Synaptotagmins: Why So Many?
Year: 2002
Type: review
Abstract: transmembrane region synaptotagmins 1–13 solubleN-ethylmaleimide-sensitive factor attachment protein receptor adaptor protein 2 Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal TMR,1 a variable linker, and two C-terminal C2-domains (1Südhof T.C. Rizo J. Neuron. 1996; 17: 379-388Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar). Synaptotagmin 1 (Syt 1) was identified as p65 in a monoclonal antibody screen for synaptic proteins (2Matthew W.D. Tsavaler L. Reichardt L.F. J. Cell Biol. 1981; 91: 257-269Crossref PubMed Scopus (423) Google Scholar) and proposed as a potential Ca2+ sensor for regulated exocytosis when its cloning revealed the presence of two C2-domains (3Perin M.S. Fried V.A. Mignery G.A. Jahn R. Südhof T.C. Nature. 1990; 345: 260-263Crossref PubMed Scopus (645) Google Scholar). Twelve additional synaptotagmins were subsequently discovered (Fig. 1 and TableI; Refs. 4Geppert M. Archer III, B.T. Südhof T.C. J. Biol. Chem. 1991; 266: 13548-13552Abstract Full Text PDF PubMed Google Scholar, 5Mizuta M. Inagaki N. Nemoto Y. Matsukura S. Takahashi M. Seino S. J. Biol. Chem. 1994; 269: 11675-11678Abstract Full Text PDF PubMed Google Scholar, 6Hilbush B.S. Morgan J.I. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8195-8199Crossref PubMed Scopus (77) Google Scholar, 7Li C. Ullrich B. Zhang Z.Z. Anderson R.G.W. Brose N. Südhof T.C. Nature. 1995; 375: 594-599Crossref PubMed Scopus (539) Google Scholar, 8Hudson A.W. Birnbaum M.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5895-5899Crossref PubMed Scopus (78) Google Scholar, 9Craxton M. Goedert M. FEBS Lett. 1995; 361: 196-200Crossref PubMed Scopus (67) Google Scholar, 10Babity J.M. Armstrong J.N. Plumier J.C. Currie R.W. Robertson H.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2638-2641Crossref PubMed Scopus (73) Google Scholar, 11von Poser C. Ichtchenko K. Shao X. Rizo J. Südhof T.C. J. Biol. Chem. 1997; 272: 14314-14319Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 12Thompson C.C. J. Neurosci. 1996; 16: 7832-7840Crossref PubMed Google Scholar, 13von Poser C. Südhof T.C. Eur. J. Cell Biol. 2000; 80: 41-47Crossref Scopus (35) Google Scholar, 14Fukuda M. Mikoshiba K. Biochem. J. 2001; 354: 249-257Crossref PubMed Scopus (39) Google Scholar). Extensive work showed that Syts 1 and 2 likely function as Ca2+ sensors in synaptic vesicle exocytosis (15Geppert M. Goda Y. Hammer R.E. Li C. Rosahl T.W. Stevens C.F. Südhof T.C. Cell. 1994; 79: 717-727Abstract Full Text PDF PubMed Scopus (1191) Google Scholar, 16Fernandez-Chacon R. Konigstorffer Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (725) Google Scholar, 17Nonet M.L. Grundahl K. Meyer B.J. Rand J.B. Cell. 1993; 73: 1291-1305Abstract Full Text PDF PubMed Scopus (458) Google Scholar, 18DiAntonio A. Parfitt K.D. Schwarz T.L. Cell. 1993; 73: 1281-1290Abstract Full Text PDF PubMed Scopus (217) Google Scholar, 19Littleton J.T. Stern M. Schulze K. Perin M. Bellen H.J. Cell. 1993; 74: 1125-1134Abstract Full Text PDF PubMed Scopus (377) Google Scholar). Much less is known about the other synaptotagmins, although many of them are abundantly co-expressed with Syts 1 and 2 in brain and are evolutionarily conserved. The most abundant of these “other” synaptotagmins, Syts 3 and 7, are localized on the plasma membrane opposite to synaptic vesicles and exhibit distinct Ca2+ affinities, suggesting that plasma membrane and vesicular synaptotagmins may function as complementary Ca2+ sensors in exocytosis with a hierarchy of Ca2+ affinities (20Butz S. Fernandez-Chacon R. Schmitz F. Jahn R. Südhof T.C. J. Biol. Chem. 1999; 274: 18290-18296Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 21Sugita S. Han W. Butz S. Liu X. Fernandez-Chacon R. Lao Y. Südhof T.C. Neuron. 2001; 30: 459-473Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 22Sugita S. Shin O.-K. Han W. Lao Y. Südhof T.C. EMBO J. 2002; (in press)PubMed Google Scholar). In the present short review, I shall discuss the synaptotagmin family as a whole and evaluate possible biological reasons for the co-expression of multiple isoforms.Table IProperties of synaptotagminsFormExpression pattern and localizationFunctionSpecial propertiesRef.Class 1, Syts 1 and 2Brain and endocranium; localized to synaptic vesicles and secretory granulesCa2+ sensor for fast exocytosisN-Glycosylated N terminus2Matthew W.D. Tsavaler L. Reichardt L.F. J. Cell Biol. 1981; 91: 257-269Crossref PubMed Scopus (423) Google Scholar–4Geppert M. Archer III, B.T. Südhof T.C. J. Biol. Chem. 1991; 266: 13548-13552Abstract Full Text PDF PubMed Google Scholar, 15Geppert M. Goda Y. Hammer R.E. Li C. Rosahl T.W. Stevens C.F. Südhof T.C. Cell. 1994; 79: 717-727Abstract Full Text PDF PubMed Scopus (1191) Google Scholar, 16Fernandez-Chacon R. Konigstorffer Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (725) Google Scholar,23Perin M.S. Brose N. Jahn R. Südhof T.C. J. Biol. Chem. 1991; 266: 623-629Abstract Full Text PDF PubMed Google ScholarClass 2, Syt 7Brain >> ubiquitous; localized to active zone and plasma membraneCa2+ sensor for exocytosis?>12 splice forms7Li C. Ullrich B. Zhang Z.Z. Anderson R.G.W. Brose N. Südhof T.C. Nature. 1995; 375: 594-599Crossref PubMed Scopus (539) Google Scholar, 21Sugita S. Han W. Butz S. Liu X. Fernandez-Chacon R. Lao Y. Südhof T.C. Neuron. 2001; 30: 459-473Abstract Full Text Full Text PDF PubMed Scopus (180) Google ScholarClass 3, Syts 3, 5, 6, and 10Brain >> ubiquitous; localized to active zone and plasma membraneCa2+ sensor for exocytosis?Disulfide bonds at N terminus5Mizuta M. Inagaki N. Nemoto Y. Matsukura S. Takahashi M. Seino S. J. Biol. Chem. 1994; 269: 11675-11678Abstract Full Text PDF PubMed Google Scholar, 7Li C. Ullrich B. Zhang Z.Z. Anderson R.G.W. Brose N. Südhof T.C. Nature. 1995; 375: 594-599Crossref PubMed Scopus (539) Google Scholar, 10Babity J.M. Armstrong J.N. Plumier J.C. Currie R.W. Robertson H.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2638-2641Crossref PubMed Scopus (73) Google Scholar, 24Fukuda M. Kanno E. Mikoshiba K. J. Biol. Chem. 1999; 274: 31421-31427Abstract Full Text Full Text PDF PubMed Scopus (147) Google ScholarClass 4, Syts 4 and 11Brain >> ubiquitous1-aBased only on RNA blotting experiments.; localization controversialUnknownAsp → Ser substitution in C2A-domain6Hilbush B.S. Morgan J.I. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 8195-8199Crossref PubMed Scopus (77) Google Scholar, 11von Poser C. Ichtchenko K. Shao X. Rizo J. Südhof T.C. J. Biol. Chem. 1997; 272: 14314-14319Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 79Berton F. Cornet V. Iborra C. Garrido J. Dargent B. Fukuda M. Seagar M. Marqueze B. Eur. J. Neurosci. 2000; 12: 1294-1302Crossref PubMed Scopus (45) Google ScholarClass 5, Syt 9Brain > ubiquitous1-aBased only on RNA blotting experiments.; localized to synaptic A.W. Birnbaum M.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5895-5899Crossref PubMed Scopus (78) Google Scholar, 9Craxton M. Goedert M. FEBS Lett. 1995; 361: 196-200Crossref PubMed Scopus (67) Google ScholarClass 6, Syts and >> ubiquitous1-aBased only on RNA blotting C. Ullrich B. Zhang Z.Z. Anderson R.G.W. Brose N. Südhof T.C. Nature. 1995; 375: 594-599Crossref PubMed Scopus (539) Google Scholar, 12Thompson C.C. J. Neurosci. 1996; 16: 7832-7840Crossref PubMed Google M. Mikoshiba K. Biochem. J. 2001; 354: 249-257Crossref PubMed Scopus (39) Google only on RNA blotting in a as a synaptotagmin protein that an N-terminal a linker, and two C-terminal C2-domains on and the synaptotagmins 1 the of synaptotagmins and the of the in the C. The N-terminal the are short and exhibit only a Syts 1 and 2 are the only synaptotagmins with an N M. Archer III, B.T. Südhof T.C. J. Biol. Chem. 1991; 266: 13548-13552Abstract Full Text PDF PubMed Google Scholar, M.S. Brose N. Jahn R. Südhof T.C. J. Biol. Chem. 1991; 266: 623-629Abstract Full Text PDF PubMed Google and Syts 3, 5, 6, and are the only synaptotagmins with at the N M. Kanno E. Mikoshiba K. J. Biol. Chem. 1999; 274: 31421-31427Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). The of synaptotagmins In for Syt an is N-terminal to the and synaptotagmins for Syt at the of the in Syts 1 and 7, of these are J. S. Brose N. Südhof T.C. Jahn R. Biochem. 1996; PubMed Scopus Google Scholar, M. FEBS Lett. 1996; PubMed Scopus Google Scholar, Poser C. Zhang C. W. Y. Südhof T.C. Anderson R.G.W. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (73) Google Scholar). Synaptotagmins in a that may M.S. Brose N. Jahn R. Südhof T.C. J. Biol. Chem. 1991; 266: 623-629Abstract Full Text PDF PubMed Google Scholar, Poser C. Zhang C. W. Y. Südhof T.C. Anderson R.G.W. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (73) Google Scholar). possible for the of synaptotagmins is to them by membrane proteins a short A. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The of the the and the C2-domains for Syt to for the splice of Syt (Fig. in Syt 1, the is by multiple protein B. J.M. Y. Jahn R. Südhof T.C. J. Biol. Chem. 1993; Full Text PDF PubMed Google S. V.A. C. J. 1999; 73: PubMed Scopus Google Scholar). The C-terminal C2-domains of synaptotagmins, to as the and for the of and only (Fig. C2-domains are of that were as the in protein L. L. T.L. E. U. 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J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the revealed that synaptotagmin and to (Syt and are The of synaptotagmin are for synaptotagmins a synaptotagmin are the Syt 4 and only are Syt with a the of the is synaptotagmins, a of synaptotagmin of the the and the C2-domains of synaptotagmins and of the of a short in the of Syt 1 (3Perin M.S. Fried V.A. Mignery G.A. Jahn R. Südhof T.C. Nature. 1990; 345: 260-263Crossref PubMed Scopus (645) Google Scholar) a the Syt region is to with in protein S. Han W. Butz S. Liu X. Fernandez-Chacon R. Lao Y. Südhof T.C. Neuron. 2001; 30: 459-473Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). are in the (Fig. in a of the of the an evolutionarily of a Syt protein S. Han W. Butz S. Liu X. Fernandez-Chacon R. Lao Y. Südhof T.C. Neuron. 2001; 30: 459-473Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). The of Syt is and suggesting that the of the C2-domains to the S. Han W. Butz S. Liu X. Fernandez-Chacon R. Lao Y. Südhof T.C. Neuron. 2001; 30: 459-473Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). that for many synaptotagmins, are by M. Goedert M. FEBS Lett. 1999; PubMed Scopus (35) Google Scholar, M. Mikoshiba K. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the of these synaptotagmins that the and C-terminal with the that synaptotagmins were the of synaptotagmin The synaptotagmin C2-domains are in that Ca2+ to the the J. Gerber S.H. Shin Y. Anderson R.G.W. Südhof T.C. Rizo J. Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Garcia J. Südhof T.C. Rizo J. Cell Biol. 1999; PubMed Scopus Google Scholar, J. Zhang X. Shao X. Südhof T.C. Rizo J. EMBO J. 17: PubMed Scopus Google Scholar, X. Südhof T.C. Rizo J. 1996; PubMed Scopus Google Scholar, X. Li C. Zhang X. Südhof T.C. Rizo J. Neuron. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). for synaptotagmin In potential of are in of with M. Liu V. M. Mikoshiba K. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar) to the that the C-terminal of the Syt 1 in synaptic vesicle In the the a J. Gerber S.H. Shin Y. Anderson R.G.W. Südhof T.C. Rizo J. Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that is to is the A. Parfitt K.D. Schwarz T.L. Cell. 1993; 73: 1281-1290Abstract Full Text PDF PubMed Scopus (217) Google Scholar, 19Littleton J.T. Stern M. Schulze K. Perin M. Bellen H.J. Cell. 1993; 74: 1125-1134Abstract Full Text PDF PubMed Scopus (377) Google Scholar). The a of the and likely with its about of the with the M. Mikoshiba K. FEBS Lett. 2000; PubMed Scopus Google Scholar, J.T. J. B. R. B. J. Neurosci. 2001; PubMed Google Scholar) are to to other of synaptotagmins that with C2-domains Ca2+ J. Südhof T.C. J. Biol. Chem. 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Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google to C2-domains for the S.H. Garcia J. Rizo J. Südhof T.C. EMBO J. 2001; PubMed Scopus Google J. Gerber S.H. Shin Y. Anderson R.G.W. Südhof T.C. Rizo J. Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Garcia J. Südhof T.C. Rizo J. Cell Biol. 1999; PubMed Scopus Google Scholar, J. Zhang X. Shao X. Südhof T.C. Rizo J. EMBO J. 17: PubMed Scopus Google suggesting that C2-domains function as Ca2+ by X. Li C. Zhang X. Südhof T.C. Rizo J. Neuron. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The C2-domains of Syt 1 as a function of Ca2+ with Ca2+ affinities that are the Ca2+ affinities R. Konigstorffer Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (725) Google Scholar, J. Gerber S.H. Shin Y. Anderson R.G.W. Südhof T.C. Rizo J. Neuron. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the on of the C2-domains additional for the R. Konigstorffer Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (725) Google Scholar, X. Rizo J. Südhof T.C. PubMed Scopus Google Scholar). is likely that by most synaptotagmins is synaptotagmins Ca2+ and Syts 4 and an evolutionarily substitution in the of the 11von Poser C. Ichtchenko K. Shao X. Rizo J. Südhof T.C. J. Biol. Chem. 1997; 272: 14314-14319Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar) that of a of Ca2+ In Syts and the of the and the of the and in The of most synaptotagmins Syt 1 and Syt 2 brain in a S. Y. Südhof T.C. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S. J.M. Jahn R. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 1996; PubMed Scopus Google Scholar, J. J. Biol. 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Cell. 1994; Full Text PDF PubMed Scopus Google and is by V. 1999; PubMed Scopus Google Scholar). of synaptotagmins and in suggesting that synaptotagmins a in M. FEBS Lett. 1996; PubMed Scopus Google Scholar). In in the a in synaptic vesicle and a and of Syt 1 K. J. Neurosci. 2001; PubMed Google Scholar, M. M. J. Neurosci. 2000; PubMed Google Scholar). proteins may with Syt 1, suggesting that a in synaptic vesicle J. Cell Biol. 2001; PubMed Scopus Google Scholar, K. M. S. S. S. V. EMBO 2001; PubMed Scopus Google Scholar). The of most synaptotagmins to the short that in K. Fukuda M. Mikoshiba K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the is with the of by that to synaptotagmin M. M. Fukuda M. M. Mikoshiba K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). of synaptic proteins may to and the of synaptotagmin is Syts 1 and 2 are localized to synaptic vesicles and secretory (2Matthew W.D. Tsavaler L. Reichardt L.F. J. Cell Biol. 1981; 91: 257-269Crossref PubMed Scopus (423) Google Scholar, M.S. Fried V.A. Mignery G.A. Jahn R. Südhof T.C. Nature. 1990; 345: 260-263Crossref PubMed Scopus (645) Google Scholar, 4Geppert M. Archer III, B.T. Südhof T.C. J. Biol. Chem. 1991; 266: 13548-13552Abstract Full Text PDF PubMed Google Scholar, 22Sugita S. Shin O.-K. Han W. Lao Y. Südhof T.C. EMBO J. 2002; (in press)PubMed Google are and are in a pattern M. Archer III, B.T. Südhof T.C. J. Biol. Chem. 1991; 266: 13548-13552Abstract Full Text PDF PubMed Google Scholar, B. Li C. Zhang Anderson M. Südhof T.C. Neuron. 1994; Full Text PDF PubMed Scopus Google B. M. Inagaki N. Seino S. Seagar M. J. Neurosci. 1995; PubMed Google Scholar, B. F. Seagar M. 2000; PubMed Scopus Google Scholar). Syts 1 and 2 function as an in fast synaptic vesicle exocytosis (15Geppert M. Goda Y. Hammer R.E. Li C. Rosahl T.W. Stevens C.F. Südhof T.C. Cell. 1994; 79: 717-727Abstract Full Text PDF PubMed Scopus (1191) Google Scholar) as by a that was the R. Konigstorffer Gerber S.H. Garcia J. Matos M.F. Stevens C.F. Brose N. Rizo J. Rosenmund C. Südhof T.C. Nature. 2001; 410: 41-49Crossref PubMed Scopus (725) Google Scholar). an in the Ca2+ of Syt 1 and a in the Ca2+ of synaptic vesicle that Ca2+ to Syt 1 is an in Syts 1 and 2 are the only Ca2+ sensor exocytosis in (15Geppert M. Goda Y. Hammer R.E. Li C. Rosahl T.W. Stevens C.F. Südhof T.C. Cell. 1994; 79: 717-727Abstract Full Text PDF PubMed Scopus (1191) Google Scholar, 17Nonet M.L. Grundahl K. Meyer B.J. Rand J.B. Cell. 1993; 73: 1291-1305Abstract Full Text PDF PubMed Scopus (458) Google Scholar, 18DiAntonio A. Parfitt K.D. Schwarz T.L. Cell. 1993; 73: 1281-1290Abstract Full Text PDF PubMed Scopus (217) Google Scholar). In to Syt 1 may function in as Syt 7, with Syt 3, is the most abundant synaptotagmin Syts 1 and Syt is in brain C. Ullrich B. Zhang Z.Z. Anderson R.G.W. Brose N. 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Source: Journal of Biological Chemistry
Author: Thomas C. Südhof
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2008146383