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Yukihiro Nakamura, Maria Reva, David A DiGregorio
The timing and probability of synaptic vesicle fusion from presynaptic terminals is governed by the strength of coupling between voltage-gated Ca2+ channels (VGCCs) and Ca2+ sensors for exocytosis. This VGCC-sensor coupling distance can be estimated from the fractional block of vesicular release by exogenous Ca2+ chelators. However, estimates of this distance can depend on many biophysical factors, whose contributions have not been thoroughly explored. Using numerical simulations of Ca2+ reaction and diffusion, as well as vesicular release, we examined the contributions of conductance, density, and open duration of VGCCs, as well as the influence of endogenous Ca2+ buffers on the inhibition of exocytosis by EGTA...
March 21, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Claudia Cavallini, Chiara Zannini, Elena Olivi, Riccardo Tassinari, Valentina Taglioli, Martina Rossi, Paola Poggi, Alexandros Chatgilialoglu, Giuliana Simonazzi, Francesco Alviano, Laura Bonsi, Carlo Ventura
Human mesenchymal stem cells (hMSCs) are an effective tool in regenerative medicine notably for their intrinsic plentiful paracrine activity rather than differentiating properties. The hMSC secretome includes a wide spectrum of regulatory and trophic factors, encompassing several naked molecules as well as different kinds of extracellular vesicles (EVs). Among EVs, exosomes represent an intriguing population, able to shuttle proteins, transcription factors, and genetic materials, with a relevant role in cell-to-cell communication, modulating biological responses in recipient cells...
January 2018: Cell Transplantation
Manami Yamashita, Shin-Ya Kawaguchi, Tetsuya Hori, Tomoyuki Takahashi
Synaptic efficacy plays crucial roles in neuronal circuit operation and synaptic plasticity. Presynaptic determinants of synaptic efficacy are neurotransmitter content in synaptic vesicles and the number of vesicles undergoing exocytosis at a time. Bursts of presynaptic firings depress synaptic efficacy, mainly due to depletion of releasable vesicles, whereas recovery from strong depression is initiated by endocytic vesicle retrieval followed by refilling of vesicles with neurotransmitter. We washed out presynaptic cytosolic GABA to induce a rundown of IPSCs at cerebellar inhibitory cell pairs in slices from rats and then allowed fast recovery by elevating GABA concentration using photo-uncaging...
March 20, 2018: Cell Reports
Anish Sharda, Robert Flaumenhaft
Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways...
2018: F1000Research
Ahmad Al-Attar, Steven R Presnell, Jody L Clasey, Douglas E Long, R Grace Walton, Morgan Sexton, Marlene E Starr, Philip A Kern, Charlotte A Peterson, Charles T Lutz
Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline...
2018: Frontiers in Immunology
Xiangyi Wen, Matthew J Van Hook, Justin J Grassmeyer, Alex I Wiesman, Grace M Rich, Karlene M Cork, Wallace B Thoreson
Endocytosis is an essential process at sites of synaptic release. Not only are synaptic vesicles recycled by endocytosis, but the removal of proteins and lipids by endocytosis is needed to restore release site function at active zones after vesicle fusion. Synaptic exocytosis from vertebrate photoreceptors involves synaptic ribbons that serve to cluster vesicles near the presynaptic membrane. In this study, we hypothesize that this clustering increases the likelihood that exocytosis at one ribbon release site may disrupt release at an adjacent site and therefore that endocytosis may be particularly important for restoring release site competence at photoreceptor ribbon synapses...
March 19, 2018: Journal of General Physiology
Hoda Fathali, Johan Dunevall, Soodabeh Majdi, Ann-Sofie Cans
Amperometry recording of cells subjected to osmotic shock show that secretory cells respond to this physical stress by reducing the exocytosis activity and the amount of neurotransmitter released from vesicles in single exocytosis events. It has been suggested that the reduction in neurotransmitters expelled is due to alterations in membrane biophysical properties when cells shrink in response to osmotic stress and with assumptions made that secretory vesicles in the cell cytoplasm are not affected by extracellular osmotic stress...
February 19, 2018: Journal of Visualized Experiments: JoVE
Xingmin Aaron Zhang, Thomas F J Martin
Here we describe two assays to measure dense core vesicle (DCV) exocytosis-mediated cargo secretion in neuroendocrine cells. To conduct siRNA screens for novel genes in regulated DCV exocytosis, we developed a plate reader-based secretion assay using DCV cargo, NPY-Venus, and an orthogonal3 H-serotonin secretion assay. The NPY-Venus secretion assay was successfully used for a high throughput siRNA screen, and the serotonin secretion assay was used to validate hits identified from the screen (Sorensen, 2017; Zhang et al...
January 5, 2018: Bio-protocol
Kamilla A Mukhutdinova, Marat R Kasimov, Arthur R Giniatullin, Guzel F Zakyrjanova, Alexey M Petrov
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the initial denervation of skeletal muscle and subsequent death of motor neurons. A dying-back pattern of ALS suggests a crucial role for neuromuscular junction dysfunction. In the present study, microelectrode recording of postsynaptic currents and optical detection of synaptic vesicle traffic (FM1-43 dye) and intracellular NO levels (DAF-FM DA) were used to examine the effect of the major brain-derived cholesterol metabolite 24S-hydroxycholesterol (24S-HC, 0...
March 14, 2018: Molecular and Cellular Neurosciences
Dafna Greitzer-Antes, Li Xie, Tairan Qin, Huanli Xie, Dan Zhu, Subhankar Dolai, Tao Liang, Fei Kang, Alexandre B Hardy, Yan He, Youhou Kang, Herbert Y Gaisano
The voltage-dependent K+ (Kv) channel Kv2.1 is a major delayed rectifier in many secretory cells, including pancreatic β-cells. In addition, Kv2.1 has a direct role in exocytosis at an undefined step, involving SNARE proteins and independent of its ion-conducting pore function. Here, we elucidated the precise step in exocytosis. We previously reported that syntaxin 3 (Syn-3) is the key syntaxin that mediates exocytosis of newcomer secretory granules that spend minimal residence time on the plasma membrane before fusion...
March 16, 2018: Journal of Biological Chemistry
Binyong Liang, Lukas K Tamm
SNARE-mediated membrane fusion is a ubiquitous process responsible for intracellular vesicle trafficking, including membrane fusion in exocytosis that leads to hormone and neurotransmitter release. The proteins that facilitate this process are highly dynamic and adopt multiple conformations when they interact with other proteins and lipids as they form highly regulated molecular machines that operate on membranes. Solution NMR is an ideal method to capture high-resolution glimpses of the molecular transformations that take place when these proteins come together and work on membranes...
April 2018: Progress in Nuclear Magnetic Resonance Spectroscopy
Aurore Quinault, Corinne Leloup, Geoffrey Denwood, Coralie Spiegelhalter, Marianne Rodriguez, Philippe Lefebvre, Nadia Messaddeq, Quan Zhang, Catherine Dacquet, Luc Pénicaud, Stephan C Collins
The rhythmic nature of insulin secretion over the 24h cycle in pancreatic islets has been mostly investigated using transcriptomics studies showing that modulation of insulin secretion over this cycle is achieved via distal stages of insulin secretion. We set out to measure β-cell exocytosis using in depth cell physiology techniques at several time points. In agreement with the activity and feeding pattern of nocturnal rodents, we find that C57/Bl6J islets in culture for 24h exhibit higher insulin secretion during the corresponding dark phase than in the light phase (Zeitgeber Time ZT20 and ZT8, respectively, in vivo)...
2018: PloS One
Marta Martínez-Calle, Bárbara Olmeda, Paul Dietl, Manfred Frick, Jesús Pérez-Gil
The release of pulmonary surfactant by alveolar type II (ATII) cells is essential for lowering surface tension at the respiratory air-liquid interface, stabilizing the lungs against physical forces tending to alveolar collapse. Hydrophobic surfactant protein (SP)-B ensures the proper packing of newly synthesized surfactant particles, promotes the formation of the surface active film at the alveolar air-liquid interface and maintains its proper structure along the respiratory dynamics. We report that membrane-associated SP-B efficiently induces secretion of pulmonary surfactant by ATII cells, at the same level as potent secretagogues such as ATP...
March 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Muhmmad Omar-Hmeadi, Nikhil Gandasi, Sebastian Barg
Phosphoinositides (PtdIns) play important roles in exocytosis and are thought to regulate secretory granule docking by co-clustering with the SNARE protein syntaxin to form a docking receptor in the plasma membrane. Here we tested this idea by high-resolution TIRF imaging of EGFP-labeled PtdIns markers or syntaxin-1 at secretory granule release sites in live insulin-secreting cells. In intact cells, PtdIns markers distributed evenly across the plasma membrane with no preference for granule docking sites. In contrast, syntaxin-1 was found clustered in the plasma membrane, mostly beneath docked granules...
March 14, 2018: Traffic
Geoffrey Masuyer, Sicai Zhang, Sulyman Barkho, Yi Shen, Linda Henriksson, Sara Košenina, Min Dong, Pål Stenmark
Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6...
March 14, 2018: Scientific Reports
Yi Yu, Su Chen, Xiaoqiang Mo, Jihong Gong, Chenhong Li, Xiaofei Yang
Complexins, binding to assembling soluble NSF-attachment protein receptor (SNARE) complexes, activate Ca2+ triggered exocytosis and clamp spontaneous release in the presynaptic terminal. Functions of complexin are structural dependent and mechanistically distinct. To further understand the functional/structural dependence of complexin, here we show that the accessory and central α-helices of complexin are sufficient in activation of Ca2+ triggered vesicle fusion but not in clamping spontaneous release. Targeting the two α-helices to synaptic vesicle suppresses spontaneous release, thus further emphasizing the importance of curvature membrane localization in clamping function...
2018: Frontiers in Molecular Neuroscience
Akiyuki Taruno
Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels...
March 11, 2018: International Journal of Molecular Sciences
Masafumi Taniwaki, Mihoko Yoshida, Yosuke Matsumoto, Kazuho Shimura, Junya Kuroda, Hiroto Kaneko
Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity...
2018: Mediterranean Journal of Hematology and Infectious Diseases
Jonas Reinholz, Christopher Diesler, Susanne Schöttler, Maria Kokkinopoulou, Sandra Ritz, Katharina Landfester, Volker Mailänder
The transport of nanocarriers through barriers like the gut in a living organism involves the transcytosis of these nanocarriers through the cell layer dividing two compartments. Understanding how this process works is not only essential to further developing strategies for a more effective nanocarrier transport system but also for providing fundamental insights into the barrier function as a means of protection against micro- and nanoplastics in the food chain. We therefore set out to investigate the different uptake mechanisms, intracellular trafficking and the routes for exocytosis for small polystyrene nanoparticles (PS-NPs ca...
March 9, 2018: Acta Biomaterialia
Priscila A C Valadão, Matheus P S M Gomes, Bárbara C Aragão, Hermann A Rodrigues, Jéssica N Andrade, Rubens Garcias, Julliane V Joviano-Santos, Murilo A Luiz, Wallace L Camargo, Lígia A Naves, Christopher Kushmerick, Walter L G Cavalcante, Márcia Gallacci, Itamar C G de Jesus, Silvia Guatimosim, Cristina Guatimosim
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination, and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model of HD (BACHD)...
March 9, 2018: Neurochemistry International
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