Key Points
-
Neuronal exocytosis is triggered by Ca2+ ions, and members of the synaptotagmin gene family (>13 isoforms) are leading candidates to serve as the Ca2+ sensors that trigger neurotransmitter release. Synaptotagmin I is the best characterized isoform, and is the most abundant Ca2+-binding protein on secretory organelles.
-
Genetic studies indicate that synaptotagmin I functions at several stages in the synaptic-vesicle cycle, including a key function between the docking and fusion of vesicles, which is consistent with its proposed role as a Ca2+ sensor during exocytosis. Synaptotagmin I also has a key role in endocytosis after fusion.
-
The structures of the Ca2+-sensing domains of synaptotagmin — C2A and C2B — and the Ca2+-binding sites of these domains have been determined.
-
Studies are now beginning to uncover how Ca2+ regulates the interaction of synaptotagmin with effectors. Ca2+ triggers the partial penetration of the Ca2+-binding loops of the C2 domains of synaptotagmin into lipid bilayers with very rapid kinetics. Penetration into the plasma membrane might pull bilayers together to facilitate fusion.
-
The C2 domains of synaptotagmin also interact directly with components of the SNARE complex, which is thought to form the core of a conserved membrane fusion machine. These interactions might facilitate the assembly of SNARE complexes to accelerate fusion.
-
Efforts at present are directed towards the reconstitution of Ca2+-triggered membrane fusion. A defined and reduced model system might make it possible to determine whether synaptotagmin is a Ca2+ sensor that triggers exocytosis.
Abstract
It has been fifty years since the discovery that Ca2+ triggers the rapid exocytosis of neurotransmitters from neurons. One of the proteins that has a crucial role in this secretion event is synaptotagmin I, an abundant constituent of synaptic vesicles that binds Ca2+ ions through two C2 domains. These properties prompted the idea that synaptotagmin I might function as a Ca2+-sensor that triggers neurotransmitter release. So does synaptotagmin trigger exocytosis in a Ca2+-dependent manner, and, if so, how does it operate?
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Jahn, R. & Sudhof, T. C. Membrane fusion and exocytosis. Annu. Rev. Biochem. 68, 863–911 (1999).
Augustine, G. J. How does calcium trigger neurotransmitter release? Curr. Opin. Neurobiol. 11, 320–326 (2001).
Almers, W. Synapses. How fast can you get? Nature 367, 682–683 (1994).
Llinas, R., Steinberg, I. Z. & Walton, K. Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys. J. 33, 323–351 (1981).
Sabatini, B. L. & Regehr, W. G. Timing of neurotransmission at fast synapses in the mammalian brain. Nature 384, 170–172 (1996).
Sun, J. Y. & Wu, L. G. Fast kinetics of exocytosis revealed by simultaneous measurements of presynaptic capacitance and postsynaptic currents at a central synapse. Neuron 30, 171–182 (2001).
Goda, Y. & Sudhof, T. C. Calcium regulation of neurotransmitter release: reliably unreliable? Curr. Opin. Cell Biol. 9, 513–518 (1997).
Renger, J. J., Egles, C. & Liu, G. A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron 29, 469–484 (2001).
Choi, S., Klingauf, J. & Tsien, R. W. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nature Neurosci. 3, 330–336 (2000).
Malenka, R. C. & Nicoll, R. A. Silent synapses speak up. Neuron 19, 473–476 (1997).
Rothman, J. E. Mechanisms of intracellular protein transport. Nature 372, 55–63 (1994).
Ferro-Novick, S. & Jahn, R. Vesicle fusion from yeast to man. Nature 370, 191–193 (1994).
Sollner, T. et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 362, 318–324 (1993).
Sutton, R. B., Fasshauer, D., Jahn, R. & Brunger, A. T. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395, 347–353 (1998).
Weber, T. et al. SNAREpins: minimal machinery for membrane fusion. Cell 92, 759–772 (1998).The first demonstration that purified SNARE proteins, when reconstituted into proteoliposomes, can catalyse membrane fusion in vitro.
Popov, S. V. & Poo, M. M. Synaptotagmin: a calcium-sensitive inhibitor of exocytosis? Cell 73, 1247–1249 (1993).
Marqueze, B., Berton, F. & Seagar, M. Synaptotagmins in membrane traffic: which vesicles do the tagmins tag? Biochimie 82, 409–420 (2000).
Katz, B. The Release of Neural Transmitter Substances (Thomas, Springfield, Illinois, 1969).
Matthew, W. D., Tsavaler, L. & Reichardt, L. F. Identification of a synaptic vesicle-specific membrane protein with a wide distribution in neuronal and neurosecretory tissue. J. Cell Biol. 91, 257–269 (1981).
Walch-Solimena, C. et al. Synaptotagmin: a membrane constituent of neuropeptide-containing large dense-core vesicles. J. Neurosci. 13, 3895–3903 (1993).
Perin, M. S., Fried, V. A., Mignery, G. A., Jahn, R. & Sudhof, T. C. Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature 345, 260–263 (1990).
Perin, M. S. et al. Structural and functional conservation of synaptotagmin (p65) in Drosophila and humans. J. Biol. Chem. 266, 615–622 (1991).
Craxton, M. Genomic analysis of synaptotagmin genes. Genomics 77, 43–49 (2001).
Chapman, E. R. & Jahn, R. Calcium-dependent interaction of the cytoplasmic region of synaptotagmin with membranes. Autonomous function of a single C2-homologous domain. J. Biol. Chem. 269, 5735–5741 (1994).
Brose, N., Petrenko, A. G., Sudhof, T. C. & Jahn, R. Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256, 1021–1025 (1992).This showed that synaptotagmin I is a Ca2+ sensor that binds membranes in response to Ca2+.
Sutton, R. B., Davletov, B. A., Berghuis, A. M., Sudhof, T. C. & Sprang, S. R. Structure of the first C2 domain of synaptotagmin I: a novel Ca2+/phospholipid-binding fold. Cell 80, 929–938 (1995).The first crystal structure of a C2 domain, which showed that Ca2+ is coordinated by residues in the two flexible loops that protrude from one end of C2 domains.
Nalefski, E. A. & Falke, J. J. The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci. 5, 2375–2390 (1996).
Fernandez, I. et al. Three-dimensional structure of the synaptotagmin 1 c(2)b-domain. Synaptotagmin 1 as a phospholipid binding machine. Neuron 32, 1057–1069 (2001).
Ubach, J., Garcia, J., Nittler, M. P., Sudhof, T. C. & Rizo, J. Structure of the Janus-faced C2B domain of rabphilin. Nature Cell Biol. 1, 106–112 (1999).
Sutton, R. B., Ernst, J. A. & Brunger, A. T. Crystal structure of the cytosolic C2A–C2B domains of synaptotagmin III. Implications for Ca2+-independent snare complex interaction. J. Cell Biol. 147, 589–598 (1999).
Perin, M. S. Mirror image motifs mediate the interaction of the COOH terminus of multiple synaptotagmins with the neurexins and calmodulin. Biochemistry 35, 13808–13816 (1996).
Fukuda, M. et al. Role of the conserved WHXL motif in the C terminus of synaptotagmin in synaptic vesicle docking. Proc. Natl Acad. Sci. USA 97, 14715–14719 (2000).
Jarousse, N. & Kelly, R. B. The AP2 binding site of synaptotagmin 1 is not an internalization signal but a regulator of endocytosis. J. Cell Biol. 154, 857–866 (2001).
Ubach, J., Zhang, X., Shao, X., Sudhof, T. C. & Rizo, J. Ca2+ binding to synaptotagmin: how many Ca2+ ions bind to the tip of a C2-domain? EMBO J. 17, 3921–3930 (1998).
Perin, M. S., Brose, N., Jahn, R. & Sudhof, T. C. Domain structure of synaptotagmin (p65). J. Biol. Chem. 266, 623–629 (1991).
Littleton, J. T., Stern, M., Perin, M. & Bellen, H. J. Calcium dependence of neurotransmitter release and rate of spontaneous vesicle fusions are altered in Drosophila synaptotagmin mutants. Proc. Natl Acad. Sci. USA 91, 10888–10892 (1994).
Bai, J., Earles, C. A., Lewis, J. L. & Chapman, E. R. Membrane-embedded synaptotagmin penetrates cis or trans target membranes and clusters via a novel mechanism. J. Biol. Chem. 275, 25427–25435 (2000).
Von Poser, C. et al. Synaptotagmin regulation of coated pit assembly. J. Biol. Chem. 275, 30916–30924 (2000).
Fukuda, M., Kanno, E. & Mikoshiba, K. Conserved N-terminal cysteine motif is essential for homo- and heterodimer formation of synaptotagmins III, V, VI, and X. J. Biol. Chem. 274, 31421–31427 (1999).
Fukuda, M., Kanno, E., Ogata, Y. & Mikoshiba, K. Mechanism of the SDS-resistant synaptotagmin clustering mediated by the cysteine cluster at the interface between the transmembrane and spacer domains. J. Biol. Chem. 276, 40319–40325 (2001).
Desai, R. C. et al. The C2B domain of synaptotagmin is a Ca2+-sensing module essential for exocytosis. J. Cell Biol. 150, 1125–1136 (2000).
Damer, C. K. & Creutz, C. E. Calcium-dependent self-association of synaptotagmin I. J. Neurochem. 67, 1661–1668 (1996).
Chapman, E. R., An, S., Edwardson, J. M. & Jahn, R. A novel function for the second C2 domain of synaptotagmin. Ca2+-triggered dimerization. J. Biol. Chem. 271, 5844–5849 (1996).
Schoch, S. et al. RIM1α forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 415, 321–326 (2002).
Osborne, S. L., Herreros, J., Bastiaens, P. I. & Schiavo, G. Calcium-dependent oligomerization of synaptotagmins I and II. Synaptotagmins I and II are localized on the same synaptic vesicle and heterodimerize in the presence of calcium. J. Biol. Chem. 274, 59–66 (1999).This study showed that native synaptotagmin I and II hetero-oligomerize in response to Ca2+.
Fukuda, M. & Mikoshiba, K. Distinct self-oligomerization activities of synaptotagmin family. Unique calcium-dependent oligomerization properties of synaptotagmin VII. J. Biol. Chem. 275, 28180–28185 (2000).
Fukuda, M. & Mikoshiba, K. Mechanism of the calcium-dependent multimerization of synaptotagmin VII mediated by its first and second C2 domains. J. Biol. Chem. 276, 27670–27676 (2001).
Sugita, S., Hata, Y. & Sudhof, T. C. Distinct Ca2+-dependent properties of the first and second C2-domains of synaptotagmin I. J. Biol. Chem. 271, 1262–1265 (1996).
Garcia, R. A., Forde, C. E. & Godwin, H. A. Calcium triggers an intramolecular association of the C2 domains in synaptotagmin. Proc. Natl Acad. Sci. USA 97, 5883–5888 (2000).
Ubach, J. et al. The C2B domain of synaptotagmin I is a Ca2+-binding module. Biochemistry 40, 5854–5860 (2001).
Littleton, J. T. et al. Synaptotagmin mutants reveal essential functions for the C2B domain in Ca2+-triggered fusion and recycling of synaptic vesicles in vivo. J. Neurosci. 21, 1421–1433 (2001).
Wang, C. T. et al. Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles. Science 294, 1111–1115 (2001).This study provided evidence that the ratio of different synaptotagmin isoforms on a secretory vesicle might determine the stability of fusion pores, which place synaptotagmins at the final steps of membrane fusion.
Augustine, G. J., Charlton, M. P. & Smith, S. J. Calcium action in synaptic transmitter release. Annu. Rev. Neurosci. 10, 633–693 (1987).
Elferink, L. A., Peterson, M. R. & Scheller, R. H. A role for synaptotagmin (p65) in regulated exocytosis. Cell 72, 153–159 (1993).
Fukuda, M. et al. Role of the C2B domain of synaptotagmin in vesicular release and recycling as determined by specific antibody injection into the squid giant synapse preterminal. Proc. Natl Acad. Sci. USA 92, 10708–10712 (1995).
Mikoshiba, K. et al. Role of the C2A domain of synaptotagmin in transmitter release as determined by specific antibody injection into the squid giant synapse preterminal. Proc. Natl Acad. Sci. USA 92, 10703–10707 (1995).
Bommert, K. et al. Inhibition of neurotransmitter release by C2-domain peptides implicates synaptotagmin in exocytosis. Nature 363, 163–165 (1993).
Geppert, M. et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 79, 717–727 (1994).
Geppert, M., Goda, Y., Stevens, C. F. & Sudhof, T. C. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature 387, 810–814 (1997).This study showed that the number of vesicles that can be released in response to hypertonic sucrose is not diminished in synaptotagmin-I-null mutants, which provides some of the first evidence to indicate that synaptotagmin I has a post-docking role in exocytosis.
Aravamudan, B., Fergestad, T., Davis, W. S., Rodesch, C. K. & Broadie, K. Drosophila UNC-13 is essential for synaptic transmission. Nature Neurosci. 2, 965–971 (1999).
Augustin, I., Rosenmund, C., Sudhof, T. C. & Brose, N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400, 457–461 (1999).
Rosenmund, C. & Stevens, C. F. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 16, 1197–1207 (1996).
Neher, E. & Penner, R. Mice sans synaptotagmin. Nature 372, 316–317 (1994).
Voets, T. et al. Intracellular calcium dependence of large dense-core vesicle exocytosis in the absence of synaptotagmin I. Proc. Natl Acad. Sci. USA 98, 11680–11685 (2001).
Kim, D. K. & Catterall, W. A. Ca2+-dependent and-independent interactions of the isoforms of the α1A subunit of brain Ca2+ channels with presynaptic SNARE proteins. Proc. Natl Acad. Sci. USA 94, 14782–14786 (1997).
Charvin, N. et al. Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the α1A subunit of the P/Q-type calcium channel. EMBO J. 16, 4591–4596 (1997).
Wiser, O., Tobi, D., Trus, M. & Atlas, D. Synaptotagmin restores kinetic properties of a syntaxin-associated N-type voltage sensitive calcium channel. FEBS Lett. 404, 203–207 (1997).
Reim, K. et al. Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell 104, 71–81 (2001).
DiAntonio, A. & Schwarz, T. L. The effect on synaptic physiology of synaptotagmin mutations in Drosophila. Neuron 12, 909–920 (1994).
Littleton, J. T., Serano, T. L., Rubin, G. M., Ganetzky, B. & Chapman, E. R. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature 400, 757–760 (1999).
Reist, N. E. et al. Morphologically docked synaptic vesicles are reduced in synaptotagmin mutants of Drosophila. J. Neurosci. 18, 7662–7673 (1998).
Vician, L. et al. Synaptotagmin IV is an immediate early gene induced by depolarization in PC12 cells and in brain. Proc. Natl Acad. Sci. USA 92, 2164–2168 (1995).
Von Poser, C., Ichtchenko, K., Shao, X., Rizo, J. & Sudhof, T. C. The evolutionary pressure to inactivate. A subclass of synaptotagmins with an amino acid substitution that abolishes Ca2+ binding. J. Biol. Chem. 272, 14314–14319 (1997).
Jorgensen, E. M. et al. Defective recycling of synaptic vesicles in synaptotagmin mutants of Caenorhabditis elegans. Nature 378, 196–199 (1995).Some of the first functional evidence that synaptotagmin might have a role in synaptic-vesicle recycling.
Takei, K. & Haucke, V. Clathrin-mediated endocytosis: membrane factors pull the trigger. Trends Cell Biol. 11, 385–391 (2001).
Slepnev, V. I. & De Camilli, P. Accessory factors in clathrin-dependent synaptic vesicle endocytosis. Nature Rev. Neurosci. 1, 161–172 (2000).
Haucke, V. & De Camilli, P. AP-2 recruitment to synaptotagmin stimulated by tyrosine-based endocytic motifs. Science 285, 1268–1271 (1999).
Schiavo, G., Gu, Q. M., Prestwich, G. D., Sollner, T. H. & Rothman, J. E. Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. Proc. Natl Acad. Sci. USA 93, 13327–13332 (1996).This study showed that the C2B domain of synaptotagmin I binds with high affinity to PtdIns(4,5)P 2 , which is a lipid that is thought to have an essential role in both exo- and endocytosis.
Micheva, K. D., Holz, R. W. & Smith, S. J. Regulation of presynaptic phosphatidylinositol 4,5-biphosphate by neuronal activity. J. Cell Biol. 154, 355–368 (2001).
Holz, R. W. et al. A pleckstrin homology domain specific for phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2) and fused to green fluorescent protein identifies plasma membrane PtdIns-4,5-P2 as being important in exocytosis. J. Biol. Chem. 275, 17878–17885 (2000).
Phillips, A. M., Smith, M., Ramaswami, M. & Kelly, L. E. The products of the Drosophila stoned locus interact with synaptic vesicles via synaptotagmin. J. Neurosci. 20, 8254–8261 (2000).
Fergestad, T. & Broadie, K. Interaction of stoned and synaptotagmin in synaptic vesicle endocytosis. J. Neurosci. 21, 1218–1227 (2001).
Walther, K. et al. Human stoned B interacts with AP-2 and synaptotagmin and facilitates clathrin-coated vesicle uncoating. EMBO Rep. 2, 634–640 (2001).
Lindau, M. & Almers, W. Structure and function of fusion pores in exocytosis and ectoplasmic membrane fusion. Curr. Opin. Cell. Biol. 7, 509–517 (1995).
Bai, J., Wang, P. & Chapman, E. R. C2A activates a cryptic Ca2+-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proc. Natl Acad. Sci. USA 99, 1665–1670 (2002).
Mayer, A. What drives membrane fusion in eukaryotes? Trends Biochem. Sci. 26, 717–723 (2001).
Chen, Y. A., Scales, S. J., Patel, S. M., Doung, Y. C. & Scheller, R. H. SNARE complex formation is triggered by Ca2+ and drives membrane fusion. Cell 97, 165–174 (1999).Compelling, albeit indirect, evidence that the SNARE complex might not form until arrival of the Ca2+ trigger.
Hu, K. et al. Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion. Nature 415, 646–650 (2002).This study describes a reconstituted system in which purified synaptic vesicles fused, in a Ca2+-dependent manner, with proteoliposomes that have purified t-SNAREs. This is the first functional, reduced system that contains the Ca2+ sensor for synaptic-vesicle fusion.
Chapman, E. R. & Davis, A. F. Direct interaction of a Ca2+-binding loop of synaptotagmin with lipid bilayers. J. Biol. Chem. 273, 13995–14001 (1998).This study showed how C2 domains interact with membranes, and showed that a Ca2+-binding loop directly penetrated bilayers.
Davis, A. F. et al. Kinetics of synaptotagmin responses to Ca2+ and assembly with the core SNARE complex onto membranes. Neuron 24, 363–376 (1999).The first kinetic analysis of synaptotagmin I, which showed that the C2 domains of synaptotagmin are specialized for speed of response. It also showed that synaptotagmin binds to the base of the SNARE complex in response to Ca2+.
Davletov, B., Perisic, O. & Williams, R. L. Calcium-dependent membrane penetration is a hallmark of the C2 domain of cytosolic phospholipase A2 whereas the C2A domain of synaptotagmin binds membranes electrostatically. J. Biol. Chem. 273, 19093–19096 (1998).
Nalefski, E. A. et al. C2 domains from different Ca2+ signaling pathways display functional and mechanistic diversity. Biochemistry 40, 3089–30100 (2001).
Earles, C. A., Bai, J., Wang, P. & Chapman, E. R. The tandem C2 domains of synaptotagmin contain redundant Ca2+ binding sites that cooperate to engage t-SNAREs and trigger exocytosis. J. Cell. Biol. 154, 1117–1123 (2001).Real-time secretion measurements from permeabilized PC12 cells were made, which provided evidence that synaptotagmin–SNARE interactions function during secretion, and showed that the Ca2+-binding sites in the tandem C2 domains of synaptotagmin I are partially 'redundant'.
Heidelberger, R., Heinemann, C., Neher, E. & Matthews, G. Calcium dependence of the rate of exocytosis in a synaptic terminal. Nature 371, 513–515 (1994).
Bollmann, J. H., Sakmann, B. & Borst, J. G. Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289, 953–957 (2000).
Schneggenburger, R. & Neher, E. Intracellular calcium dependence of transmitter release rates at a fast central synapse. Nature 406, 889–893 (2000).
Popoli, M., Venegoni, A., Buffa, L. & Racagni, G. Ca2+/phospholipid-binding and syntaxin-binding of native synaptotagmin I. Life Sci. 61, 711–721 (1997).
Li, C., Davletov, B. A. & Sudhof, T. C. Distinct Ca2+ and Sr2+ binding properties of synaptotagmins. Definition of candidate Ca2+ sensors for the fast and slow components of neurotransmitter release. J. Biol. Chem. 270, 24898–24902 (1995).
Li, C. et al. Ca2+-dependent and-independent activities of neural and non-neural synaptotagmins. Nature 375, 594–599 (1995).
Ullrich, B. et al. Functional properties of multiple synaptotagmins in brain. Neuron 13, 1281–1291 (1994).
Sugita, S., Shin, O. H., Han, W., Lao, Y. & Sudhof, T. C. Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities. EMBO J. 21, 270–280 (2002).
Klenchin, V. A. & Martin, T. F. Priming in exocytosis: attaining fusion-competence after vesicle docking. Biochimie 82, 399–407 (2000).
Davletov, B. A. & Sudhof, T. C. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J. Biol. Chem. 268, 26386–26390 (1993).
Fernandez-Chacon, R. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410, 41–49 (2001).
Fukuda, M., Kabayama, H. & Mikoshiba, K. Drosophila AD3 mutation of synaptotagmin impairs calcium-dependent self-oligomerization activity. FEBS Lett. 482, 269–272 (2000).
Xu, T. & Bajjalieh, S. M. SV2 modulates the size of the readily releasable pool of secretory vesicles. Nature Cell Biol. 3, 691–698 (2001).
Bennett, M. K., Calakos, N. & Scheller, R. H. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 257, 255–259 (1992).
Sollner, T., Bennett, M. K., Whiteheart, S. W., Scheller, R. H. & Rothman, J. E. A protein assembly–disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75, 409–418 (1993).The follow-up study to this group's discovery of the SNARE complex. Here, they characterize SNARE-complex disassembly by N -ethyl-maleimide-sensitive fusion protein (NSF) and show that a fourth component — synaptotagmin I — is bound to the complex.
Chapman, E. R., Hanson, P. I., An, S. & Jahn, R. Ca2+ regulates the interaction between synaptotagmin and syntaxin 1. J. Biol. Chem. 270, 23667–23671 (1995).
Schiavo, G., Stenbeck, G., Rothman, J. E. & Sollner, T. H. Binding of the synaptic vesicle v-SNARE, synaptotagmin, to the plasma membrane t-SNARE, SNAP-25, can explain docked vesicles at neurotoxin-treated synapses. Proc. Natl Acad. Sci. USA 94, 997–1001 (1997).
Gerona, R. R., Larsen, E. C., Kowalchyk, J. A. & Martin, T. F. The C terminus of SNAP25 is essential for Ca2+-dependent binding of synaptotagmin to SNARE complexes. J. Biol. Chem. 275, 6328–6336 (2000).
Mehta, P. P., Battenberg, E. & Wilson, M. C. SNAP-25 and synaptotagmin involvement in the final Ca2+-dependent triggering of neurotransmitter exocytosis. Proc. Natl Acad. Sci. USA 93, 10471–10476 (1996).
Leveque, C., Boudier, J. A., Takahashi, M. & Seagar, M. Calcium-dependent dissociation of synaptotagmin from synaptic SNARE complexes. J. Neurochem. 74, 367–374 (2000).
Kee, Y. & Scheller, R. H. Localization of synaptotagmin-binding domains on syntaxin. J. Neurosci. 16, 1975–1981 (1996).
Matos, M. F., Rizo, J. & Sudhof, T. C. The relation of protein binding to function: what is the significance of munc18 and synaptotagmin binding to syntaxin 1, and where are the corresponding binding sites? Eur. J. Cell Biol. 79, 377–382 (2000).
Xu, T. et al. Inhibition of SNARE complex assembly differentially affects kinetic components of exocytosis. Cell 99, 713–722 (1999).
Zhang, X., Kim-Miller, M. J., Fukuda, M., Kowalchyk, J. A. & Martin, T. F. J. Calcium-dependent synaptotagmin binding to SNAP-25 is essential for Ca2+-triggered exocytosis. Neuron 34, 599–611 (2002).
Shao, X. et al. Synaptotagmin–syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch. Neuron 18, 133–142 (1997).
Fernandez, I. et al. Three-dimensional structure of an evolutionarily conserved N-terminal domain of syntaxin 1A. Cell 94, 841–849 (1998).
Kozlov, M. M. & Chernomordik, L. V. The protein coat in membrane fusion: lessons from fission. Traffic 3, 256–267 (2002).
Chernomordik, L. V., Frolov, V. A., Leikina, E., Bronk, P. & Zimmerberg, J. The pathway of membrane fusion catalyzed by influenza hemagglutinin: restriction of lipids, hemifusion, and lipidic fusion pore formation. J. Cell Biol. 140, 1369–1382 (1998).
Lewis, J. L., Dong, M., Earles, C. A. & Chapman, E. R. The transmembrane domain of syntaxin 1A is critical for cytoplasmic domain protein–protein interactions. J. Biol. Chem. 276, 15458–15465 (2001).
Mackler, J. M. & Reist, N. E. Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions. J. Comp. Neurol. 436, 4–16 (2001).
Sato, K. & Wickner, W. Functional reconstitution of ypt7p GTPase and a purified vacuole SNARE complex. Science 281, 700–702 (1998).
Ungermann, C., Sato, K. & Wickner, W. Defining the functions of trans-SNARE pairs. Nature 396, 543–548 (1998).
Nishizuka, Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334, 661–665 (1988).
Clark, J. D. et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043–1051 (1991).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Nakayama, S., Kawasaki, H. & Kretsinger, R. H. Evolution of EF-hand proteins. Topics Biol. Inorg. Chem. 3, 29–58 (2000).
Artalejo, C. R., Elhamdani, A. & Palfrey, H. C. Calmodulin is the divalent cation receptor for rapid endocytosis, but not exocytosis, in adrenal chromaffin cells. Neuron 16, 195–205 (1996).
Sakaba, T. & Neher, E. Calmodulin mediates rapid recruitment of fast-releasing synaptic vesicles at a calyx-type synapse. Neuron 32, 1119–1131 (2001).
Sugita, S. et al. Synaptotagmin VII as a plasma membrane Ca2+ sensor in exocytosis. Neuron 30, 459–473 (2001).
Chen, Y. A. et al. Calcium regulation of exocytosis in PC12 cells. J. Biol. Chem. 276, 26680–26687 (2001).
Butz, S., Fernandez-Chacon, R., Schmitz, F., Jahn, R. & Sudhof, T. C. The subcellular localizations of atypical synaptotagmins III and VI. Synaptotagmin III is enriched in synapses and synaptic plasma membranes but not in synaptic vesicles. J. Biol. Chem. 274, 18290–18296 (1999).
Shoji-Kasai, Y. et al. Neurotransmitter release from synaptotagmin-deficient clonal variants of PC12 cells. Science 256, 1821–1823 (1992).
Fukuda, M., Kowalchyk, J. A., Zhang, X., Martin, T. F. & Mikoshiba, K. Synaptotagmin IX regulates Ca2+-dependent secretion in PC12 cells. J. Biol. Chem. 277, 4601–4604 (2002).
Martinez, I. et al. Synaptotagmin VII regulates Ca2+-dependent exocytosis of lysosomes in fibroblasts. J. Cell. Biol. 148, 1141–1149 (2000).
Valtorta, F., Meldolesi, J. & Fesce, R. Synaptic vesicles: is kissing a matter of competence? Trends Cell Biol. 11, 324–328 (2001).
Hua, Y. & Scheller, R. H. Three SNARE complexes cooperate to mediate membrane fusion. Proc. Natl Acad. Sci. USA 98, 8065–8070 (2001).
Author information
Authors and Affiliations
Related links
Related links
DATABASES
Interpro
LocusLink
Swiss-Prot
Glossary
- ACTION POTENTIAL
-
A propagating impulse of voltage in excitable cells.
- ACTIVE ZONES
-
Electron-dense regions in the presynaptic plasma membrane, onto which synaptic vesicles dock and fuse.
- PRIMING
-
A series of reactions that are required to make secretory vesicles competent for fusion.
- LARGE DENSE CORE VESICLES
-
Relatively large (≥100 nm) secretory vesicles that are released with slower kinetics than synaptic vesicles, and that often contain peptide hormones.
- V0 SECTOR
-
The membrane-associated part of the vacuolar H+-ATPase, which is composed of five different subunits (a, d, c, c′ and c″).
- VACUOLAR H+-ATPASE
-
A proton pump that controls the pH of many intracellular compartments.
- EC50 VALUE
-
The concentration of an agent at which a half-maximal effect is observed.
- FLASH PHOTOLYSIS OF CAGED Ca2+
-
A technique in which Ca2+ is sequestered into a 'cage' until the cage is destroyed by a pulse of light, which gives rise to a rapid increase in the free Ca2+ concentration.
- EF-HAND
-
A graphical description for the structure of a Ca2+-binding motif that was first described in parvalbumin (for review, see Ref. 129).
- HYPOMORPHS
-
Mutations that cause a partial loss of function of a given gene or protein.
- INTRAGENIC COMPLEMENTATION
-
A situation in which a heterozygote carrying two different mutations that affect the same polypeptide has a phenotype that is closer to the wild-type than that of either of the respective homozygotes. In most cases, this results from effects on subunit interactions in multimeric proteins.
- ZWITTERIONIC LIPIDS
-
Lipids that carry both positive and negative charges.
Rights and permissions
About this article
Cite this article
Chapman, E. Synaptotagmin: A Ca2+ sensor that triggers exocytosis?. Nat Rev Mol Cell Biol 3, 498–508 (2002). https://doi.org/10.1038/nrm855
Issue Date:
DOI: https://doi.org/10.1038/nrm855
This article is cited by
-
The glutamatergic synapse: a complex machinery for information processing
Cognitive Neurodynamics (2021)
-
Simple capacitor-switch model of excitatory and inhibitory neuron with all parts biologically explained allows input fire pattern dependent chaotic oscillations
Scientific Reports (2020)
-
Gβγ SNARE Interactions and Their Behavioral Effects
Neurochemical Research (2019)
-
Blocking dephosphorylation at Serine 120 residue in t-SNARE SNAP-23 leads to massive inhibition in exocytosis from mast cells
Journal of Biosciences (2018)
-
The Association of SNAP25 Gene Polymorphisms in Attention Deficit/Hyperactivity Disorder: a Systematic Review and Meta-Analysis
Molecular Neurobiology (2017)