synaptotagmin i


Summary: A vesicular transport protein expressed predominately in NEURONS. Synaptotagmin helps regulate EXOCYTOSIS of SYNAPTIC VESICLES and appears to serve as a calcium sensor to trigger NEUROTRANSMITTER release. It also acts as a nerve cell receptor for certain BOTULINUM TOXINS.

Top Publications

  1. Shahin V, Datta D, Hui E, Henderson R, Chapman E, Edwardson J. Synaptotagmin perturbs the structure of phospholipid bilayers. Biochemistry. 2008;47:2143-52 pubmed publisher
    b>Synaptotagmin I (syt), an integral protein of the synaptic vesicle membrane, is believed to act as a Ca2+ sensor for neuronal exocytosis. Syt's cytoplasmic domain consists largely of two C2 domains, C2A and C2B...
  2. Pang Z, Shin O, Meyer A, Rosenmund C, Sudhof T. A gain-of-function mutation in synaptotagmin-1 reveals a critical role of Ca2+-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex binding in synaptic exocytosis. J Neurosci. 2006;26:12556-65 pubmed
    ..These data establish that fast vesicle exocytosis is driven by a dual Ca2+-dependent activity of synaptotagmin-1, namely Ca2+-dependent binding both to SNARE complexes and to phospholipids. ..
  3. Littleton J, Serano T, Rubin G, Ganetzky B, Chapman E. Synaptic function modulated by changes in the ratio of synaptotagmin I and IV. Nature. 1999;400:757-60 pubmed
    ..Genetic and biochemical evidence indicates that synaptotagmin I may function as a Ca2+ sensor in neuronal exocytosis because it can bind Ca2+ and penetrate into lipid ..
  4. Bai J, Wang P, Chapman E. C2A activates a cryptic Ca(2+)-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proc Natl Acad Sci U S A. 2002;99:1665-70 pubmed
    ..A number of proteins contain more than one C2 domain; the findings reported here suggest these domains may harbor cryptic activities that are not detected when they are studied in isolation. ..
  5. Hueting R, Tavare R, Dilworth J, Mullen G. Copper-64 radiolabelling of the C2A domain of synaptotagmin I using a functionalised bis(thiosemicarbazone): A pre- and post-labelling comparison. J Inorg Biochem. 2013;128:108-11 pubmed publisher
    ..The C2A domain of rat synaptotagmin I binds to phosphatidylserine (PS) exposed during cell death and modification to its lysine residues has been ..
  6. Schaub J, Lu X, Doneske B, Shin Y, McNew J. Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nat Struct Mol Biol. 2006;13:748-50 pubmed
    ..When the calcium sensor synaptotagmin is added in the presence of calcium, inhibition by complexin is relieved and full fusion rapidly proceeds. ..
  7. Cheng Y, Sequeira S, Malinina L, Tereshko V, Sollner T, Patel D. Crystallographic identification of Ca2+ and Sr2+ coordination sites in synaptotagmin I C2B domain. Protein Sci. 2004;13:2665-72 pubmed
    b>Synaptotagmin I has two tandem Ca(2+)-binding C(2) domains, which are essential for fast synchronous synaptic transmission in the central nervous system...
  8. Powell C, Schoch S, Monteggia L, Barrot M, Matos M, Feldmann N, et al. The presynaptic active zone protein RIM1alpha is critical for normal learning and memory. Neuron. 2004;42:143-53 pubmed
  9. Pang Z, Sun J, Rizo J, Maximov A, Sudhof T. Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+-triggered neurotransmitter release. EMBO J. 2006;25:2039-50 pubmed

More Information


  1. Gauer J, Sisk R, Murphy J, Jacobson H, Sutton R, GILLISPIE G, et al. Mechanism for calcium ion sensing by the C2A domain of synaptotagmin I. Biophys J. 2012;103:238-46 pubmed publisher
    The C2A domain is one of two calcium ion (Ca(2+))- and membrane-binding domains within synaptotagmin I (Syt I), the identified Ca(2+) sensor for regulated exocytosis of neurotransmitter...
  2. Kuo W, Herrick D, Ellena J, Cafiso D. The calcium-dependent and calcium-independent membrane binding of synaptotagmin 1: two modes of C2B binding. J Mol Biol. 2009;387:284-94 pubmed publisher
    ..This Ca2+-triggered conformational change may act as a switch to modulate the accessibility of the polybasic face of C2B and control interactions of syt1 with other components of the fusion machinery. ..
  3. Shin O, Rhee J, Tang J, Sugita S, Rosenmund C, Sudhof T. Sr2+ binding to the Ca2+ binding site of the synaptotagmin 1 C2B domain triggers fast exocytosis without stimulating SNARE interactions. Neuron. 2003;37:99-108 pubmed
    ..Thus, triggering of the fast component of release by Sr(2+) as a Ca(2+) agonist involves the formation of synaptotagmin/phospholipid complexes, but does not require stimulated SNARE binding. ..
  4. Cnops L, Hu T, Vanden Broeck J, Burnat K, Van den Bergh G, Arckens L. Age- and experience-dependent expression of dynamin I and synaptotagmin I in cat visual system. J Comp Neurol. 2007;504:254-64 pubmed publisher
    Dynamin I (Dyn I) and Synaptotagmin I (Syt I) are essential for endocytosis-exocytosis processes, thus for neurotransmission...
  5. Hui E, Gaffaney J, Wang Z, Johnson C, Evans C, Chapman E. Mechanism and function of synaptotagmin-mediated membrane apposition. Nat Struct Mol Biol. 2011;18:813-21 pubmed publisher
    ..Thus, membrane aggregation and t-SNARE assembly appear to be two key aspects of fusion reactions that are regulated by Ca(2+)-bound synaptotagmin-1 and catalyzed by SNAREs. ..
  6. Burgalossi A, Jung S, Meyer G, Jockusch W, Jahn O, Taschenberger H, et al. SNARE protein recycling by ?SNAP and ?SNAP supports synaptic vesicle priming. Neuron. 2010;68:473-87 pubmed publisher
    ..Our analysis of ?- and ?SNAP deletion mutant neurons shows that the two NSF cofactors support synaptic vesicle priming by determining the availability of free SNARE components, particularly during phases of high synaptic activity. ..
  7. Chapman E, Davis A. Direct interaction of a Ca2+-binding loop of synaptotagmin with lipid bilayers. J Biol Chem. 1998;273:13995-4001 pubmed
    ..The penetration of C2A into membranes may function to bring components of the fusion machinery into contact with the lipid bilayer to initiate exocytosis. ..
  8. Groffen A, Martens S, Díez Arazola R, Cornelisse L, Lozovaya N, de Jong A, et al. Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science. 2010;327:1614-8 pubmed publisher
  9. Textor B, Licht A, Tuckermann J, Jessberger R, Razin E, Angel P, et al. JunB is required for IgE-mediated degranulation and cytokine release of mast cells. J Immunol. 2007;179:6873-80 pubmed
    ..Thus, JunB is a critical regulator of intrinsic mast cell functions including cross-talk with endothelial cells. ..
  10. Kim J, Choi B, Choi M, Kim S, Lai Y, Shin Y, et al. Solution single-vesicle assay reveals PIP2-mediated sequential actions of synaptotagmin-1 on SNAREs. EMBO J. 2012;31:2144-55 pubmed publisher
    ..The results show that ALEX is a powerful method to dissect multiple kinetic steps in the vesicle fusion pathway. ..
  11. Yoshihara M, Adolfsen B, Littleton J. Is synaptotagmin the calcium sensor?. Curr Opin Neurobiol. 2003;13:315-23 pubmed
    After much debate, recent progress indicates that the synaptic vesicle protein synaptotagmin I probably functions as the calcium sensor for synchronous neurotransmitter release...
  12. Marek K, Davis G. Transgenically encoded protein photoinactivation (FlAsH-FALI): acute inactivation of synaptotagmin I. Neuron. 2002;36:805-13 pubmed
    ..fluorescein derivative 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FlAsH) was engineered into synaptotagmin I (Syt I4C)...
  13. Zhang Z, Hui E, Chapman E, Jackson M. Regulation of exocytosis and fusion pores by synaptotagmin-effector interactions. Mol Biol Cell. 2010;21:2821-31 pubmed publisher
    ..This associates the syt-PS interaction with two distinct kinetic steps in Ca(2+) triggered exocytosis and supports a role for the syt-PS interaction in stabilizing open fusion pores. ..
  14. Rufener E, Frazier A, Wieser C, Hinderliter A, Cafiso D. Membrane-bound orientation and position of the synaptotagmin C2B domain determined by site-directed spin labeling. Biochemistry. 2005;44:18-28 pubmed
    ..spin labeling is used to determine the orientation and depth of insertion of the second C2 domain from synaptotagmin I (C2B) into membrane vesicles composed of phosphatidylcholine (PC) and phosphatidylserine (PS)...
  15. Yoshihara M, Guan Z, Littleton J. Differential regulation of synchronous versus asynchronous neurotransmitter release by the C2 domains of synaptotagmin 1. Proc Natl Acad Sci U S A. 2010;107:14869-74 pubmed publisher
    ..These results suggest that the tandem C2 domains of Syt 1 play independent roles in neurotransmission, as Ca(2+) binding to C2A suppresses asynchronous release, whereas Ca(2+) binding to C2B mediates synchronous fusion. ..
  16. Lai Y, Diao J, Liu Y, Ishitsuka Y, Su Z, Schulten K, et al. Fusion pore formation and expansion induced by Ca2+ and synaptotagmin 1. Proc Natl Acad Sci U S A. 2013;110:1333-8 pubmed publisher
    ..The results also show that complexin 1 stimulates pore expansion significantly, which could put bias between two pathways of vesicle recycling. ..
  17. Xu J, Pang Z, Shin O, Sudhof T. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nat Neurosci. 2009;12:759-66 pubmed publisher
    ..These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis. ..
  18. Kimura N, Shiraishi S, Mizunashi K, Ohtsu H, Kimura I. Synaptotagmin I expression in mast cells of normal human tissues, systemic mast cell disease, and a human mast cell leukemia cell line. J Histochem Cytochem. 2001;49:341-6 pubmed
    b>Synaptotagmin I (STG I) is a Ca(2+) sensor and one of the synaptic vesicle proteins that mediate exocytosis...
  19. Rizo J, Rosenmund C. Synaptic vesicle fusion. Nat Struct Mol Biol. 2008;15:665-74 pubmed
    ..Elucidation of the release mechanism will require a full understanding of the network of interactions among all these proteins and the membranes. ..
  20. Johnson S, Franz C, Kuhn S, Furness D, Rüttiger L, Münkner S, et al. Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses. Nat Neurosci. 2010;13:45-52 pubmed publisher
    ..We propose that the differential expression of synaptotagmins determines the characteristic Ca(2+) sensitivity of vesicle fusion at hair cell synapses. ..
  21. Dai H, Shen N, Arac D, Rizo J. A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release. J Mol Biol. 2007;367:848-63 pubmed
    ..We propose a model whereby the highly positive electrostatic potential at the tip of the SSCAP complex helps to induce membrane fusion during release. ..
  22. Borden C, Stevens C, Sullivan J, Zhu Y. Synaptotagmin mutants Y311N and K326/327A alter the calcium dependence of neurotransmission. Mol Cell Neurosci. 2005;29:462-70 pubmed
    b>Synaptotagmin I, a calcium-binding synaptic vesicle protein, is thought to act as the calcium sensor for fast neurotransmission, but what synaptotagmin I does, upon binding calcium, to trigger exocytosis is still unknown...
  23. Kang R, Swayze R, Lise M, Gerrow K, Mullard A, Honer W, et al. Presynaptic trafficking of synaptotagmin I is regulated by protein palmitoylation. J Biol Chem. 2004;279:50524-36 pubmed
    ..In this study, we have analyzed the role of palmitoylation in trafficking of synaptotagmin I and its modulation by synaptic activity...
  24. Marqueze B, Berton F, Seagar M. Synaptotagmins in membrane traffic: which vesicles do the tagmins tag?. Biochimie. 2000;82:409-20 pubmed
    The aim of this review is to give a broad picture of what is actually known about the synaptotagmin family. Synaptotagmin I is an abundant synaptic vesicle and secretory granule protein in neurons and endocrine cells which plays a key ..
  25. Wu Y, He Y, Bai J, Ji S, Tucker W, Chapman E, et al. Visualization of synaptotagmin I oligomers assembled onto lipid monolayers. Proc Natl Acad Sci U S A. 2003;100:2082-7 pubmed
    ..b>Synaptotagmin I (syt I) is a Ca(2+)-sensing protein proposed to regulate fusion pore dynamics via Ca(2+)-promoted binding of ..
  26. Peng W, Premkumar A, Mossner R, Fukuda M, Lesch K, Simantov R. Synaptotagmin I and IV are differentially regulated in the brain by the recreational drug 3,4-methylenedioxymethamphetamine (MDMA). Brain Res Mol Brain Res. 2002;108:94-101 pubmed
    ..Herein, the effect of MDMA on expression of both synaptotagmin I and IV was studied in detail, since the two proteins are functionally interrelated...
  27. Gerber S, Rizo J, Sudhof T. Role of electrostatic and hydrophobic interactions in Ca(2+)-dependent phospholipid binding by the C(2)A-domain from synaptotagmin I. Diabetes. 2002;51 Suppl 1:S12-8 pubmed
    ..We have now examined this question for the C(2)A-domain of synaptotagmin I, a membrane protein of secretory vesicles with an essential function in Ca(2+)-triggered exocytosis...
  28. Bhalla A, Tucker W, Chapman E. Synaptotagmin isoforms couple distinct ranges of Ca2+, Ba2+, and Sr2+ concentration to SNARE-mediated membrane fusion. Mol Biol Cell. 2005;16:4755-64 pubmed
    ..Our data demonstrate that different syt isoforms are specialized to sense different ranges of divalent cations and that PS is an essential effector of Ca2+.syt action. ..
  29. Poopatanapong A, Teramitsu I, Byun J, Vician L, Herschman H, White S. Singing, but not seizure, induces synaptotagmin IV in zebra finch song circuit nuclei. J Neurobiol. 2006;66:1613-29 pubmed
    ..Our findings indicate that, within this neural circuit for a procedurally learned sensorimotor behavior, Syt IV is selective and requires precisely patterned neural activity and/or neuromodulation associated with singing. ..
  30. Hilfiker S, Pieribone V, Nordstedt C, Greengard P, Czernik A. Regulation of synaptotagmin I phosphorylation by multiple protein kinases. J Neurochem. 1999;73:921-32 pubmed
    b>Synaptotagmin I has been suggested to function as a low-affinity calcium sensor for calcium-triggered exocytosis from neurons and neuroendocrine cells...
  31. Dai H, Shin O, Machius M, Tomchick D, Sudhof T, Rizo J. Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. Nat Struct Mol Biol. 2004;11:844-9 pubmed
  32. Wang F, Fang W, Zhang M, Zhao M, Liu B, Wang Z, et al. Evaluation of chemotherapy response in VX2 rabbit lung cancer with 18F-labeled C2A domain of synaptotagmin I. J Nucl Med. 2011;52:592-9 pubmed publisher
    The C2A domain of synaptotagmin I can target apoptotic cells by binding to exposed anionic phospholipids...
  33. Tucker W, Chapman E. Role of synaptotagmin in Ca2+-triggered exocytosis. Biochem J. 2002;366:1-13 pubmed
    The Ca(2+)-binding synaptic-vesicle protein synaptotagmin I has attracted considerable interest as a potential Ca(2+) sensor that regulates exocytosis from neurons and neuroendocrine cells...
  34. Jung N, Wienisch M, Gu M, Rand J, Müller S, Krause G, et al. Molecular basis of synaptic vesicle cargo recognition by the endocytic sorting adaptor stonin 2. J Cell Biol. 2007;179:1497-510 pubmed publisher
    ..Synaptotagmin-binding-defective UNC-41B is unable to rescue paralysis in C. elegans stonin mutant animals, suggesting that the mechanism of stonin-mediated SV cargo recognition is conserved from worms to mammals. ..
  35. Hu Z, Chen M, Ping Z, Dong Y, Zhang R, Xu T, et al. Synaptotagmin IV regulates dense core vesicle (DCV) release in LbetaT2 cells. Biochem Biophys Res Commun. 2008;371:781-6 pubmed publisher
    ..Downregulation of Syt IV clearly reduced Ca(2+)-triggered exocytosis of dense core vesicles (DCVs) in LbetaT2 cells. Syt I silencing, however, had no effect on vesicular release. ..
  36. Shao X, Li C, Fernandez I, Zhang X, Sudhof T, Rizo J. Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch. Neuron. 1997;18:133-42 pubmed
    b>Synaptotagmin I is a synaptic vesicle protein that is thought to act as a Ca2+ sensor in neurotransmitter release...
  37. Kohli B, Pflieger D, Mueller L, Carbonetti G, Aebersold R, Nitsch R, et al. Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. J Proteome Res. 2012;11:4075-90 pubmed publisher
  38. Wang F, Fang W, Zhao M, Wang Z, Ji S, Li Y, et al. Imaging paclitaxel (chemotherapy)-induced tumor apoptosis with 99mTc C2A, a domain of synaptotagmin I: a preliminary study. Nucl Med Biol. 2008;35:359-64 pubmed publisher
    ..cell lung cancer (NSCLC) apoptosis induced by paclitaxel treatment using 99mTc-labeled C2A domain of synaptotagmin I in a mouse model...
  39. Martens S, Kozlov M, McMahon H. How synaptotagmin promotes membrane fusion. Science. 2007;316:1205-8 pubmed
    ..Thus, synaptotagmin-1 triggers the fusion of docked vesicles by local Ca2+-dependent buckling of the plasma membrane together with the zippering of SNAREs. This mechanism may be widely used in membrane fusion. ..
  40. Chapman E, Desai R, Davis A, Tornehl C. Delineation of the oligomerization, AP-2 binding, and synprint binding region of the C2B domain of synaptotagmin. J Biol Chem. 1998;273:32966-72 pubmed
    Biochemical and genetic studies indicate that synaptotagmin I functions as a Ca2+ sensor during synaptic vesicle exocytosis and as a membrane receptor for the clathrin adaptor complex, AP-2, during endocytosis...
  41. Tocco G, Bi X, Vician L, Lim I, Herschman H, Baudry M. Two synaptotagmin genes, Syt1 and Syt4, are differentially regulated in adult brain and during postnatal development following kainic acid-induced seizures. Brain Res Mol Brain Res. 1996;40:229-39 pubmed
    ..Our results suggest that the differential regulation of different synaptotagmin genes following excessive neuronal activity might participate in rapid adaptation of subsequent transmitter release. ..
  42. Kanno E, Fukuda M. Increased plasma membrane localization of O-glycosylation-deficient mutant of synaptotagmin I in PC12 cells. J Neurosci Res. 2008;86:1036-43 pubmed
    b>Synaptotagmin I (Syt I) is a Ca2+-binding protein on synaptic vesicles and presumably functions as a Ca2+ sensor for neurotransmitter release...
  43. Shin O, Xu J, Rizo J, Sudhof T. Differential but convergent functions of Ca2+ binding to synaptotagmin-1 C2 domains mediate neurotransmitter release. Proc Natl Acad Sci U S A. 2009;106:16469-74 pubmed publisher
  44. Zhao M, Zhu X, Ji S, Zhou J, Ozker K, Fang W, et al. 99mTc-labeled C2A domain of synaptotagmin I as a target-specific molecular probe for noninvasive imaging of acute myocardial infarction. J Nucl Med. 2006;47:1367-74 pubmed
    ..Our aim was to develop a radiotracer based on the PtdS-binding activity of the C2A domain of synaptotagmin I and assess 99mTc-C2A-GST (GST is glutathione S-transferase) using a reperfused acute myocardial infarction (..
  45. Bhalla A, Chicka M, Tucker W, Chapman E. Ca(2+)-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion. Nat Struct Mol Biol. 2006;13:323-30 pubmed
    ..Ca(2+)-syt drove assembly of SNAP-25 onto membrane-embedded syntaxin, providing direct evidence that Ca(2+)-syt alters t-SNARE structure. ..
  46. Adolfsen B, Saraswati S, Yoshihara M, Littleton J. Synaptotagmins are trafficked to distinct subcellular domains including the postsynaptic compartment. J Cell Biol. 2004;166:249-60 pubmed
    ..In addition, the identification of a postsynaptic synaptotagmin suggests calcium-dependent membrane-trafficking functions on both sides of the synapse. ..
  47. Fukuda M. RNA interference-mediated silencing of synaptotagmin IX, but not synaptotagmin I, inhibits dense-core vesicle exocytosis in PC12 cells. Biochem J. 2004;380:875-9 pubmed
    ..The results indicate that Syts I and IX are not functionally equivalent and that Syt IX, and not Syt I, is indispensable for the regulation of Ca2+-dependent dense-core vesicle exocytosis in PC12 cells. ..
  48. Heindel U, Schmidt M, Veit M. Palmitoylation sites and processing of synaptotagmin I, the putative calcium sensor for neurosecretion. FEBS Lett. 2003;544:57-62 pubmed
    b>Synaptotagmin I, the calcium sensor for neurotransmission, is palmitoylated. We have identified the palmitoylation sites as five cysteine residues located between the transmembrane and cytoplasmic regions...
  49. Evans G, Morgan A. Phosphorylation-dependent interaction of the synaptic vesicle proteins cysteine string protein and synaptotagmin I. Biochem J. 2002;364:343-7 pubmed
    ..Western blotting of the CSP-binding proteins identified synaptotagmin I to be a putative binding partner...
  50. Jarousse N, Kelly R. The AP2 binding site of synaptotagmin 1 is not an internalization signal but a regulator of endocytosis. J Cell Biol. 2001;154:857-66 pubmed
    ..We propose that internalization of synaptotagmin 1 is regulated in this way to allow it to couple the processes of endocytosis and calcium-mediated exocytosis in cells of the neuroendocrine lineage. ..
  51. Lynch K, Gerona R, Kielar D, Martens S, McMahon H, Martin T. Synaptotagmin-1 utilizes membrane bending and SNARE binding to drive fusion pore expansion. Mol Biol Cell. 2008;19:5093-103 pubmed publisher
    ..The results indicate that Syt-1 uses both Ca(2+)-dependent membrane insertion and SNARE binding to drive fusion pore expansion. ..
  52. Roden W, Papke J, Moore J, Cahill A, Macarthur H, Harkins A. Stable RNA interference of synaptotagmin I in PC12 cells results in differential regulation of transmitter release. Am J Physiol Cell Physiol. 2007;293:C1742-52 pubmed
    ..Electron micrographs show that large dense core vesicles are synthesized and available for release in cells that lack syt I. These results are consistent with syt I regulating differential release of transmitters. ..
  53. Herrick D, Sterbling S, Rasch K, Hinderliter A, Cafiso D. Position of synaptotagmin I at the membrane interface: cooperative interactions of tandem C2 domains. Biochemistry. 2006;45:9668-74 pubmed
    b>Synaptotagmin I is a synaptic vesicle associated membrane protein that appears to regulate Ca(2+)-mediated exocytosis...