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https://www.readbyqxmd.com/read/28880480/monoacylglycerol-signalling-and-abhd6-in-health-and-disease
#1
REVIEW
Pegah Poursharifi, Sri Ramachandra Murthy Madiraju, Marc Prentki
Lipid metabolism dysregulation underlies chronic pathologies such as obesity, diabetes and cancer. Besides their role in structure and energy storage, lipids are also important signalling molecules regulating multiple biological functions. Thus, understanding the precise lipid metabolism enzymatic steps that are altered in some pathological conditions is helpful for designing better treatment strategies. Several monoacylglycerol (MAG) species are only recently being recognized as signalling lipid molecules in different tissues...
September 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28864210/inhibition-of-the-mevalonate-pathway-by-simvastatin-interferes-with-mast-cell-degranulation-by-disrupting-the-interaction-between-rab27a-and-double-c2-alpha-proteins
#2
Muhammad Novrizal Abdi Sahid, Shuang Liu, Takeshi Kiyoi, Kazutaka Maeyama
Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which block the mevalonate pathway. The activity of statins not only decreases cholesterol levels but also ameliorates inflammation and modulates the immune system. In this study, we investigated the effects of simvastatin on histamine release using rat basophilic leukaemia (RBL-2H3) cells, and examined its interaction with proteins involved in the exocytosis process. Treatment with simvastatin for 24h inhibited histamine release in RBL-2H3 cells in a concentration-dependent manner after stimulation with dinitrophenylated bovine serum albumin (DNP-BSA, as an antigen), ionomycin (a calcium ion [Ca(2+)] ionophore), and thapsigargin (an inhibitor of Ca(2+)-ATPase in the endoplasmic reticulum)...
August 29, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28860966/a-stimulation-function-of-synaptotagmin-1-in-ternary-snare-complex-formation-dependent-on-munc18-and-munc13
#3
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
#4
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 Ca(2+)-dependent synaptic vesicle fusion. The assays monitor fusion between proteoliposomes containing the synaptic vesicle SNARE synaptobrevin (with or without the Ca(2+) 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
https://www.readbyqxmd.com/read/28852855/how-does-the-stimulus-define-exocytosis-in-adrenal-chromaffin-cells
#5
REVIEW
Fernando D Marengo, Ana M Cárdenas
The extent and type of hormones and active peptides secreted by the chromaffin cells of the adrenal medulla have to be adjusted to physiological requirements. The chromaffin cell secretory activity is controlled by the splanchnic nerve firing frequency, which goes from approximately 0.5 Hz in basal conditions to more than 15 Hz in stress. Thus, these neuroendocrine cells maintain a tonic release of catecholamines under resting conditions, massively discharge intravesicular transmitters in response to stress, or adequately respond to moderate stimuli...
August 29, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28821673/unc-18-and-tomosyn-antagonistically-control-synaptic-vesicle-priming-downstream-of-unc-13-in-caenorhabditis-elegans
#6
Seungmee Park, Na-Ryum Bin, Bin Yu, Raymond Wong, Ewa Sitarska, Kyoko Sugita, Ke Ma, Junjie Xu, Chi-Wei Tien, Arash Algouneh, Ekaterina Turlova, Siyan Wang, Pranay Siriya, Waleed Shahid, Lorraine Kalia, Zhong-Ping Feng, Philippe P Monnier, Hong-Shuo Sun, Mei Zhen, Shangbang Gao, Josep Rizo, Shuzo Sugita
Munc18-1/UNC-18 is believed to prime SNARE-mediated membrane fusion, yet the underlying mechanisms remain enigmatic. Here, we examine how potential gain-of-function mutations of Munc18-1/UNC-18 affect locomotory behavior and synaptic transmission, and how Munc18-1-mediated priming is related to Munc13-1/UNC-13 and Tomosyn/TOM-1, positive and negative SNARE regulators, respectively. We show that a Munc18-1(P335A)/UNC-18(P334A) mutation leads to significantly increased locomotory activity and acetylcholine release in Caenorhabditis elegans, as well as enhanced synaptic neurotransmission in cultured mammalian neurons...
September 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28776026/reconstitution-of-calcium-mediated-exocytosis-of-dense-core-vesicles
#7
Alex J B Kreutzberger, Volker Kiessling, Binyong Liang, Patrick Seelheim, Shrutee Jakhanwal, Reinhard Jahn, J David Castle, Lukas K Tamm
Regulated exocytosis is a process by which neurotransmitters, hormones, and secretory proteins are released from the cell in response to elevated levels of calcium. In cells, secretory vesicles are targeted to the plasma membrane, where they dock, undergo priming, and then fuse with the plasma membrane in response to calcium. The specific roles of essential proteins and how calcium regulates progression through these sequential steps are currently incompletely resolved. We have used purified neuroendocrine dense-core vesicles and artificial membranes to reconstruct in vitro the serial events that mimic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-dependent membrane docking and fusion during exocytosis...
July 2017: Science Advances
https://www.readbyqxmd.com/read/28772123/molecular-mechanisms-of-synaptic-vesicle-priming-by-munc13-and-munc18
#8
Ying Lai, Ucheor B Choi, Jeremy Leitz, Hong Jun Rhee, Choongku Lee, Bekir Altas, Minglei Zhao, Richard A Pfuetzner, Austin L Wang, Nils Brose, JeongSeop Rhee, Axel T Brunger
Munc13 catalyzes the transit of syntaxin from a closed complex with Munc18 into the ternary SNARE complex. Here we report a new function of Munc13, independent of Munc18: it promotes the proper syntaxin/synaptobrevin subconfiguration during assembly of the ternary SNARE complex. In cooperation with Munc18, Munc13 additionally ensures the proper syntaxin/SNAP-25 subconfiguration. In a reconstituted fusion assay with SNAREs, complexin, and synaptotagmin, inclusion of both Munc13 and Munc18 quadruples the Ca(2+)-triggered amplitude and achieves Ca(2+) sensitivity at near-physiological concentrations...
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28772122/a-c1-c2-module-in-munc13-inhibits-calcium-dependent-neurotransmitter-release
#9
Francesco Michelassi, Haowen Liu, Zhitao Hu, Jeremy S Dittman
Almost all known forms of fast chemical synaptic transmission require the synaptic hub protein Munc13. This essential protein has also been implicated in mediating several forms of use-dependent plasticity, but the mechanisms by which it controls vesicle fusion and plasticity are not well understood. Using the C. elegans Munc13 ortholog UNC-13, we show that deletion of the C2B domain, the most highly conserved domain of Munc13, enhances calcium-dependent exocytosis downstream of vesicle priming, revealing a novel autoinhibitory role for the C2B...
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28739947/morphologies-of-synaptic-protein-membrane-fusion-interfaces
#10
Preeti Gipson, Yoshiyuki Fukuda, Radostin Danev, Ying Lai, Dong-Hua Chen, Wolfgang Baumeister, Axel T Brunger
Neurotransmitter release is orchestrated by synaptic proteins, such as SNAREs, synaptotagmin, and complexin, but the molecular mechanisms remain unclear. We visualized functionally active synaptic proteins reconstituted into proteoliposomes and their interactions in a native membrane environment by electron cryotomography with a Volta phase plate for improved resolvability. The images revealed individual synaptic proteins and synaptic protein complex densities at prefusion contact sites between membranes. We observed distinct morphologies of individual synaptic proteins and their complexes...
August 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28713022/resveratrol-inhibits-phorbol-ester-induced-membrane-translocation-of-presynaptic-munc13-1
#11
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
#12
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
RAB3A-interacting molecule (RIM) 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...
August 16, 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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