Tissue-Specific Dynamin-1 Deletion at the Calyx of Held Decreases Short
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SNARE Proteins and the Timing of Neurotransmitter Release
Molecular Psychiatry (1998) 3, 293–297 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 NEWS & VIEWS SNARE proteins and the timing of neurotransmitter release The SNARE complex proteins have been implicated in exocytotic neurotransmitter release and other forms of membrane fusion. Recent work shows that NSF, the ATPase of the SNARE complex, regulates the kinetics of neurotransmitter release and can thereby control the inte- grative properties of synapses. Time is one of the most critical parameters in the func- hydrolyzes ATP. Because SNAREs are found on both tioning of the brain. Information transfer on the time- the synaptic vesicle membrane and the plasma mem- scale of milliseconds (10−3 seconds) is typical through- brane, it has been postulated that the various SNARE out the brain and in certain brain regions, such as the complexes mediate the interaction between the two auditory brainstem, time differences on the order of membranes before fusion and thus may be necessary microseconds (10−6 seconds) are used to define the fre- for neurotransmitter release.2 quency and location of perceived sounds. Thus infor- Evidence for a role for SNARE proteins in neuro- mation processing not only depends on a fast underly- transmitter release has come from a variety of sources. ing process but also on the precise timing of synaptic The most compelling indication of the central impor- activity. Such high temporal fidelity must rely upon tance of the three membrane SNARE proteins is that very finely-regulated molecular mechanisms. However, these proteins are remarkably specific targets of tetanus until recently the identity of these mechanisms has and botulinum toxins, a group of potent neurotoxins been remarkably elusive. -
Identification of Synaptic Proteins and Their Isoform Mrnas In
Proc. Natl. Acad. Sci. USA Vol. 91, pp. 12487-12491, December 1994 Cell Biology Identification of synaptic proteins and their isoform mRNAs in compartments of pancreatic endocrine cells (exocytosis/secretion/insulin/diabetes) GUNILLA JACOBSSON*, ANDREW J. BEANt, RICHARD H. SCHELLERt, LISA JUNTTI-BERGGRENt, JUDE T. DEENEYt, PER-OLOF BERGGRENt AND BJORN MEISTER*§ *Department of Neuroscience and tRolf Luft's Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institute, S-171 77 Stockholm, Sweden; and tDepartment of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Beckman Center, Stanford University, Stanford, CA 94305 Communicated by Tomas Hokfelt, August 30, 1994 ABSTRACT Several proteins that are of importance for clostridial neurotoxins, including tetanus toxin and botuli- membrane trafficking in the nerve terminal have recently been num neurotoxin B, whereas botulinum neurotoxins D and F characterized. We have used Western blot and immunohis- are capable of cleaving both forms of VAMP (10-12). tochemistry to show that synaptotagmin, synaptobrevin/VAMP VAMP-1 and VAMP-2 are encoded by two distinct genes (13) (vesicle-associated membrane protein), SNAP-25 (synaptosom- and are differentially expressed in the nervous system (14). al-associated protein of 25 kDa), and syntaxin proteins are Cellubrevin is a homologue of VAMP, which is present in a present in cells of the islets of Langerhans in the endocrine wide variety of tissues and may be a membrane trafficking pancreas. Synaptotagmin-like immunoreactivity (-LI) was lo- protein of a constitutively recycling pathway (15). calized to granules within the cytoplasm of a few endocrine cells In contrast to synaptotagmin and VAMP, the synaptoso- located in the periphery of the islets, identified as somatostatin- mal-associated protein of 25 kDa (SNAP-25) is located at the containing cells, and in many nerve fibers within the islets. -
Variable Priming of a Docked Synaptic Vesicle PNAS PLUS
Variable priming of a docked synaptic vesicle PNAS PLUS Jae Hoon Junga,b,c, Joseph A. Szulea,c, Robert M. Marshalla,c, and Uel J. McMahana,c,1 aDepartment of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305; bDepartment of Physics, Stanford University School of Humanities and Sciences, Stanford, CA 94305; and cDepartment of Biology, Texas A&M University, College Station, TX 77845 Edited by Thomas S. Reese, National Institutes of Health, Bethesda, MD, and approved January 12, 2016 (received for review November 30, 2015) The priming of a docked synaptic vesicle determines the proba- transition. Biochemical and electrophysiological approaches have bility of its membrane (VM) fusing with the presynaptic membrane provided evidence that priming is mediated by interactions be- (PM) when a nerve impulse arrives. To gain insight into the nature tween the SNARE proteins and their regulators (7, 12–14, 24) and of priming, we searched by electron tomography for structural can involve differences in positioning of docked SVs relative to + relationships correlated with fusion probability at active zones of Ca2 channels (25). Biochemistry has also led to the suggestion axon terminals at frog neuromuscular junctions. For terminals that primed SVs may become deprimed (26). fixed at rest, the contact area between the VM of docked vesicles We have previously shown by electron tomography on frog and PM varied >10-fold with a normal distribution. There was no neuromuscular junctions (NMJs) fixed at rest that there are, for merging of the membranes. For terminals fixed during repetitive docked SVs, variations in the extent of the VM–PM contact area evoked synaptic transmission, the normal distribution of contact and in the length of the several AZM macromolecules linking areas was shifted to the left, due in part to a decreased number of the VM to the PM, the so-called ribs, pegs, and pins (2, 27). -
Mechanisms of Synaptic Plasticity Mediated by Clathrin Adaptor-Protein Complexes 1 and 2 in Mice
Mechanisms of synaptic plasticity mediated by Clathrin Adaptor-protein complexes 1 and 2 in mice Dissertation for the award of the degree “Doctor rerum naturalium” at the Georg-August-University Göttingen within the doctoral program “Molecular Biology of Cells” of the Georg-August University School of Science (GAUSS) Submitted by Ratnakar Mishra Born in Birpur, Bihar, India Göttingen, Germany 2019 1 Members of the Thesis Committee Prof. Dr. Peter Schu Institute for Cellular Biochemistry, (Supervisor and first referee) University Medical Center Göttingen, Germany Dr. Hans Dieter Schmitt Neurobiology, Max Planck Institute (Second referee) for Biophysical Chemistry, Göttingen, Germany Prof. Dr. med. Thomas A. Bayer Division of Molecular Psychiatry, University Medical Center, Göttingen, Germany Additional Members of the Examination Board Prof. Dr. Silvio O. Rizzoli Department of Neuro-and Sensory Physiology, University Medical Center Göttingen, Germany Dr. Roland Dosch Institute of Developmental Biochemistry, University Medical Center Göttingen, Germany Prof. Dr. med. Martin Oppermann Institute of Cellular and Molecular Immunology, University Medical Center, Göttingen, Germany Date of oral examination: 14th may 2019 2 Table of Contents List of abbreviations ................................................................................. 5 Abstract ................................................................................................... 7 Chapter 1: Introduction ............................................................................ -
SNAP-24, a Novel Drosophila SNARE Protein 4057 Proteins Were Purified on Glutathione Beads and Cleaved from the GST Fig
Journal of Cell Science 113, 4055-4064 (2000) 4055 Printed in Great Britain © The Company of Biologists Limited 2000 JCS1894 SNAP-24, a Drosophila SNAP-25 homologue on granule membranes, is a putative mediator of secretion and granule-granule fusion in salivary glands Barbara A. Niemeyer*,‡ and Thomas L. Schwarz§ Department of Molecular and Cellular Physiology, Stanford Medical School, Stanford, CA 94305, USA *Present address: Department of Pharmacology and Toxicology, School of Medicine, University of Saarland, D-66421 Homburg, Germany ‡Author for correspondence (e-mail: [email protected]) §Present address: Harvard Medical School, Division of Neuroscience, The Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA Accepted 16 September; published on WWW 31 October 2000 SUMMARY Fusion of vesicles with target membranes is dependent is not concentrated in synaptic regions. In vitro studies, on the interaction of target (t) and vesicle (v) SNARE however, show that SNAP-24 can form core complexes with (soluble NSF (N-ethylmaleimide-sensitive fusion protein) syntaxin and both synaptic and non-synaptic v-SNAREs. attachment protein receptor) proteins located on opposing High levels of SNAP-24 are found in larval salivary glands, membranes. For fusion at the plasma membrane, the t- where SNAP-24 localizes mainly to granule membranes SNARE SNAP-25 is essential. In Drosophila, the only rather than the plasma membrane. During glue secretion, known SNAP-25 isoform is specific to neuronal axons and the massive exocytotic event of these glands, SNAP-24 synapses and additional t-SNAREs must exist that mediate containing granules fuse with one another and the apical both non-synaptic fusion in neurons and constitutive and membrane, suggesting that glue secretion utilizes regulated fusion in other cells. -
Is Synaptotagmin the Calcium Sensor? Motojiro Yoshihara, Bill Adolfsen and J Troy Littleton
315 Is synaptotagmin the calcium sensor? Motojiro Yoshihara, Bill Adolfsen and J Troy Littletonà After much debate, recent progress indicates that the synaptic synaptotagmins, which are transmembrane proteins con- vesicle protein synaptotagmin I probably functions as the taining tandem calcium-binding C2 domains (C2A and calcium sensor for synchronous neurotransmitter release. C2B) (Figure 1a). Synaptotagmin I is an abundant cal- Following calcium influx into presynaptic terminals, cium-binding synaptic vesicle protein [8,9] that has been synaptotagmin I rapidly triggers the fusion of synaptic vesicles demonstrated via genetic studies to be important for with the plasma membrane and underlies the fourth-order efficient synaptic transmission in vivo [10–13]. The C2 calcium cooperativity of release. Biochemical and genetic domains of synaptotagmin I bind negatively-charged studies suggest that lipid and SNARE interactions underlie phospholipids in a calcium-dependent manner [9,14,15, synaptotagmin’s ability to mediate the incredible speed of 16–18]. There is compelling evidence that phospholipid vesicle fusion that is the hallmark of fast synaptic transmission. binding is an effector interaction in vesicle fusion, as the calcium dependence of this process ( 74 mM) and its Addresses rapid kinetics (on a millisecond scale) (Figure 1b) fit Picower Center for Learning and Memory, Department of Biology and reasonably well with the predicted requirements of Department of Brain and Cognitive Sciences, Massachusetts synaptic transmission [15]. In addition to phospholipid Institute of Technology, Cambridge, MA 02139, USA Ãe-mail: [email protected] binding, the calcium-stimulated interaction between synaptotagmin and the t-SNAREs syntaxin and SNAP- 25 [15,19–23] provides a direct link between calcium and Current Opinion in Neurobiology 2003, 13:315–323 the fusion complex. -
Liquid-Liquid Phase Separation in Physiology and Pathophysiology of the Nervous System
The Journal of Neuroscience, 0, 2021 • 00(00):000 • 1 Symposium Liquid-Liquid Phase Separation in Physiology and Pathophysiology of the Nervous System Yasunori Hayashi,1 Lenzie K. Ford,2 Luana Fioriti,3 Leeanne McGurk,4 and Mingjie Zhang5,6 1Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan, 2Zuckerman Mind, Brain, Behavior Institute, Columbia University, New York, New York 10027, 3Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Istituto Di Ricovero e Cura a Carattere Scientifico, Milan 20156, Italy, 4Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom, 5Division of Life Science, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China, and 6School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China Molecules within cells are segregated into functional domains to form various organelles. While some of those organelles are delimited by lipid membranes demarcating their constituents, others lack a membrane enclosure. Recently, liquid-liquid phase separation (LLPS) revolutionized our view of how segregation of macromolecules can produce membraneless organelles. While the concept of LLPS has been well studied in the areas of soft matter physics and polymer chemistry, its significance has only recently been recognized in the field of biology. It occurs typically between macromolecules that have multivalent interactions. Interestingly, these features are -
RIM-BP2 Primes Synaptic Vesicles Via Recruitment of Munc13-1 At
RESEARCH ARTICLE RIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses Marisa M Brockmann1†, Marta Maglione2,3,4†, Claudia G Willmes5†, Alexander Stumpf6, Boris A Bouazza1, Laura M Velasquez6, M Katharina Grauel1, Prateep Beed6, Martin Lehmann3, Niclas Gimber6, Jan Schmoranzer4, Stephan J Sigrist2,4,5*, Christian Rosenmund1,4*, Dietmar Schmitz4,5,6* 1Institut fu¨ r Neurophysiologie, Charite´ – Universita¨ tsmedizin Berlin, corporate member of Freie Universita¨ t Berlin, Humboldt-Universita¨ t zu Berlin, and Berlin Institute of Health, Berlin, Germany; 2Freie Universita¨ t Berlin, Institut fu¨ r Biologie, Berlin, Germany; 3Leibniz-Forschungsinstitut fu¨ r Molekulare Pharmakologie (FMP), Berlin, Germany; 4NeuroCure Cluster of Excellence, Berlin, Germany; 5DZNE, German Center for Neurodegenerative Diseases, Berlin, Germany; 6Neuroscience Research Center, Charite´ – Universita¨ tsmedizin Berlin, corporate member of Freie Universita¨ t Berlin, Humboldt-Universita¨ t zu Berlin, and Berlin Institute of Health, Berlin, Germany Abstract All synapses require fusion-competent vesicles and coordinated Ca2+-secretion coupling for neurotransmission, yet functional and anatomical properties are diverse across *For correspondence: different synapse types. We show that the presynaptic protein RIM-BP2 has diversified functions in [email protected] (SJS); neurotransmitter release at different central murine synapses and thus contributes to synaptic [email protected] diversity. At hippocampal pyramidal CA3-CA1 synapses, RIM-BP2 loss has a mild effect on (CR); neurotransmitter release, by only regulating Ca2+-secretion coupling. However, at hippocampal [email protected] (DS) mossy fiber synapses, RIM-BP2 has a substantial impact on neurotransmitter release by promoting †These authors contributed vesicle docking/priming and vesicular release probability via stabilization of Munc13-1 at the active equally to this work zone. -
Interaction Between Liprin-Αand GIT1 Is Required for AMPA Receptor
The Journal of Neuroscience, March 1, 2003 • 23(5):1667–1677 • 1667 Interaction between Liprin-␣ and GIT1 Is Required for AMPA Receptor Targeting Jaewon Ko,1 Seho Kim,1 Juli G. Valtschanoff,2 Hyewon Shin,1 Jae-Ran Lee,1 Morgan Sheng,3 Richard T. Premont,4 Richard J. Weinberg,2 and Eunjoon Kim1 1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea, 2Department of Cell Biology and Anatomy, University of North Carolina Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, 3Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and 4Department of Medicine (Gastroenterology), Duke University Medical Center, Durham, North Carolina 27710 Liprin-␣ is a multidomain protein that interacts with the LAR family of receptor protein tyrosine phosphatases and the GRIP/ABP family of AMPA receptor-interacting proteins. Previous studies have indicated that liprin-␣ regulates the development of presynaptic active zones and that the association of liprin-␣ with GRIP is required for postsynaptic targeting of AMPA receptors. However, the underlying molecular mechanisms are not well understood. Here we report that liprin-␣ directly interacts with GIT1, a multidomain protein with GTPase-activating protein activity for the ADP-ribosylation factor family of small GTPases known to regulate protein trafficking and the actin cytoskeleton. Electron microscopic analysis indicates that GIT1 distributes to the region of postsynaptic density (PSD) as well as presynaptic active zones. GIT1 is enriched in PSD fractions and forms a complex with liprin-␣, GRIP, and AMPA receptors in brain. -
Analysis of Protein Phosphorylation in Nerve Terminal Reveals Extensive
RESEARCH ARTICLE Analysis of protein phosphorylation in nerve terminal reveals extensive changes in active zone proteins upon exocytosis Mahdokht Kohansal-Nodehi1, John JE Chua2,3,4,5, Henning Urlaub6,7, Reinhard Jahn1*, Dominika Czernik1* 1Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Go¨ ttingen, Germany; 2Interactomics and Intracellular Trafficking laboratory, National University of Singapore, Singapore, Singapore; 3Department of Physiology, National University of Singapore, Singapore, Singapore; 4Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 5Neurobiology/ Ageing Programme, National University of Singapore, Singapore, Singapore; 6Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Go€ttingen, Germany; 7Bioanalytics Group, University Medical Center Go¨ ttingen, Go¨ ttingen, Germany Abstract Neurotransmitter release is mediated by the fast, calcium-triggered fusion of synaptic vesicles with the presynaptic plasma membrane, followed by endocytosis and recycling of the membrane of synaptic vesicles. While many of the proteins governing these processes are known, their regulation is only beginning to be understood. Here we have applied quantitative phosphoproteomics to identify changes in phosphorylation status of presynaptic proteins in resting and stimulated nerve terminals isolated from the brains of Wistar rats. Using rigorous quantification, we identified 252 phosphosites that are either up- or downregulated upon triggering -
Changes in Synaptic Active Zone Proteins in Huntington's Disease
Huang et al. Acta Neuropathologica Communications (2020) 8:77 https://doi.org/10.1186/s40478-020-00949-y RESEARCH Open Access No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease Ting-Ting Huang1, Ruben Smith2, Karl Bacos3, Dong-Yan Song1, Richard M. Faull4, Henry J. Waldvogel4 and Jia-Yi Li1,5,6* Abstract Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reducedinmouseandcellculturemodelsofHDandinbrain tissues of patients with HD. Moreover, a striking re- distribution of a complex of proteins including Bassoon, Piccolo and Munc 13–1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was age- dependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. -
Molecular Mechanism of Fusion Pore Formation Driven by the Neuronal SNARE Complex
Molecular mechanism of fusion pore formation driven by the neuronal SNARE complex Satyan Sharmaa,1 and Manfred Lindaua,b aLaboratory for Nanoscale Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany and bSchool of Applied and Engineering Physics, Cornell University, Ithaca, NY 14850 Edited by Axel T. Brunger, Stanford University, Stanford, CA, and approved November 1, 2018 (received for review October 2, 2018) Release of neurotransmitters from synaptic vesicles begins with a systems in which various copy numbers of syb2 were incorporated narrow fusion pore, the structure of which remains unresolved. To in an ND while the t-SNAREs were present on a liposome have obtain a structural model of the fusion pore, we performed coarse- been used experimentally to study SNARE-mediated mem- grained molecular dynamics simulations of fusion between a brane fusion (13, 17). The small dimensions of the ND compared nanodisc and a planar bilayer bridged by four partially unzipped with a spherical vesicle makes such systems ideally suited for MD SNARE complexes. The simulations revealed that zipping of SNARE simulations without introducing extreme curvature, which is well complexes pulls the polar C-terminal residues of the synaptobrevin known to strongly influence the propensity of fusion (18–20). 2 and syntaxin 1A transmembrane domains to form a hydrophilic MARTINI-based CGMD simulations have been used in several – core between the two distal leaflets, inducing fusion pore forma- studies of membrane fusion (16, 21 23). To elucidate the fusion tion. The estimated conductances of these fusion pores are in good pore structure and the mechanism of its formation, we performed agreement with experimental values.