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https://www.readbyqxmd.com/read/29615494/small-molecules-that-inhibit-the-late-stage-of-munc13-4-dependent-secretory-granule-exocytosis-in-mast-cells
#1
Stephen Bruinsma, Declan J James, Melanie Quintana Serrano, Joseph Esquibel, Sang Su Woo, Elle Kielar-Grevstad, Ellen Crummy, Rehan Quraishi, Judy A Kowalchyk, Thomas F J Martin
Ca2+ -dependent secretory granule fusion with the plasma membrane is the final step for the exocytic release of inflammatory mediators, neuropeptides, and peptide hormones. Secretory cells use a similar protein machinery at late steps in the regulated secretory pathway employing protein isoforms from Rab, Sec1/Munc18, Munc13/CAPS, SNARE, and synaptotagmin protein families. However, no small molecule inhibitors of secretory granule exocytosis that target these proteins are currently available, but could have clinical utility...
April 3, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29599294/munc18-2-but-not-munc18-1-or-munc18-3-controls-compound-and-single-vesicle-regulated-exocytosis-in-mast-cells
#2
Berenice A Gutierrez, Miguel A Chavez, Alejandro I Rodarte, Marco Ramos, Andrea Dominguez, Youlia Petrova, Alfredo J Davalos, Renan M Costa, Ramon Elizondo, Michael J Tuvim, Burton F Dickey, Alan R Burns, Ruth Heidelberger, Roberto Adachi
Mast cells (MCs) play pivotal roles in many inflammatory conditions including infections, anaphylaxis and asthma. MCs store immunoregulatory compounds in their large cytoplasmic granules and, upon stimulation, secrete them via regulated exocytosis. Exocytosis in many cells requires the participation of Munc18 proteins (also known as syntaxin-binding proteins), and we found that mature MCs express all three mammalian isoforms: Munc18 1, 2 and 3. To study their functions in MC effector responses and test the role of MC degranulation in anaphylaxis, we used conditional knockout (cKO) mice in which each Munc18 protein was deleted exclusively in MCs...
March 29, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29548989/snap-25a-and-snap-25b-differently-mediate-interactions-with-munc18-1-and-g%C3%AE-%C3%AE-subunits
#3
Teresa Daraio, Ismael Valladolid-Acebes, Kerstin Brismar, Christina Bark
SNAP-25 is a protein involved in regulated membrane fusion and part of the SNARE complex. It exists as two splicing variants, SNAP-25a and SNAP-25b, which differ in 9 out of 206 amino acids. SNAP-25 together with Syntaxin 1 and VAMP-2 forms the ternary SNARE complex essential for mediating activity-dependent release of hormones and neurotransmitters. The functional difference between SNAP-25a and SNAP-25b is poorly understood as both can participate in SNARE complexes and mediate membrane fusion. However, we recently demonstrated that SNAP-25b-deficiency results in metabolic disease and increased insulin secretion...
March 13, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29538625/protein-instability-haploinsufficiency-and-cortical-hyper-excitability-underlie-stxbp1-encephalopathy
#4
Jovana Kovacevic, Gregoire Maroteaux, Desiree Schut, Maarten Loos, Mohit Dubey, Julika Pitsch, Esther Remmelink, Bastijn Koopmans, James Crowley, L Niels Cornelisse, Patrick F Sullivan, Susanne Schoch, Ruud F Toonen, Oliver Stiedl, Matthijs Verhage
De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background...
March 12, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29419372/snare-encoding-genes-vdsec22-and-vdsso1-mediate-protein-secretion-required-for-full-virulence-in-verticillium-dahliae
#5
Jie Wang, Li Tian, Dandan Zhang, Dylan P G Short, Lei Zhou, Shuangshuang Song, Yan Liu, Dan Wang, Zhiqiang Kong, Weiye Cui, Xuefeng Ma, Steven J Klosterman, Krishna Subbarao, Jie-Yin Chen, Xiaofeng Dai
Proteins that mediate cellular and subcellular membrane fusion are key factors in vesicular trafficking in all eukaryotic cells, including the secretion and transport of plant pathogen virulence factors. In this study, we identified vesicle fusion components that included 22 soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), 4 Sec1/Munc18 (SM) family proteins, and 10 Rab GTPases encoded in the genome of the vascular wilt pathogen, Verticillium dahliae strain Vd991. Targeted deletion of two SNARE-encoding genes in V...
February 8, 2018: Molecular Plant-microbe Interactions: MPMI
https://www.readbyqxmd.com/read/29386300/in-vivo-analysis-of-a-gain-of-function-mutation-confirms-unc18-munc18-s-role-in-priming
#6
Leonardo A Parra
No abstract text is available yet for this article.
January 31, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29317735/syntaxins-on-granules-promote-docking-of-granules-via-interactions-with-munc18
#7
Maria Borisovska
SNAREs and SNARE-binding accessory proteins are believed to be central molecular components of neurotransmitter release, although the precise sequence of molecular events corresponding to distinct physiological states is unclear. The mechanism of docking of vesicles to the plasma membrane remains elusive, as the anchoring protein residing on vesicles is unknown. Here I show that targeting small amounts of syntaxin to granules by transmembrane domain alteration leads to a substantial enhancement of syntaxin clustering beneath granules, as well as of morphological granule docking...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29284677/depletion-of-the-membrane-fusion-regulator-munc18c-attenuates-caerulein-hyperstimulation-induced-pancreatitis
#8
Subhankar Dolai, Tao Liang, Abrahim I Orabi, Li Xie, Douglas Holmyard, Tanveer A Javed, Nestor A Fernandez, Huanli Xie, Mark S Cattral, Debbie C Thurmond, Peter Thorn, Herbert Y Gaisano
Epithelial pancreatic acinar cells perform crucial functions in food digestion, and acinar cell homeostasis required for secretion of digestive enzymes relies on SNARE-mediated exocytosis. The ubiquitously expressed Sec1/Munc18 protein mammalian uncoordinated-18c (Munc18c) regulates membrane fusion by activating syntaxin-4 (STX-4) to bind cognate SNARE proteins to form a SNARE complex that mediates exocytosis in many cell types. However, in the acinar cell, Munc18c's functions in exocytosis and homeostasis remain inconclusive...
February 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29218528/proximity-ligation-assay-to-study-the-glut4-membrane-trafficking-machinery
#9
Dimitrios Kioumourtzoglou, Gwyn W Gould, Nia J Bryant
In this chapter a detailed protocol of proximity ligation assay (PLA) is described thoroughly. PLA is a technique that allows detection of protein associations in situ, providing a sensitive and selective approach for protein-protein interaction studies. We demonstrate the technique by applying it for trafficking studies of the facilitative glucose transporter GLUT4. Trafficking of GLUT4 from perinuclear depots to the plasma membrane is regulated by insulin in adipocytes and muscle cells, and mediated by formation of functional SNARE complexes containing Syntaxin4, SNAP23, and VAMP2...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29217410/munc18-1-haploinsufficiency-impairs-learning-and-memory-by-reduced-synaptic-vesicular-release-in-a-model-of-ohtahara-syndrome
#10
Albert Orock, Sreemathi Logan, Ferenc Deak
Ohtahara syndrome, also known as type 4 of Early Infantile Epileptic Encephalopathy with suppression bursts (EIEE-4) is currently an untreatable disorder that presents with seizures and impaired cognition. EIEE-4 patients have mutations most frequently in the STXBP1 gene encoding a Sec protein, munc18-1. The exact molecular mechanism of how these munc18-1 mutations cause impaired cognition, remains elusive. The leading haploinsufficiency hypothesis posits that mutations in munc18-1 render the protein unstable leading to its degradation...
December 5, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29208657/assembly-of-intermediates-for-rapid-membrane-fusion
#11
Max Harner, William Wickner
Membrane fusion is essential for intracellular protein sorting, cell growth, hormone secretion, and neurotransmission. Rapid membrane fusion requires tethering and Sec1-Munc18 (SM) function to catalyze R-, Qa-, Qb-, and Qc-SNARE complex assembly in trans , as well as SNARE engagement by the SNARE-binding chaperone Sec17/αSNAP. The hexameric vacuolar HOPS (<u>ho</u>motypic fusion and vacuole<u>p</u>rotein<u>s</u>orting) complex in the yeast Saccharomyces cerevisiae tethers membranes through its affinities for the membrane Rab GTPase Ypt7...
January 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29191246/munc18-1-gene-abnormalities-are-involved-in-neurodevelopmental-disorders-through-defective-cortical-architecture-during-brain-development
#12
Nanako Hamada, Ikuko Iwamoto, Hidenori Tabata, Koh-Ichi Nagata
While Munc18-1 interacts with Syntaxin1 and controls the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex to regulate presynaptic vesicle fusion in developed neurons, this molecule is likely to be involved in brain development since its gene abnormalities cause early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome), neonatal epileptic encephalopathy and other neurodevelopmental disorders. We thus analyzed physiological significance of Munc18-1 during cortical development...
November 30, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29150433/tyrosine-phosphorylation-of-munc18-1-inhibits-synaptic-transmission-by-preventing-snare%C3%A2-assembly
#13
Marieke Meijer, Bernhard Dörr, Hanna Ca Lammertse, Chrysanthi Blithikioti, Jan Rt van Weering, Ruud Fg Toonen, Thomas H Söllner, Matthijs Verhage
Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29046354/evidence-for-a-conserved-inhibitory-binding-mode-between-the-membrane-fusion-assembly-factors-munc18-and-syntaxin-in-animals
#14
COMPARATIVE STUDY
Czuee Morey, C Nickias Kienle, Tobias H Klöpper, Pawel Burkhardt, Dirk Fasshauer
The membrane fusion necessary for vesicle trafficking is driven by the assembly of heterologous SNARE proteins orchestrated by the binding of Sec1/Munc18 (SM) proteins to specific syntaxin SNARE proteins. However, the precise mode of interaction between SM proteins and SNAREs is debated, as contrasting binding modes have been found for different members of the SM protein family, including the three vertebrate Munc18 isoforms. While different binding modes could be necessary, given their roles in different secretory processes in different tissues, the structural similarity of the three isoforms makes this divergence perplexing...
December 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29040524/potentiation-of-excitatory-synaptic-transmission-ameliorates-aggression-in-mice-with-stxbp1-haploinsufficiency
#15
Hiroyuki Miyamoto, Atsushi Shimohata, Manabu Abe, Teruo Abe, Emi Mazaki, Kenji Amano, Toshimitsu Suzuki, Tetsuya Tatsukawa, Shigeyoshi Itohara, Kenji Sakimura, Kazuhiro Yamakawa
Genetic studies point to a major role of de novo mutations in neurodevelopmental disorders of intellectual disability, autism spectrum disorders, and epileptic encephalopathy. The STXBP1 gene encodes the syntaxin-binding protein 1 (Munc18-1) that critically controls synaptic vesicle exocytosis and synaptic transmission. This gene harbors a high frequency of de novo mutations, which may play roles in these neurodevelopmental disorders. However, the system and behavioral-level pathophysiological changes caused by these genetic defects remain poorly understood...
December 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29029784/regulation-of-insulin-exocytosis-by-calcium-dependent-protein-kinase-c-in-beta-cells
#16
REVIEW
Adam J Trexler, Justin W Taraska
The control of insulin release from pancreatic beta cells helps ensure proper blood glucose level, which is critical for human health. Protein kinase C has been shown to be one key control mechanism for this process. After glucose stimulation, calcium influx into beta cells triggers exocytosis of insulin-containing dense-core granules and activates protein kinase C via calcium-dependent phospholipase C-mediated generation of diacylglycerol. Activated protein kinase C potentiates insulin release by enhancing the calcium sensitivity of exocytosis, likely by affecting two main pathways that could be linked: (1) the reorganization of the cortical actin network, and (2) the direct phosphorylation of critical exocytotic proteins such as munc18, SNAP25, and synaptotagmin...
November 2017: Cell Calcium
https://www.readbyqxmd.com/read/28887593/v-snare-function-in-chromaffin-cells
#17
REVIEW
Madhurima Dhara, Ralf Mohrmann, Dieter Bruns
Vesicle fusion is elementary for intracellular trafficking and release of signal molecules, thus providing the basis for diverse forms of intercellular communication like hormonal regulation or synaptic transmission. A detailed characterization of the mechanisms underlying exocytosis is key to understand how the nervous system integrates information and generates appropriate responses to stimuli. The machinery for vesicular release employs common molecular players in different model systems including neuronal and neuroendocrine cells, in particular members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) protein family, Sec1/Munc18-like proteins, and other accessory factors...
January 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28880475/recent-new-insights-into-the-role-of-snare-and-associated-proteins-in-insulin-granule-exocytosis
#18
REVIEW
Herbert Y Gaisano
Initial work on the exocytotic machinery of predocked insulin secretory granules (SGs) in pancreatic β-cells mimicked the SNARE hypothesis work in neurons, which includes SM/SNARE complex and associated priming proteins, fusion clamps and Ca(2+) sensors. However, β-cell SGs, unlike neuronal synaptic vesicles, exhibit a biphasic secretory response that requires additional distinct features in exocytosis including newcomer SGs that undergo minimal docking time at the plasma membrane (PM) before fusion and multi-SG (compound) fusion...
September 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28860966/a-stimulation-function-of-synaptotagmin-1-in-ternary-snare-complex-formation-dependent-on-munc18-and-munc13
#19
Yun Li, Shen Wang, Tianzhi Li, Le Zhu, Yuanyuan Xu, Cong Ma
The Ca(2+) sensor synaptotagmin-1 (Syt1) plays an essential function in synaptic exocytosis. Recently, Syt1 has been implicated in synaptic vesicle priming, a maturation step prior to Ca(2+)-triggered membrane fusion that is believed to involve formation of the ternary SNARE complex and require priming proteins Munc18-1 and Munc13-1. However, the mechanisms of Syt1 in synaptic vesicle priming are still unclear. In this study, we found that Syt1 stimulates the transition from the Munc18-1/syntaxin-1 complex to the ternary SNARE complex catalyzed by Munc13-1...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28858288/simultaneous-lipid-and-content-mixing-assays-for-in-vitro-reconstitution-studies-of-synaptic-vesicle-fusion
#20
Xiaoxia Liu, Alpay Burak Seven, Junjie Xu, Victoria Esser, Lijing Su, Cong Ma, Josep Rizo
This protocol describes reconstitution assays to study how the neurotransmitter release machinery triggers Ca2+-dependent synaptic vesicle fusion. The assays monitor fusion between proteoliposomes containing the synaptic vesicle SNARE synaptobrevin (with or without the Ca2+ sensor synaptotagmin-1) and proteoliposomes initially containing the plasma membrane SNAREs syntaxin-1 and soluble NSF attachment protein (SNAP)-25. Lipid mixing (from fluorescence de-quenching of Marina-Blue-labeled lipids) and content mixing (from development of fluorescence resonance energy transfer (FRET) between phycoerythrin-biotin (PhycoE-Biotin) and Cy5-streptavidin trapped in the two proteoliposome populations) are measured simultaneously to ensure that true, nonleaky membrane fusion is monitored...
September 2017: Nature Protocols
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