Synaptotagmins: Why So Many?

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. Steven