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https://www.readbyqxmd.com/read/28713022/resveratrol-inhibits-phorbol-ester-induced-membrane-translocation-of-presynaptic-munc13-1
#1
Satyabrata Pany, Anamitra Ghosh, Youngki You, Nga Nguyen, Joydip Das
BACKGROUND: Resveratrol (1) is a naturally occurring polyphenol that has been implicated in neuroprotection. One of resveratrol's several biological targets is Ca(2+)-sensitive protein kinase C alpha (PKCα). Resveratrol inhibits PKCα by binding to its activator-binding C1 domain. Munc13-1 is a C1 domain-containing Ca(2+)-sensitive SNARE complex protein essential for vesicle priming and neurotransmitter release. METHODS: To test if resveratrol could also bind and inhibit Munc13-1, we studied the interaction of resveratrol and its derivatives, (E)-1,3-dimethoxy-5-(4-methoxystyryl)benzene, (E)-5,5'-(ethene-1,2-diyl)bis(benzene-1,2,3-triol), (E)-1,2-bis(3,4,5-trimethoxyphenyl)ethane, and (E)-5-(4-(hexadecyloxy)-3,5-dihydroxystyryl)benzene-1,2,3-triol with Munc13-1 by studying its membrane translocation from cytosol to plasma membrane in HT22 cells and primary hippocampal neurons...
July 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28701482/analysis-of-rim-expression-and-function-at-mouse-photoreceptor-ribbon-synapses
#2
Martina Löhner, Norbert Babai, Tanja Müller, Kaspar Gierke, Jenny Atorf, Anneka Joachimsthaler, Angela Peukert, Henrik Martens, Andreas Feigenspan, Jan Kremers, Susanne Schoch, Johann Helmut Brandstätter, Hanna Regus-Leidig
RIM (RAB3A-interacting molecule) proteins are important regulators of transmitter release from active zones. At conventional chemical synapses, RIMs contribute substantially to vesicle priming and docking, and their loss reduces the readily releasable pool of synaptic vesicles by up to 75 %. The priming function of RIMs is mediated via the formation of a tripartite complex with Munc13 and RAB3A, which brings synaptic vesicles in close proximity to Ca(2+) channels and the fusion site, and activates Munc13. We reported previously that at mouse photoreceptor ribbon synapses vesicle priming is Munc13-independent...
July 12, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28685386/vertebrate-presynaptic-active-zone-assembly-a-role-accomplished-by-diverse-molecular-and-cellular-mechanisms
#3
REVIEW
Viviana I Torres, Nibaldo C Inestrosa
Among all the biological systems in vertebrates, the central nervous system (CNS) is the most complex, and its function depends on specialized contacts among neurons called synapses. The assembly and organization of synapses must be exquisitely regulated for a normal brain function and network activity. There has been a tremendous effort in recent decades to understand the molecular and cellular mechanisms participating in the formation of new synapses and their organization, maintenance, and regulation. At the vertebrate presynapses, proteins such as Piccolo, Bassoon, RIM, RIM-BPs, CAST/ELKS, liprin-α, and Munc13 are constant residents and participate in multiple and dynamic interactions with other regulatory proteins, which define network activity and normal brain function...
July 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28673385/exophilin-8-assembles-secretory-granules-for-exocytosis-in-the-actin-cortex-via-interaction-with-rim-bp2-and-myosin-viia
#4
Fushun Fan, Kohichi Matsunaga, Hao Wang, Ray Ishizaki, Eri Kobayashi, Hiroshi Kiyonari, Yoshiko Mukumoto, Katsuhide Okunishi, Tetsuro Izumi
Exophilin-8 has been reported to play a role in anchoring secretory granules within the actin cortex, due to its direct binding activities to Rab27 on the granule membrane and to F-actin and its motor protein, myosin-Va. Here, we show that exophilin-8 accumulates granules in the cortical F-actin network not by direct interaction with myosin-Va, but by indirect interaction with a specific form of myosin-VIIa through its previously unknown binding partner, RIM-BP2. RIM-BP2 also associates with exocytic machinery, Cav1...
July 4, 2017: ELife
https://www.readbyqxmd.com/read/28635948/munc13-1-and-munc18-1-together-prevent-nsf-dependent-de-priming-of-synaptic-vesicles
#5
Enqi He, Keimpe Wierda, Rhode van Westen, Jurjen H Broeke, Ruud F Toonen, L Niels Cornelisse, Matthijs Verhage
Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant...
June 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28626002/ride-the-wave-retrograde-trafficking-becomes-ca-2-dependent-with-baiap3
#6
Jakob B Sørensen
The functions of four of the five proteins in the mammalian uncoordinated-13 (Munc13) family have been identified as priming factors in SNARE-dependent exocytosis. In this issue, Zhang et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702099) show that the fifth member, BAIAP3 (brain-specific angiogenesis inhibitor I-associated protein 3), acts in retrograde trafficking by returning secretory vesicle material to the trans-Golgi network. In its absence, secretory vesicle formation is impaired, leading to accumulation of immature vesicles, or lysosomal vesicle degradation...
July 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28626000/baiap3-a-c2-domain-containing-munc13-protein-controls-the-fate-of-dense-core-vesicles-in-neuroendocrine-cells
#7
Xingmin Zhang, Shan Jiang, Kelly A Mitok, Lingjun Li, Alan D Attie, Thomas F J Martin
Dense-core vesicle (DCV) exocytosis is a SNARE (soluble N-ethylmaleimide-sensitive fusion attachment protein receptor)-dependent anterograde trafficking pathway that requires multiple proteins for regulation. Several C2 domain-containing proteins are known to regulate Ca(2+)-dependent DCV exocytosis in neuroendocrine cells. In this study, we identified others by screening all (∼139) human C2 domain-containing proteins by RNA interference in neuroendocrine cells. 40 genes were identified, including several encoding proteins with known roles (CAPS [calcium-dependent activator protein for secretion 1], Munc13-2, RIM1, and SYT10) and many with unknown roles...
July 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28489077/heterodimerization-of-munc13-c2a-domain-with-rim-regulates-synaptic-vesicle-docking-and-priming
#8
Marcial Camacho, Jayeeta Basu, Thorsten Trimbuch, Shuwen Chang, Cristina Pulido-Lozano, Shwu-Shin Chang, Irina Duluvova, Masin Abo-Rady, Josep Rizo, Christian Rosenmund
The presynaptic active zone protein Munc13 is essential for neurotransmitter release, playing key roles in vesicle docking and priming. Mechanistically, it is thought that the C2A domain of Munc13 inhibits the priming function by homodimerization, and that RIM disrupts the autoinhibitory homodimerization forming monomeric priming-competent Munc13. However, it is unclear whether the C2A domain mediates other Munc13 functions in addition to this inactivation-activation switch. Here, we utilize mutations that modulate the homodimerization and heterodimerization states to define additional roles of the Munc13 C2A domain...
May 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28481223/ca2-channel-clustering-with-insulin-containing-granules-is-disturbed-in-type-2-diabetes
#9
Nikhil R Gandasi, Peng Yin, Michela Riz, Margarita V Chibalina, Giuliana Cortese, Per-Eric Lund, Victor Matveev, Patrik Rorsman, Arthur Sherman, Morten G Pedersen, Sebastian Barg
Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28477408/autoinhibition-of-munc18-1-modulates-synaptobrevin-binding-and-helps-to-enable-munc13-dependent-regulation-of-membrane-fusion
#10
Ewa Sitarska, Junjie Xu, Seungmee Park, Xiaoxia Liu, Bradley Quade, Karolina Stepien, Kyoko Sugita, Chad A Brautigam, Shuzo Sugita, Josep Rizo
Munc18-1 orchestrates SNARE complex assembly together with Munc13-1 to mediate neurotransmitter release. Munc18-1 binds to synaptobrevin, but the relevance of this interaction and its relation to Munc13 function are unclear. NMR experiments now show that Munc18-1 binds specifically and non-specifically to synaptobrevin. Specific binding is inhibited by a L348R mutation in Munc18-1 and enhanced by a D326K mutation designed to disrupt the 'furled conformation' of a Munc18-1 loop. Correspondingly, the activity of Munc18-1 in reconstitution assays that require Munc18-1 and Munc13-1 for membrane fusion is stimulated by the D326K mutation and inhibited by the L348R mutation...
May 6, 2017: ELife
https://www.readbyqxmd.com/read/28468610/a-case-report-of-novel-mutation-in-prf1-gene-which-causes-familial-autosomal-recessive-hemophagocytic-lymphohistiocytosis
#11
Mohammad Reza Bordbar, Farzaneh Modarresi, Mohammad Ali Farazi Fard, Hassan Dastsooz, Nader Shakib Azad, Mohammad Ali Faghihi
BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis...
May 3, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28450451/a-novel-munc13-4-s100a10-annexin-a2-complex-promotes-weibel-palade-body-exocytosis-in-endothelial-cells
#12
Tarek Chehab, Nina Criado Santos, Anna Holthenrich, Sophia N Koerdt, Jennifer Disse, Christian Schuberth, Ali Reza Nazmi, Maaike Neeft, Henriette Koch, Kwun Nok M Man, Sonja M Wojcik, Thomas F J Martin, Peter van der Sluijs, Nils Brose, Volker Gerke
Endothelial cells respond to blood vessel injury by the acute release of the procoagulant von Willebrand factor, which is stored in unique secretory granules called Weibel-Palade bodies (WPBs). Stimulated WPB exocytosis critically depends on their proper recruitment to the plasma membrane, but factors involved in WPB-plasma membrane tethering are not known. Here we identify Munc13-4, a protein mutated in familial hemophagocytic lymphohistiocytosis 3, as a WPB-tethering factor. Munc13-4 promotes histamine-evoked WPB exocytosis and is present on WPBs, and secretagogue stimulation triggers an increased recruitment of Munc13-4 to WPBs and a clustering of Munc13-4 at sites of WPB-plasma membrane contact...
June 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28348137/early-golgi-abnormalities-and-neurodegeneration-upon-loss-of-presynaptic-proteins-munc18-1-syntaxin-1-or-snap-25
#13
Tatiana C Santos, Keimpe Wierda, Jurjen H Broeke, Ruud F Toonen, Matthijs Verhage
The loss of presynaptic proteins Munc18-1, syntaxin-1 or SNAP-25 is known to produce cell death, but the underlying features have not been compared experimentally. Here, we investigated these features in cultured mouse CNS and dorsal root ganglion neurons. Side-by-side comparisons confirmed massive cell death, before synaptogenesis, within 1-4 days in vitro (DIV) upon loss of t-SNAREs (syntaxin-1, SNAP-25) or Munc18-1, but not v-SNAREs (synaptobrevins/VAMP1/2/3 using Tetanus Neurotoxin (TeNT), also in TI-VAMP/VAMP7 knock-out (KO) neurons)...
March 27, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28336773/elks1-helps-neuronal-synapses-diversify
#14
Ben Short
Study reveals how neurons vary the properties of individual synapses by recruiting different Munc13 proteins to presynaptic active zones.
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28264913/elks1-localizes-the-synaptic-vesicle-priming-protein-bmunc13-2-to-a-specific-subset-of-active-zones
#15
Hiroshi Kawabe, Miso Mitkovski, Pascal S Kaeser, Johannes Hirrlinger, Felipe Opazo, Dennis Nestvogel, Stefan Kalla, Anna Fejtova, Sophie E Verrier, Simon R Bungers, Benjamin H Cooper, Frederique Varoqueaux, Yun Wang, Ralf B Nehring, Eckart D Gundelfinger, Christian Rosenmund, Silvio O Rizzoli, Thomas C Südhof, Jeong-Seop Rhee, Nils Brose
Presynaptic active zones (AZs) are unique subcellular structures at neuronal synapses, which contain a network of specific proteins that control synaptic vesicle (SV) tethering, priming, and fusion. Munc13s are core AZ proteins with an essential function in SV priming. In hippocampal neurons, two different Munc13s-Munc13-1 and bMunc13-2-mediate opposite forms of presynaptic short-term plasticity and thus differentially affect neuronal network characteristics. We found that most presynapses of cortical and hippocampal neurons contain only Munc13-1, whereas ∼10% contain both Munc13-1 and bMunc13-2...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28222617/presynaptic-calmodulin-targets-lessons-from-structural-proteomics
#16
Noa Lipstein, Melanie Göth, Christine Piotrowski, Kevin Pagel, Andrea Sinz, Olaf Jahn
Calmodulin (CaM) is a highly conserved Ca(2+)-binding protein that is exceptionally abundant in the brain. In the presynaptic compartment of neurons, CaM transduces changes in Ca(2+) concentration into the regulation of synaptic transmission dynamics. Areas covered: We review selected literature including published CaM interactor screens and outline established and candidate presynaptic CaM targets. We present a workflow of biochemical and structural proteomic methods that were used to identify and characterize the interactions between CaM and Munc13 proteins...
March 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28192369/synaptic-unc13a-protein-variant-causes-increased-neurotransmission-and-dyskinetic-movement-disorder
#17
Noa Lipstein, Nanda M Verhoeven-Duif, Francesco E Michelassi, Nathaniel Calloway, Peter M van Hasselt, Katarzyna Pienkowska, Gijs van Haaften, Mieke M van Haelst, Ron van Empelen, Inge Cuppen, Heleen C van Teeseling, Annemieke M V Evelein, Jacob A Vorstman, Sven Thoms, Olaf Jahn, Karen J Duran, Glen R Monroe, Timothy A Ryan, Holger Taschenberger, Jeremy S Dittman, Jeong-Seop Rhee, Gepke Visser, Judith J Jans, Nils Brose
Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1)...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28177287/mechanistic-insights-into-neurotransmitter-release-and-presynaptic-plasticity-from-the-crystal-structure-of-munc13-1-c1c2bmun
#18
Junjie Xu, Marcial Camacho, Yibin Xu, Victoria Esser, Xiaoxia Liu, Thorsten Trimbuch, Yun-Zu Pan, Cong Ma, Diana R Tomchick, Christian Rosenmund, Josep Rizo
Munc13-1 acts as a master regulator of neurotransmitter release, mediating docking-priming of synaptic vesicles and diverse presynaptic plasticity processes. It is unclear how the functions of the multiple domains of Munc13-1 are coordinated. The crystal structure of a Munc13-1 fragment including its C1, C2B and MUN domains (C1C2BMUN) reveals a 19.5 nm-long multi-helical structure with the C1 and C2B domains packed at one end. The similar orientations of the respective diacyglycerol- and Ca(2+)-binding sites of the C1 and C2B domains suggest that the two domains cooperate in plasma-membrane binding and that activation of Munc13-1 by Ca(2+) and diacylglycerol during short-term presynaptic plasticity are closely interrelated...
February 8, 2017: ELife
https://www.readbyqxmd.com/read/28137749/conformational-change-of-syntaxin-linker-region-induced-by-munc13s-initiates-snare-complex-formation-in-synaptic-exocytosis
#19
Shen Wang, Ucheor B Choi, Jihong Gong, Xiaoyu Yang, Yun Li, Austin L Wang, Xiaofei Yang, Axel T Brunger, Cong Ma
The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1 adopts a closed conformation when bound to Munc18-1, preventing binding to synaptobrevin-2 and SNAP-25 to form the ternary SNARE complex. Although it is known that the MUN domain of Munc13-1 catalyzes the transition from the Munc18-1/syntaxin-1 complex to the SNARE complex, the molecular mechanism is unclear. Here, we identified two conserved residues (R151, I155) in the syntaxin-1 linker region as key sites for the MUN domain interaction...
March 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28118494/strain-dependent-effects-of-acute-alcohol-on-synaptic-vesicle-recycling-and-post-tetanic-potentiation-in-medial-glutamate-inputs-to-the-mouse-basolateral-amygdala
#20
Dominic A Gioia, Brian McCool
BACKGROUND: Inbred mouse strains are differentially sensitive to the acute effects of ethanol (EtOH) and are useful tools for examining how unique genomes differentially affect alcohol-related behaviors and physiology. DBA/2J mice have been shown to be sensitive to the acute anxiolytic effects of alcohol as well as the anxiogenic effects of withdrawal from chronic alcohol exposure, while B6 mice are resistant to both. Considering that the basolateral amygdala (BLA) is an important brain region for the acute and chronic effects of EtOH on fear and anxiety related behaviors, we hypothesized that there would be strain-dependent differences in the acute effects of EtOH in BLA slices...
April 2017: Alcoholism, Clinical and Experimental Research
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