Synaptic Vesicle Fusion

Thomas FJ Martin, University of Wisconsin Madison, Wisconsin, USA

Published online: February 2003

DOI: 10.1038/npg.els.0000209

Neurotransmitter release from synaptic terminals occurs by the rapid, calcium-dependent fusion of transmitter-containing synaptic vesicles with the presynaptic membrane. The core machinery that mediates membrane fusion is thought to consist of the neuronal SNARE proteins (VAMP/synaptobrevin, syntaxin and SNAP-25). Accessory proteins operate at various stages to mediate the priming of vesicles to fusion competence (NSF/SNAP, munc18, munc13) and the detection of calcium increases that trigger fusion (synaptotagmin).

Keywords: synaptic vesicle; membrane fusion; exocytosis; neurotransmitter secretion; calcium regulation

Figure 1. Molecular mechanisms underlying synaptic vesicle exocytosis. A reserve pool of synaptic vesicles (1), linked to actin by synapsin, is recruited to docking sites at the active zone by vesicle detachment followed by movement via myosin motors. Following vesicle docking at the presynaptic active zone (2), vesicles are rendered fusion-competent by a series of priming steps (2 5 or 6) that may involve ATP-dependent, NSF-mediated disassembly of cis SNARE complexes (2 3), ATP-dependent synthesis of PI(4,5)P2 (2 3), munc18 dissociation from syntaxin possibly catalysed by munc13 (3 4), and the formation of loosely assembled (4 5) or fully assembled (4 6) trans SNARE complexes.  Ca2+ triggering of fusion is depicted as mediated through synaptotagmins on either vesicle or presynaptic membrane.  Ca2+ binding to synaptotagmins could promote formation of fully assembled trans SNARE complexes and fusion (5 7). Alternatively, a fully assembled trans SNARE complex that initiated hemi-fusion (6) could be acted upon by  Ca2+-bound synaptotagmin to promote transition to fusion pore formation and full fusion (6 7). Subsequent dilation of the fusion pore and release of neurotransmitter is depicted in (8).
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 References
    Ahmari SE, Buchanan J and Smith SJ (2000) Assembly of presynaptic active zones from cytoplasmic transport packets. Nature Neuroscience 3: 445–451.
    Ales E, Tabares L, Poyato JM et al. (1999) High calcium concentrations shift the mode of exocytosis to the kiss-and-run mechanism. Nature Cell Biology 1: 40–44.
    Betz WJ and Angleson JK (1998) The synaptic vesicle cycle. Annual Review of Physiology 60: 347–363.
    Bock JB and Scheller RH (1999) SNARE proteins mediate lipid bilayer fusion. Proceedings of the National Academy of Sciences of the USA 96: 12227–12229.
    Butz S, Fernandez-Chacon R, Schmitz F, Jahn R and Sudhof TC (1999) The subcellular localization of atypical synaptotagmins III and VI. Journal of Biological Chemistry 274: 18290–18296.
    Chen YA, Scales SJ, Patel SM, Doung Y-C and Scheller RH (1999) SNARE complex formation is triggered by  Ca2+ and drives membrane fusion. Cell 97: 165–174.
    Chernomordik LV, Frolov VA, Leikina E, Bronk P and Zimmerberg J (1998) The pathway of membrane fusion catalyzed by influenza hemagglutinin: restriction of lipids, hemifusion, and lipidic fusion pore formation. Journal of Cell Biology 140: 1369–1382.
    DeCamilli P (1995) Keeping synapses up to speed. Nature 375: 450–451.
    Desai RC, Vyas B, Earles CA et al. (2000) The C2B domain of synaptotagmin is a  Ca2+-sensing module essential for exocytosis. Journal of Cell Biology 150: 1125–1135.
    Geppert M, Goda Y, Hammer RE et al. (1994) Synaptotagmin I: a major  Ca2+ sensor for transmitter release at a central synapse. Cell 79: 717–727.
    Hanson PI, Heuser JE and Jahn R (1997) Neurotransmitter release – four years of SNARE complexes. Current Opinion in Neurobiology 7: 310–315.
    Jahn R and Sudhof TC (1999) Membrane fusion and exocytosis. Annual Review of Biochemistry 68: 863–911.
    Jahn R (2000) Sec1/Munc18 proteins: mediators of membrane fusion moving to center stage. Neuron 27: 201–204.
    Li C, Ullrich B, Zhang JZ et al. (1995)  Ca2+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature 375: 594–599.
    Lindau M and Almers W (1995) Structure and function of fusion pores in exocytosis and ectoplasmic membrane fusion. Current Opinion in Cell Biology 7: 509–517.
    Littleton JT and Bellen HJ (1995) Synaptotagmin controls and modulates synaptic vesicle fusion in a  Ca2+-dependent manner. Trends in Neuroscience 18: 177–183.
    Lonart G and Sudhof TC (2000) Assembly of SNARE complexes occurs prior to transmitter release to set the readily-releasable pool of synaptic vesicles. Journal of Biological Chemistry 275: 27703–27707.
    Martin TFJ (1997) Stages of regulated exocytosis. Trends in Cell Biology 7: 271–276.
    Pieribone VA, Shupliakov O, Brodin L et al. (1995) Distinct pools of synaptic vesicles in neurotransmitter release. Nature 375: 493–497.
    Rizo J and Sudhof TC (1998) C2 domains, structure and function of a universal  Ca2+-binding domain. Journal of Biological Chemistry 273: 15879–15882.
    Robinson LJ and Martin TFJ (1998) Docking and fusion in neurosecretion. Current Opinion in Cell Biology 10: 483–492.
    Rosahl TW, Spillane D, Missler M et al. (1995) Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 375: 488–497.
    Ryan TA (1999) Inhibitors of myosin light chain kinase block synaptic vesicle pool mobilization during action potential firing. Journal of Neuroscience 19: 1317–1323.
    Sabatini BL and Regehr WG (1999) Timing of synaptic transmission. Annual Review Physiology 61: 521–542.
    Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 375: 645–653.
    Sutton RB, Fasshauer D, Jahn R and Brunger AT (1998) Crystal structure of SNARE complex involved in synaptic exocytosis at 2.4 angstroms resolution. Nature 395: 347–353.
    Ungermann C, Sato K and Wickner W (1998) Defining the functions of trans SNARE pairs. Nature 396: 543–548.
    Weber T, Zemelman BV, McNew JA et al. (1998) SNAREpins: minimal machinery for membrane fusion. Cell 92: 759–772.
    Xu T, Rammner B, Margittai M et al. (1999) Inhibition of SNARE complex assembly differentially affects kinetic components of exocytosis. Cell 99: 713–722.
 Further Reading
    book Bellen H (1999) Neurotransmitter Release. Oxford: Oxford University Press.
    Fasshauer D, Sutton BR, Brunger AT and Jahn R (1998) Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. Proceedings of the National Academy of Sciences of the USA 95: 15781–15786.
    Greengard P, Valtorta F, Czernik AJ and Benfenati F (1993) Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259: 780–785.
    Hughson FM (1999) Membrane fusion: structure snared at last. Current Biology 9: R49–R52.
    McNew JA, Parlati F, Fukuda R et al. (2000) Compartmental specificity of cellular membrane fusion encoded in SNARE proteins. Nature 407: 153–159.
    Weimbs T, Low SH, Chapin SJ et al. (1997) A conserved domain is present in different families of vesicular fusion proteins: a new superfamily. Proceedings of the National Academy of Sciences of the USA 94: 3046–3051.

Related Sub-Topics:

Neurotransmitters | Synaptic Transmission
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Article Title: Synaptic Vesicle Fusion
 
How to Cite close
Martin, Thomas FJ(Feb 2003) Synaptic Vesicle Fusion. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0000209]