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report robust elevation in the probability of Release of readily releasable Vesicles with both high and low Release probabilities at a variety of synapse types from knockout mice missing all four family members. Neither the number of readily releasable Vesicles, nor the timing of recruitment to the readily releasable pool was affected. The results suggest that family members serve as negative regulators of neurotransmission, acting directly at the level of exocytosis to dampen connection strength selectively when preSynaptic action potentials fire at low frequency. The widespread expression suggests that chemical synapses may play a frequency filtering role in biological computation that is more elemental than presently envisioned. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Haowen Liu - One of the best experts on this subject based on the ideXlab platform.
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a hyperactive form of unc 13 enhances ca2 sensitivity and Synaptic Vesicle Release probability in c elegans
Cell Reports, 2019Co-Authors: Haowen Liu, Qi Hall, Wei Wang, Joshua M KaplanAbstract:Summary Munc13 proteins play several roles in regulating short-term Synaptic plasticity. However, the underlying molecular mechanisms remain largely unclear. Here we report that C. elegans UNC-13L, a Munc13-1 ortholog, has three domains that inhibit Synaptic Vesicle (SV) exocytosis. These include the X (sequence between C2A and C1), C1, and C2B domains. Deleting all three inhibitory domains produces a hyperactive UNC-13 (sUNC-13) that exhibits dramatically increased neurotransmitter Release, Ca2+ sensitivity of Release, and Release probability. The vesicular pool in unc-13 mutants rescued by sUNC-13 exhibits a faster Synaptic recovery and replenishment rate, demonstrating an important role of sUNC-13 in regulating Synaptic plasticity. Analysis of double mutants suggests that sUNC-13 enhances tonic Release by increasing the open probability of UNC-64/syntaxin-1A, whereas its effects on evoked Release appear to be mediated by additional functions, presumably by further regulating the activity of the assembled soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) complex.
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heterodimerization of unc 13 rim regulates Synaptic Vesicle Release probability but not priming in c elegans
eLife, 2019Co-Authors: Haowen Liu, Qi Hall, Daniel Nedelcu, Wei Wang, Lijun Zhou, Joshua M KaplanAbstract:UNC-13 proteins play an essential role in Synaptic transmission by recruiting Synaptic Vesicles (SVs) to become available for Release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L's C2A promotes Synaptic transmission by regulating a post-priming process. Stimulus-evoked Release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased Release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on Synaptic transmission, but fully restored the evoked Release and the Release probability of unc-10/RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A Releases UNC-13L from an autoinhibitory homodimeric complex to become fusion-competent by functioning as a switch only.
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heterodimerization of unc 13 rim regulates Synaptic Vesicle Release probability but not priming
bioRxiv, 2018Co-Authors: Joshua M Kaplan, Qi Hall, Haowen Liu, Daniel Nedelcu, Wei Wang, Lijun ZhouAbstract:UNC-13 proteins play an essential role in Synaptic transmission by recruiting Synaptic Vesicles (SVs) to become available for Release, which is termed SV priming. Here we show that the C2A domain of UNC-13L, like the corresponding domain in mammalian Munc13-1, displays two conserved binding modes: forming C2A/C2A homodimers, or forming a heterodimer with the zinc finger domain of UNC-10/RIM (C2A/RIM). Functional analysis revealed that UNC-13L’s C2A promotes Synaptic transmission by regulating a post-priming process. Stimulus-evoked Release but not SV priming, was impaired in unc-10 mutants deficient for C2A/RIM heterodimerization, leading to decreased Release probability. Disrupting C2A/C2A homodimerization in UNC-13L-rescued animals had no effect on Synaptic transmission, but fully restored the evoked Release and the Release probability of unc-10 /RIM mutants deficient for C2A/RIM heterodimerization. Thus, our results support the model that RIM binding C2A Releases UNC-13L from an autoinhibitory homodimeric complex to become fusion-competent by functioning as a switch only.
Osvaldo Delbono - One of the best experts on this subject based on the ideXlab platform.
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aging blunts sympathetic neuron regulation of motoneurons Synaptic Vesicle Release mediated by β1 and α2b adrenergic receptors in geriatric mice
Journals of Gerontology Series A-biological Sciences and Medical Sciences, 2020Co-Authors: Zhongmin Wang, Anna Carolina Zaia Rodrigues, Maria Laura Messi, Osvaldo DelbonoAbstract:This study was designed to determine whether and how the sympathetic nervous system (SNS) regulates motoneuron axon function and neuromuscular transmission in young (3-4-month) and geriatric (31-month) mice. Our approach included sciatic-peroneal nerve immunolabeling coregistration, and electrophysiological recordings in a novel mouse ex-vivo preparation, the sympathetic-peroneal nerve-lumbricalis muscle (SPNL). Here, the interaction between the motoneuron and SNS at the neuromuscular junction (NMJ) and muscle innervation reflect the complexity of the living mouse. Our data show that electrical stimulation of the sympathetic neuron at the paravertebral ganglia chain enhances motoneuron Synaptic Vesicle Release at the NMJ in young mice, while in geriatric mice, this effect is blunted. We also found that blocking β-AR prevents the sympathetic neuron from increasing NMJ transmission. Immunofluorescence coexpression analysis of immunolabeled ARs with choline acetyltransferase-, tyrosine hydroxylase-, or calcitonin gene-related peptide immunoreactive axons showed that α2B-AR is found mainly in sympathetic neurons, β1-AR in sympathetic- and motor-neurons, and both decline significantly with aging. In summary, this study unveils the molecular substrate accounting for the influence of endogenous sympathetic neurons on motoneuron-muscle transmission in young mice and its decline with aging.
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sympathomimetics regulate neuromuscular junction transmission through trpv1 p q and n type ca2 channels
Molecular and Cellular Neuroscience, 2019Co-Authors: Anna Zaia Carolina Rodrigues, Zhongmin Wang, Maria Laura Messi, Osvaldo DelbonoAbstract:Abstract Increasing evidence indicates that, first, the sympathetic nervous system interacts extensively with both vasculature and skeletal muscle fibers near neuromuscular junctions (NMJs) and, second, its neurotransmitter, noradrenaline, influences myofiber molecular composition and function and motor innervation. Since sympathomimetic agents have been reported to improve NMJ transmission, we examined whether two in clinical use, salbutamol and clenbuterol, affect the motor axon terminal via extracellular Ca2+ and molecular targets, such as TRPV1 and P/Q- and N-type voltage-activated Ca2+ channels. Electrophysiological recordings in ex-vivo preparations of peroneal nerves and lumbricalis muscles from young adult mice focused on spontaneous miniature end-plate potentials and singly and repetitively evoked end-plate potentials. Adding one dose of salbutamol or clenbuterol to the nerve/muscle preparation or repeatedly administering salbutamol to a mouse for 4 weeks increased spontaneous and evoked Synaptic Vesicle Release but induced a steep decline in EPP amplitude in response to repetitive nerve stimulation. These effects were mediated primarily by ω-agatoxin IVA-sensitive P/Q-type and secondarily by ω-conotoxin GVIA-sensitive N-type Ca2+ channels. PreSynaptic arvanil-sensitive TRPV1 channels seem to regulate Ca2+ at the motor neuron terminal at rest, while putative preSynaptic β-adrenergic receptors may mediate sympathomimetic and catecholamine effects on preSynaptic Ca2+ channels during NMJ activation.
Yishi Jin - One of the best experts on this subject based on the ideXlab platform.
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position of unc 13 in the active zone regulates Synaptic Vesicle Release probability and Release kinetics
eLife, 2013Co-Authors: Keming Zhou, Tamara M Stawicki, Alexandr Goncharov, Yishi JinAbstract:The preSynaptic active zone proteins UNC-13/Munc13s are essential for Synaptic Vesicle (SV) exocytosis by directly interacting with SV fusion apparatus. An open question is how their association with active zones, hence their position to Ca(2+) entry sites, regulates SV Release. The N-termini of major UNC-13/Munc13 isoforms contain a non-calcium binding C2A domain that mediates protein homo- or hetero-meric interactions. Here, we show that the C2A domain of Caenorhabditis elegans UNC-13 regulates Release probability of evoked Release and its precise active zone localization. Kinetics analysis of SV Release supports that the proximity of UNC-13 to Ca(2+) entry sites, mediated by the C2A-domain containing N-terminus, is critical for accelerating neurotransmitter Release. Additionally, the C2A domain is specifically required for spontaneous Release. These data reveal multiple roles of UNC-13 C2A domain, and suggest that spontaneous Release and the fast phase of evoked Release may involve a common pool of SVs at the active zone. DOI: http://dx.doi.org/10.7554/eLife.01180.001.
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defective recycling of Synaptic Vesicles in synaptotagmin mutants of caenorhabditis elegans
Nature, 1995Co-Authors: Michael L Nonet, Yishi Jin, Erik M Jorgensen, Erika Hartwieg, Kim Schuske, Robert H HorvitzAbstract:SYNAPTOTAGMIN, an integral membrane protein of the Synaptic Vesicle1,2, binds calcium and interacts with proteins of the plasma membrane4–6. These observations suggest several possible functions for synaptotagmin in Synaptic Vesicle dynamics: it could facilitate exocytosis by promoting calcium-dependent fusion3, inhibit exocytosis by preventing fusion7, or facilitate endocytosis of Synaptic Vesicles from the plasma membrane by acting as a receptor for the endocytotic proteins of the clathrin AP2 complex8. Here we show that Synaptic Vesicles are depleted at Synaptic terminals in synaptotagmin mutants of the nematode Caenorhabditis elegans. This depletion is not caused by a defect in transport or by increased Synaptic Vesicle Release, but rather by a defect in retrieval of Synaptic Vesicles from the plasma membrane. Thus we propose that, as well as being involved in exocytosis, synaptotagmin functions in vesicular recycling.
