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https://www.readbyqxmd.com/read/29767240/munc13%C3%A2-4-mediates-human-neutrophil-elastase%C3%A2-induced-airway-mucin5ac-hypersecretion-by-interacting-with-syntaxin2
#1
Rui Xu, Jia Zhou, Xiang-Dong Zhou, Qi Li, Juliy M Perelman, Victor P Kolosov
The overexpression and hypersecretion of mucus is a hallmark of chronic pulmonary inflammatory disease. Mucin5AC (MUC5AC) is a major component of airway gel‑forming mucin. Members of the Unc13 (Munc13) protein family act as important activators of granule exocytosis from various types of mammalian cells. The present study aimed to determine the role of Munc13 family proteins in MUC5AC secretion via an in vitro study with BEAS‑2B and Calu‑3 cell lines. Reverse transcription‑quantitative polymerase chain reaction and western blotting indicated that stimulation of the cells with 100 nM human neutrophil elastase (hNE) for 1 h did not affect the expression of either unc13 homolog B (Munc13‑2) or unc13 homolog D (Munc13‑4), but immunofluorescence analysis demonstrated that hNE treatment was associated with the recruitment of Munc13‑4 to the plasma membrane...
May 14, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29706534/ca-2-triggered-synaptic-vesicle-fusion-initiated-by-release-of-inhibition
#2
REVIEW
Axel T Brunger, Jeremy Leitz, Qiangjun Zhou, Ucheor B Choi, Ying Lai
Recent structural and functional studies of the synaptic vesicle fusion machinery suggest an inhibited tripartite complex consisting of neuronal soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), synaptotagmin, and complexin prior to Ca2+ -triggered synaptic vesicle fusion. We speculate that Ca2+ -triggered fusion commences with the release of inhibition by Ca2+ binding to synaptotagmin C2 domains. Subsequently, fusion is assisted by SNARE complex zippering and by active membrane remodeling properties of synaptotagmin...
April 26, 2018: Trends in Cell Biology
https://www.readbyqxmd.com/read/29696584/how-to-spot-congenital-myasthenic-syndromes-resembling-the-lambert-eaton-myasthenic-syndrome-a-brief-review-of-clinical-electrophysiological-and-genetics-features
#3
REVIEW
Paulo José Lorenzoni, Rosana Herminia Scola, Claudia Suemi Kamoi Kay, Lineu Cesar Werneck, Rita Horvath, Hanns Lochmüller
Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases in which neuromuscular transmission is compromised. CMS resembling the Lambert-Eaton myasthenic syndrome (CMS-LEMS) are emerging as a rare group of distinct presynaptic CMS that share the same electrophysiological features. They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation. Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS...
April 25, 2018: Neuromolecular Medicine
https://www.readbyqxmd.com/read/29674495/platelet-munc13-4-regulates-hemostasis-thrombosis-and-airway-inflammation
#4
Eduardo I Cardenas, Keegan Breaux, Qi Da, Jose R Flores, Marco A Ramos, Michael J Tuvim, Alan R Burns, Rolando E Rumbaut, Roberto Adachi
Platelet degranulation is crucial for hemostasis and may participate in inflammation. Exocytosis in platelets is mediated by SNARE proteins and should be controlled by Munc13 proteins. We found that platelets express Munc13-2 and -4. We assessed platelet granule exocytosis in Munc13-2 and -4 global and conditional KO mice, and observed that deletion of Munc13-4 ablates dense granule release and indirectly impairs alpha granule exocytosis. We found no exocytic role for Munc13-2 in platelets, not even in the absence of Munc13-4...
April 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29615494/small-molecules-that-inhibit-the-late-stage-of-munc13-4-dependent-secretory-granule-exocytosis-in-mast-cells
#5
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/29596912/characterization-of-a-large-unc13d-gene-duplication-in-a-patient-with-familial-hemophagocytic-lymphohistiocytosis-type-3
#6
Eitaro Hiejima, Hirofumi Shibata, Takahiro Yasumi, Saeko Shimodera, Masayuki Hori, Kazushi Izawa, Tomoki Kawai, Masaki Matsuoka, Yasuko Kojima, Akira Ohara, Ryuta Nishikomori, Osamu Ohara, Toshio Heike
Familial hemophagocytic lymphohistiocytosis (FHL) type 3 is a life-threatening immune dysregulation syndrome caused by mutations in the UNC13D gene, encoding the munc13-4 protein, which is important for function of cytotoxic lymphocytes. FHL3 accounts for 30-40% of FHL cases, and more than 100 mutations in the UNC13D gene have been described to date. We describe the first case of FHL3 carrying an intragenic duplication of UNC13D, apparently mediated by recombination of Alu elements. NK cell degranulation and munc13-4 protein expression assays are useful for early identification of such mutations, which may be missed by analysis of genomic DNA alone...
March 26, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29549174/human-ctl-based-functional-analysis-shows-the-reliability-of-a-munc13-4-protein-expression-assay-for-fhl3-diagnosis
#7
Hirofumi Shibata, Takahiro Yasumi, Saeko Shimodera, Eitaro Hiejima, Kazushi Izawa, Tomoki Kawai, Ryutaro Shirakawa, Taizo Wada, Ryuta Nishikomori, Hisanori Horiuchi, Osamu Ohara, Eiichi Ishii, Toshio Heike
Familial hemophagocytic lymphohistiocytosis (FHL) is the major form of hereditary hemophagocytic lymphohistiocytosis (HLH); as such, it requires prompt and accurate diagnosis. We previously reported that FHL type 3 (FHL3) can be rapidly screened by detecting munc13-4 expression in platelets using flow cytometry; however, the reliability of the munc13-4 expression assay for FHL3 diagnosis is unclear. Regardless of the type of UNC13D mutation, all reported FHL3 cases examined for munc13-4 protein showed significantly reduced expression...
March 16, 2018: Blood
https://www.readbyqxmd.com/read/29466725/munc13-3-is-required-for-the-developmental-localization-of-ca-2-channels-to-active-zones-and-the-nanopositioning-of-ca-v-2-1-near-release-sensors
#8
Valentin Kusch, Grit Bornschein, Desiree Loreth, Julia Bank, Johannes Jordan, David Baur, Masahiko Watanabe, Akos Kulik, Manfred Heckmann, Jens Eilers, Hartmut Schmidt
Spatial relationships between Cav channels and release sensors at active zones (AZs) are a major determinant of synaptic fidelity. They are regulated developmentally, but the underlying molecular mechanisms are largely unclear. Here, we show that Munc13-3 regulates the density of Cav 2.1 and Cav 2.2 channels, alters the localization of Cav 2.1, and is required for the development of tight, nanodomain coupling at parallel-fiber AZs. We combined EGTA application and Ca2+ -channel pharmacology in electrophysiological and two-photon Ca2+ imaging experiments with quantitative freeze-fracture immunoelectron microscopy and mathematical modeling...
February 20, 2018: Cell Reports
https://www.readbyqxmd.com/read/29439199/liprin-%C3%AE-3-controls-vesicle-docking-and-exocytosis-at-the-active-zone-of-hippocampal-synapses
#9
Man Yan Wong, Changliang Liu, Shan Shan H Wang, Aram C F Roquas, Stephen C Fowler, Pascal S Kaeser
The presynaptic active zone provides sites for vesicle docking and release at central nervous synapses and is essential for speed and accuracy of synaptic transmission. Liprin-α binds to several active zone proteins, and loss-of-function studies in invertebrates established important roles for Liprin-α in neurodevelopment and active zone assembly. However, Liprin-α localization and functions in vertebrates have remained unclear. We used stimulated emission depletion superresolution microscopy to systematically determine the localization of Liprin-α2 and Liprin-α3, the two predominant Liprin-α proteins in the vertebrate brain, relative to other active-zone proteins...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29355968/the-unfolding-landscape-of-the-congenital-myasthenic-syndromes
#10
REVIEW
Andrew G Engel, Xin-Ming Shen, Duygu Selcen
Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. Since the advent of next-generation sequencing methods, the discovery of novel CMS targets and phenotypes has proceeded at an accelerated rate. Here, we review the current classification of CMS and describe our findings in five of these targets identified and investigated in our laboratory in the past 5 years. Defects in LRP4 hinder synaptic development and maintenance; the defects in PREPL are predicted to diminish filling of the synaptic vesicle with acetylcholine; and defects in SNAP25, Munc13-1, and synaptotbrevin-1 impede synaptic vesicle exocytosis...
February 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29296930/gene-transfer-into-hematopoietic-stem-cells-reduces-hlh-manifestations-in-a-murine-model-of-munc13-4-deficiency
#11
Tayebeh Soheili, Amandine Durand, Fernando E Sepulveda, Julie Rivière, Chantal Lagresle-Peyrou, Hanem Sadek, Geneviève de Saint Basile, Samia Martin, Fulvio Mavilio, Marina Cavazzana, Isabelle André-Schmutz
Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients...
December 26, 2017: Blood Advances
https://www.readbyqxmd.com/read/29280494/bidirectional-modulation-of-glutamatergic-synaptic-transmission-by-metabotropic-glutamate-type-7-receptors-at-schaffer-collateral-ca1-hippocampal-synapses
#12
Ricardo Martín, José Javier Ferrero, Andrea Collado-Alsina, Carolina Aguado, Rafael Luján, Magdalena Torres, José Sánchez-Prieto
KEY POINTS: Neurotransmitter release is inhibited by metabotropic glutamate type 7 (mGlu7 ) receptors that reduce Ca2+ influx, yet synapses lacking this receptor also produce weaker release, suggesting that mGlu7 receptors may also prime synaptic vesicles for release. Prolonged activation of mGlu7 receptors with the agonist l-AP4 first reduces and then enhances the amplitude of EPSCs through a presynaptic effect. The inhibitory response is blocked by pertussis toxin, while the potentiating response is prevented by a phospholipase C inhibitor (U73122) and an inhibitor of diacylglycerol (DAG) binding (calphostin C), suggesting that this receptor also couples to pathways that generate DAG...
March 1, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29275163/cast-its-molecular-structure-and-phosphorylation-dependent-regulation-of-presynaptic-plasticity
#13
REVIEW
Shun Hamada, Toshihisa Ohtsuka
Our brain functions rely on sophisticated communication between synapses in the nervous system. Most synapses utilize a specialized submembranous structure, the so-called 'active zone', for the efficient transmission of chemical signals. The presynaptic active zone plays pivotal roles in the precise regulation of neurotransmitter release from the nerve terminals in a temporally and spatially coordinated manner. During the last two decades, several active zone-specific proteins have been isolated and characterized, including Bassoon, Piccolo/Aczonin, RIM, Munc13-1, ELKS, and CAST...
February 2018: Neuroscience Research
https://www.readbyqxmd.com/read/29274147/doc2b-acts-as-a-calcium-sensor-for-vesicle-priming-requiring-synaptotagmin-1-munc13-2-and-snares
#14
Sébastien Houy, Alexander J Groffen, Iwona Ziomkiewicz, Matthijs Verhage, Paulo S Pinheiro, Jakob Balslev Sørensen
Doc2B is a cytosolic protein with binding sites for Munc13 and Tctex-1 (dynein light chain), and two C2-domains that bind to phospholipids, Ca2+ and SNAREs. Whether Doc2B functions as a calcium sensor akin to synaptotagmins, or in other calcium-independent or calcium-dependent capacities is debated. We here show by mutation and overexpression that Doc2B plays distinct roles in two sequential priming steps in mouse adrenal chromaffin cells. Mutating Ca2+ -coordinating aspartates in the C2A-domain localizes Doc2B permanently at the plasma membrane, and renders an upstream priming step Ca2+ -independent, whereas a separate function in downstream priming depends on SNARE-binding, Ca2+ -binding to the C2B-domain of Doc2B, interaction with ubMunc13-2 and the presence of synaptotagmin-1...
December 23, 2017: ELife
https://www.readbyqxmd.com/read/29244485/critical-role-of-trp-588-of-presynaptic-munc13-1-for-ligand-binding-and-membrane-translocation
#15
Joydip Das, Noemi Kedei, Jessica S Kelsey, Youngki You, Satyabrata Pany, Gary A Mitchell, Nancy E Lewin, Peter M Blumberg
Munc13-1 is a presynaptic active-zone protein essential for neurotransmitter release and presynaptic plasticity in the brain. This multidomain scaffold protein contains a C1 domain that binds to the activator diacylglycerol/phorbol ester. Although the C1 domain bears close structural homology with the C1 domains of protein kinase C (PKC), the tryptophan residue at position 22 (588 in the full-length Munc13-1) occludes the activator binding pocket, which is not the case for PKC. To elucidate the role of this tryptophan, we generated W22A, W22K, W22D, W22Y, and W22F substitutions in the full-length Munc13-1, expressed the GFP-tagged constructs in Neuro-2a cells, and measured their membrane translocation in response to phorbol ester treatment by imaging of the live cells using confocal microscopy...
February 6, 2018: Biochemistry
https://www.readbyqxmd.com/read/29230050/synaptic-weight-set-by-munc13-1-supramolecular-assemblies
#16
Hirokazu Sakamoto, Tetsuroh Ariyoshi, Naoya Kimpara, Kohtaroh Sugao, Isamu Taiko, Kenji Takikawa, Daisuke Asanuma, Shigeyuki Namiki, Kenzo Hirose
The weight of synaptic connections, which is controlled not only postsynaptically but also presynaptically, is a key determinant in neuronal network dynamics. The mechanisms controlling synaptic weight, especially on the presynaptic side, remain elusive. Using single-synapse imaging of the neurotransmitter glutamate combined with super-resolution imaging of presynaptic proteins, we identify a presynaptic mechanism for setting weight in central glutamatergic synapses. In the presynaptic terminal, Munc13-1 molecules form multiple and discrete supramolecular self-assemblies that serve as independent vesicular release sites by recruiting syntaxin-1, a soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) protein essential for synaptic vesicle exocytosis...
January 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29225210/inhibitory-role-of-munc13-1-in-antigen-induced-mast-cell-degranulation
#17
Hironori Higashio, Yoh-Ichi Satoh, Tomoyuki Saino
Secretory granules (SGs) of mast cells are lysosome-related organelles that contain various inflammatory molecules such as histamine, which are stored in the cytoplasm. Mast cell degranulation is the regulated exocytosis of SGs in response to external stimuli, such as the antigen-mediated cross-linking of the high-affinity IgE receptor, FcεRI. Upon stimulation, SGs undergo priming to become fusion-competent prior to fusing with the plasma membrane, which is mediated by Munc13-4, one of the five members of the vesicle-priming Munc13 protein family...
2017: Biomedical Research
https://www.readbyqxmd.com/read/29150658/differential-regulation-of-synaptic-ap-2-clathrin-vesicle-uncoating-in-synaptic-plasticity
#18
Ermes Candiello, Ratnakar Mishra, Bernhard Schmidt, Olaf Jahn, Peter Schu
AP-1/σ1B-deficiency causes X-linked intellectual disability. AP-1/σ1B -/- mice have impaired synaptic vesicle recycling, fewer synaptic vesicles and enhanced endosome maturation mediated by AP-1/σ1A. Despite defects in synaptic vesicle recycling synapses contain two times more endocytic AP-2 clathrin-coated vesicles. We demonstrate increased formation of two classes of AP-2/clathrin coated vesicles. One which uncoats readily and a second with a stabilised clathrin coat. Coat stabilisation is mediated by three molecular mechanisms: reduced recruitment of Hsc70 and synaptojanin1 and enhanced μ2/AP-2 phosphorylation and activation...
November 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141910/munc13-proteins-control-regulated-exocytosis-in-mast-cells
#19
Elsa M Rodarte, Marco A Ramos, Alfredo J Davalos, Daniel C Moreira, David S Moreno, Eduardo I Cardenas, Alejandro I Rodarte, Youlia Petrova, Sofia Molina, Luis E Rendon, Elizabeth Sanchez, Keegan Breaux, Alejandro Tortoriello, John Manllo, Erika A Gonzalez, Michael J Tuvim, Burton F Dickey, Alan R Burns, Ruth Heidelberger, Roberto Adachi
Mast cells (MCs) are involved in host defenses against pathogens and inflammation. Stimulated MCs release substances stored in their granules via regulated exocytosis. In other cell types, Munc13 (mammalian homolog of Caenorhabditis elegans uncoordinated gene 13) proteins play essential roles in regulated exocytosis. Here, we found that MCs express Munc13-2 and -4, and we studied their roles using global and conditional knock-out (KO) mice. In a model of systemic anaphylaxis, we found no difference between WT and Munc13-2 KO mice, but global and MC-specific Munc13-4 KO mice developed less hypothermia...
January 5, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29068313/phosphatidylinositol-4-5-bisphosphate-optical-uncaging-potentiates-exocytosis
#20
Alexander M Walter, Rainer Müller, Bassam Tawfik, Keimpe Db Wierda, Paulo S Pinheiro, André Nadler, Anthony W McCarthy, Iwona Ziomkiewicz, Martin Kruse, Gregor Reither, Jens Rettig, Martin Lehmann, Volker Haucke, Bertil Hille, Carsten Schultz, Jakob Balslev Sørensen
Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2 ] is essential for exocytosis. Classical ways of manipulating PI(4,5)P2 levels are slower than its metabolism, making it difficult to distinguish effects of PI(4,5)P2 from those of its metabolites. We developed a membrane-permeant, photoactivatable PI(4,5)P2 , which is loaded into cells in an inactive form and activated by light, allowing sub-second increases in PI(4,5)P2 levels. By combining this compound with electrophysiological measurements in mouse adrenal chromaffin cells, we show that PI(4,5)P2 uncaging potentiates exocytosis and identify synaptotagmin-1 (the Ca2+ sensor for exocytosis) and Munc13-2 (a vesicle priming protein) as the relevant effector proteins...
October 25, 2017: ELife
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