UNC-31的结构域在线虫神经元分泌过程中的功能研究
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摘要
生物体的生命活动是在多方面因素的严格调控下进行的,囊泡的分泌过程在对生物体的调控作用中起着重要作用,是大多数宏观调控过程的分子基础。通过高分辨率电子显微镜观察发现,囊泡可以分为致密核心大囊泡(LDCVs)和突触小囊泡(SVs)两类。致密核心大囊泡中的内涵物主要是大分子蛋白质和神经肽类物质,突触小囊泡中的内涵物则主要是一些神经递质。而近年来随着电生理技术和细胞成像技术的迅猛发展,我们可以直接对活体细胞中囊泡的分泌事件进行高时间分辨率和高空间分辨率的观测,从而研究在这一过程功能基团(如蛋白质)之间的相互作用及其作用机理。
UNC-31是由S.Brenner于1974年在筛选表型异常的EMS诱变的线虫时发现的。缺失UNC-31的线虫表现出运动共济失调(UNC)、反应迟钝、产卵障碍等表型。其哺乳动物中的同源物CAPS(Ca2+-dependent activator protein for secretion)于1992年在鼠脑中发现,已经证实其一种与囊泡分泌过程中不可缺少的重要蛋白,随即成为分泌研究领域中的热点对象之一。这一蛋白含有5个预测的功能结构域,从N端到C端,分别是动力蛋白激活蛋白1结合结构域(DBD)、C2结构域、PH结构域、Munc-13同源结构域以及致密核心大囊泡结合结构域(DCVBD)。一些侧面研究(如同源序列比对,竞争性过表达)表明这些结构域有着各自的功能,但是尚无直接的证据证明这些结构域确实在UNC-31行使其囊泡分泌相关功能中发挥作用或者仅仅是进化过程中的无实际作用的遗留片段。
本文以此为切入点,将线虫作为模式生物,有机的结合了传统的线虫行为、药理学分析和近年来兴起的电生理技术、全内反射细胞成像技术以及活体荧光检测技术对这些结构域的功能进行了研究,这样就将微观上的分子或细胞水平上的观测结果和宏观上的表型联系起来。我们的结果表明：综合来看,这些功能结构域对于UNC-31行使分泌过程中的功能是缺一不可的,但Munc-13同源结构域却表现出一些特殊的性质。当线虫中的UNC-31缺少这一结构域时,其神经元细胞在电生理实验中分泌状态正常,类似于野生型；而其他实验中,如果线虫中UNC-31缺少这一结构域却都表现出类似于UNC-31基因缺失的突变体的表型。我们猜测这一异常的结果可能是由于电生理实验中必须的较高的基础钙浓度导致的特殊现象。
Life activities of organisms is under strict control by a variety of regulation factors, in which the secretion of vesicle plays an important role and is the molecular basis of macro-control process. Observed by high resolution electron microscopy, vesicles can be divided into large dense core vesicles (LDCVs) and synaptic vesicles (SVs) categories. Large dense core vesicles mainly contain macromolecular protein and neuropeptides, and synaptic vesicles mainly carry neurotransmitter. With the rapid development of electrophysiological techniques and cellular imaging technology in recent years, we can directly monitor secretory vesicles in the high time resolution and high spatial resolution on the living cells, and to study the functional groups (such as proteins) interaction in the process and its mechanism.
UNC-31 is discovered by S.Brenner in 1974 in the screening of EMS induced nematode mutation. Lack of UNC-31 in C. elegans leads to uncoordinated movement (UNC), unresponsive to stimulation, and defect in spawning. The mammalian homolog of CAPS (Ca2+-dependent activator protein for secretion) was found in 1992 in rat brain and has been confirmed one of indispensable protein in the process of vesicle secretion. Then It soon became a hot spot in filed of secretion study. This protein contains five predicted functional domains, from N-terminus to C terminus, they are dynactin 1 binding domain (DBD), C2 domain, PH domain, Munc-13 homology domain, and large dense core vesicle binding domain (DCVBD). Some oblique studies (such as sequence alignment, competitive overexpression) showed that these domains have their own features, but there is no direct evidence that these domains play roles in the UNC-31 functions in vesicle secretion process or only the none sense meaningless legacy of evolution.
This thesis selects C. elegans as model organism, and combined of the traditional worm behavior and pharmacological assay, recently developed electrophysiological technique, total internal reflection fluorescence microscopy technique and in vivo fluorescence imaging to detect function of these domains. Our results demonstrate that these domains are all indispensible for the function of UNC-31 in exocytosis process, but the Munc-13 homology domain has shown some special properties. UNC-31 without this domain can still works in electrophysiological experiments, the neuron cells of C.elegans express a normal secretion, similar to wild type. In other experiments if knock out this domain from UNC-31 the worm shown phenotypes similar to the UNC-31 gene deletion mutants. We suspect that this special phenomenon may be due to extra high basis calcium concentration in electrophysiological experiments.
UNC-31是由S.Brenner于1974年在筛选表型异常的EMS诱变的线虫时发现的。缺失UNC-31的线虫表现出运动共济失调(UNC)、反应迟钝、产卵障碍等表型。其哺乳动物中的同源物CAPS(Ca2+-dependent activator protein for secretion)于1992年在鼠脑中发现,已经证实其一种与囊泡分泌过程中不可缺少的重要蛋白,随即成为分泌研究领域中的热点对象之一。这一蛋白含有5个预测的功能结构域,从N端到C端,分别是动力蛋白激活蛋白1结合结构域(DBD)、C2结构域、PH结构域、Munc-13同源结构域以及致密核心大囊泡结合结构域(DCVBD)。一些侧面研究(如同源序列比对,竞争性过表达)表明这些结构域有着各自的功能,但是尚无直接的证据证明这些结构域确实在UNC-31行使其囊泡分泌相关功能中发挥作用或者仅仅是进化过程中的无实际作用的遗留片段。
本文以此为切入点,将线虫作为模式生物,有机的结合了传统的线虫行为、药理学分析和近年来兴起的电生理技术、全内反射细胞成像技术以及活体荧光检测技术对这些结构域的功能进行了研究,这样就将微观上的分子或细胞水平上的观测结果和宏观上的表型联系起来。我们的结果表明：综合来看,这些功能结构域对于UNC-31行使分泌过程中的功能是缺一不可的,但Munc-13同源结构域却表现出一些特殊的性质。当线虫中的UNC-31缺少这一结构域时,其神经元细胞在电生理实验中分泌状态正常,类似于野生型；而其他实验中,如果线虫中UNC-31缺少这一结构域却都表现出类似于UNC-31基因缺失的突变体的表型。我们猜测这一异常的结果可能是由于电生理实验中必须的较高的基础钙浓度导致的特殊现象。
Life activities of organisms is under strict control by a variety of regulation factors, in which the secretion of vesicle plays an important role and is the molecular basis of macro-control process. Observed by high resolution electron microscopy, vesicles can be divided into large dense core vesicles (LDCVs) and synaptic vesicles (SVs) categories. Large dense core vesicles mainly contain macromolecular protein and neuropeptides, and synaptic vesicles mainly carry neurotransmitter. With the rapid development of electrophysiological techniques and cellular imaging technology in recent years, we can directly monitor secretory vesicles in the high time resolution and high spatial resolution on the living cells, and to study the functional groups (such as proteins) interaction in the process and its mechanism.
UNC-31 is discovered by S.Brenner in 1974 in the screening of EMS induced nematode mutation. Lack of UNC-31 in C. elegans leads to uncoordinated movement (UNC), unresponsive to stimulation, and defect in spawning. The mammalian homolog of CAPS (Ca2+-dependent activator protein for secretion) was found in 1992 in rat brain and has been confirmed one of indispensable protein in the process of vesicle secretion. Then It soon became a hot spot in filed of secretion study. This protein contains five predicted functional domains, from N-terminus to C terminus, they are dynactin 1 binding domain (DBD), C2 domain, PH domain, Munc-13 homology domain, and large dense core vesicle binding domain (DCVBD). Some oblique studies (such as sequence alignment, competitive overexpression) showed that these domains have their own features, but there is no direct evidence that these domains play roles in the UNC-31 functions in vesicle secretion process or only the none sense meaningless legacy of evolution.
This thesis selects C. elegans as model organism, and combined of the traditional worm behavior and pharmacological assay, recently developed electrophysiological technique, total internal reflection fluorescence microscopy technique and in vivo fluorescence imaging to detect function of these domains. Our results demonstrate that these domains are all indispensible for the function of UNC-31 in exocytosis process, but the Munc-13 homology domain has shown some special properties. UNC-31 without this domain can still works in electrophysiological experiments, the neuron cells of C.elegans express a normal secretion, similar to wild type. In other experiments if knock out this domain from UNC-31 the worm shown phenotypes similar to the UNC-31 gene deletion mutants. We suspect that this special phenomenon may be due to extra high basis calcium concentration in electrophysiological experiments.
引文
[1]. S. Brenner, The genetics of Caenorhabditis elegans. Genetics,1974.77(1):71-94.
[2]. C. Kenyon, The nematode Caenorhabditis elegans. Science,1988.240(4858): 1448-53.
[3]. S. Guo and K.J. Kemphues, par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed Cell,1995.81(4):611-20.
[4]. A. Fire, S. Xu, M.K. Montgomery, et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998.391(6669): 806-11.
[5]. T. Kim, M.C. Gondre-Lewis, I. Arnaoutova, et al., Dense-core secretory granule biogenesis. Physiology,2006.21:124-133.
[6]. T.C. Suedof, Neurotransmitter release, in Handbook of Experimental Pharmacology, T.C. Sudhof and K. Starke, Editors.2008, Springer-Verlag Berlin. p. 1-21.
[7]. S. Sugita, Mechanisms of exocytosis. Acta Physiologica,2008.192(2):185-193.
[8]. J.C. Hay and T.F. Martin, Resolution of regulated secretion into sequential MgATP-dependent and calcium-dependent stages mediated by distinct cytosolic proteins. J Cell Biol,1992.119(1):139-51.
[9]. S.P. Gandhi and C.F. Stevens, Three modes of synaptic vesicular recycling revealed by single-vesicle imaging. Nature,2003.423(6940):607-13.
[10]. D.L. Baillie, K.A. Beckenbach, and A.M. Rose, Cloning within the unc-43 to unc-31 interval (linkage group IV) of the Caenorhabditis elegans genome using Tcl linkage selection. Can J Genet Cytol,1985.27(4):457-66.
[11]. J. Malsam, S. Kreye, and T.H. Sollner, Membrane fusion:SNAREs and regulation. Cell Mol Life Sci,2008.65(18):2814-32.
[12]. R. Jahn and R.H. Scheller, SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol,2006.7(9):631-43.
[13]. W. Hong, SNAREs and traffic Biochim Biophys Acta,2005.1744(3):493-517.
[14]. T. Lang and R. Jahn, Core proteins of the secretory machinery. Handb Exp Pharmacol,2008(184):107-27.
[15]. R.B. Sutton, D. Fasshauer, R. Jahn, et al., Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 angstrom resolution. Nature,1998. 395(6700):347-353.
[16]. F. Li, F. Pincet, E. Perez, et al., Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat Struct Mol Biol,2007.14(10):890-6.
[17]. F.S. Cohen and GB. Melikyan, The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement J Membr Biol,2004. 199(1):1-14.
[18]. Y. Hua and R.H. Scheller, Three SNARE complexes cooperate to mediate membrane fusion. Proc Natl Acad Sci U S A,2001.98(14):8065-70.
[19]. P.I. Hanson, R. Roth, H. Morisaki, et al., Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy. Cell,1997.90(3):523-35.
[20]. T.M. Hohl, F. Parlati, C. Wimmer, et al., Arrangement of subunits in 20 S particles consisting of NSF, SNAPs, and SNARE complexes. Mol Cell,1998.2(5):539-48.
[21]. T. Sollner, M.K. Bennett, S.W. Whiteheart, et al., A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell,1993.75(3):409-18.
[22]. A. Mayer, W. Wickner, and A. Haas, Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell,1996.85(1): 83-94.
[23]. J.T. Littleton, R.J. Barnard, S.A. Titus, et al., SNARE-complex disassembly by NSF follows synaptic-vesicle fusion. Proc Natl Acad Sci U S A,2001.98(21): 12233-8.
[24]. M.K. Bennett, N. Calakos, and R.H. Scheller, Syntaxin:a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science, 1992.257(5067):255-9.
[25]. M.K. Bennett, J.E. Garcia-Arraras, L.A. Elferink, et al., The syntaxin family of vesicular transport receptors. Cell,1993.74(5):863-73.
[26]. F.Y. Teng, Y. Wang, and B.L. Tang, The syntaxins. Genome Biol,2001.2(11): REVIEWS3012.
[27]. T. Weimbs, S.H. Low, S.J. Chapin, et al., A conserved domain is present in different families of vesicular fusion proteins:A new superfamily. Proceedings of the National Academy of Sciences of the United States of America,1997.94(7): 3046-3051.
[28]. J.C. Lerman, J. Robblee, R. Fairman, et al., Structural analysis of the neuronal SNARE protein syntaxin-1A Biochemistry,2000.39(29):8470-9.
[29]. O. Saifee, L.P. Wei, and M.L. Nonet, The Caenorhabditis elegans unc-64 locus encodes a syntaxin that interacts genetically with synaptobrevin. Molecular Biology of the Cell,1998.9(6):1235-1252.
[30]. H. Ogawa, S. Harada, T. Sassa, et al., Functional properties of the unc-64 gene encoding a Caenorhabditis elegans syntaxin. Journal of Biological Chemistry,1998. 273(4):2192-2198.
[31]. M.C. Wilson, P.P. Mehta, and E.J. Hess, SNAP-25, enSNAREd in neurotransmission and regulation of behaviour. Biochem Soc Trans,1996.24(3): 670-76.
[32]. A. Hodel, Snap-25. Int J Biochem Cell Biol,1998.30(10):1069-73.
[33]. D. Fasshauer, D. Bruns, B. Shen, et al., A structural change occurs upon binding of syntaxin to SNAP-25. Journal of Biological Chemistry,1997.272(7):4582-4590.
[34]. G.Y. Wang, J.W. Witkin, GM. Hao, et al., Syndet is a novel SNAP-25 related protein expressed in many tissues. Journal of Cell Science,1997.110:505-513.
[35]. P.I. Hanson, J.E. Heuser, and R. Jahn, Neurotransmitter release - four years of SNARE complexes. Current Opinion in Neurobiology,1997.7(3):310-315.
[36]. L.M. Gutierrez, S. Viniegra, J. Rueda, et al., A peptide that mimics the C-terminal sequence of SNAP-25 inhibits secretory vesicle docking in chromaffin cells. Journal of Biological Chemistry,1997.272(5):2634-2639.
[37]. G.W. Lawrence, P. Foran, N. Mohammed, et al., Importance of two adjacent C-terminal sequences of SNAP-25 in exocytosis from intact and permeabilized chromaffin cells revealed by inhibition with botulinum neurotoxins A and E Biochemistry,1997.36(11):3061-3067.
[38]. P.P. Mehta, E. Battenberg, and M.C. Wilson, SNAP-25 and synaptotagmin involvement in the final Ca2+-dependent triggering of neurotransmitter exocytosis. Proceedings of the National Academy of Sciences of the United States of America, 1996.93(19):10471-10476.
[39]. W.S. Trimble, D.M. Cowan, and R.H. Scheller, VAMP-1 - a synaptic vesicle associated integral membrane proten. Proceedings of the National Academy of Sciences of the United States of America,1988.85(12):4538-4542.
[40]. M. Baumert, P.R. Maycox, F. Navone, et al., Synaptobrevin:an integral membrane protein of 18000 daltons present in small synaptic vesicles of rat brain Embo Journal,1989.8(2):379-384.
[41]. J.E. Gerst, SNAREs and SNARE regulators in membrane fusion and exocytosis. Cellular and Molecular Life Sciences,1999.55(5):707-734.
[42]. D. Fasshauer, H. Otto, W.K. Eliason, et al., Structural changes are associated with soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complex formation. Journal of Biological Chemistry,1997.272(44):28036-28041.
[43]. L.M. Rice, P. Brennwald, and A.T. Brunger, Formation of a yeast SNARE complex is accompanied by significant structural changes. Febs Letters,1997.415(1): 49-55.
[44]. D. Fasshauer, W.K. Eliason, A.T. Brunger, et al., Identification of a minimal core of the synaptic SNARE complex sufficient for reversible assembly and disassembly. Biochemistry,1998.37(29):10354-10362.
[45]. T. Weber, B.V. Zemelman, J.A. McNew, et al., SNAREpins:Minimal machinery for membrane fusion. Cell,1998.92(6):759-772.
[46]. H.Y. Gaisano, L. Sheu, J.K. Foskett, et al., Tetanus toxin light chain cleaves a vesicle-associated membrane protein (VAMP) isoform 2 in rat pancreatic zymogen granules and inhibits enzyme secretion. Journal of Biological Chemistry,1994. 269(25):17062-17066.
[47]. H. Misonou, M. OharaImaizumi, and K. Kumakura, Regulation of the priming of exocytosis and the dissociation of SNAP-25 and VAMP-2 in adrenal chromaffin cells. Neuroscience Letters,1997.232(3):182-184.
[48]. A.L. Olson, J.B. Knight, and J.E. Pessin, Syntaxin 4, VAMP2, and/or VAMP3/cellubrevin are functional target membrane and vesicle SNAP receptors for insulin-stimulated GLUT4 translocation in adipocytes. Molecular and Cellular Biology,1997.17(5):2425-2435.
[49]. O. Rossetto, L. Gorza, G. Schiavo, et al., VAMP synaptobrevin isoforms 1 and 2 are widely and differentially expressed in nonneuronal tissues. Journal of Cell Biology,1996.132(1-2):167-179.
[50]. Y. Tamori, M. Hashiramoto, S. Araki, et al., Cleavage of vesicle-associated membrane protein (VAMP)-2 and cellubrevin on GLUT4-containing vesicles inhibits the translocation of GLUT4 in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications,1996.220(3):740-745.
[51]. L.A. Elferink, W.S. Trimble, and R.H. Scheller, Two vesicle-associated membrane protein genes are differentially expressed in the rat central nervous system. Journal of Biological Chemistry,1989.264(19):11061-11064.
[52]. S. Nielsen, D. Marples, H. Birn, et al., Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. Colocalization with Aquaporin-2 water channels. Journal of Clinical Investigation,1995.96(4):1834-1844.
[53]. R. Mandic, W.S. Trimble, and A.W. Lowe, Tissue-specific alternative RNA splicing of rat vesicle-associated membrane protein-1 (VAMP-1). Gene,1997. 199(1-2):173-179.
[54]. S. Isenmann, Y. Khew-Goodall, J. Gamble, et al., A splice-isoform of vesicle-associated membrane protein-1 (VAMP-1) contains a mitochondrial targeting signal. Molecular Biology of the Cell,1998.9(7):1649-1660.
[55]. H.T. McMahon, Y.A. Ushkaryov, L. Edelmann, et al., Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature,1993.364(6435):346-349.
[56]. T. Galli, A. Zahraoui, V.V. Vaidyanathan, et al., A novel tetanus neurotoxin-insensitive vesicle-associated membrane protein in SNARE complexes of the apical plasma membrane of epithelial cells. Molecular Biology of the Cell, 1998.9(6):1437-1448.
[57]. J.C. Aledo, E. Hajduch, F. Darakhshan, et al., Analyses of the co-localization of cellubrevin and the GLUT4 glucose transporter in rat and human insulin-responsive tissues. Febs Letters,1996.395(2-3):211-216.
[58]. A. Volchuk, Y. Mitsumoto, L.J. He, et al., Expression of vesicle-associated membrane protein 2 (VAMP-2)/synaptobrevin Ⅱ and cellubrevin in rat skeletal muscle and in a muscle cell line. Biochemical Journal,1994.304:139-145.
[59]. D. Sengupta, F.D. Gumkowski, L.H. Tang, et al., Localization of cellubrevin to the Golgi complex in pancreatic acinar cells. European Journal of Cell Biology,1996. 70(4):306-314.
[60]. T.J. Chilcote, T. Galli,O. Mundigl, et al., Cellubrevin and synaptobrevins:similar subcellular localization and biochemical properties in PC12 cells. Journal of Cell Biology,1995.129(1):219-231.
[61]. T. Galli, T. Chilcote,O. Mundigl, et al., Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. Journal of Cell Biology,1994.125(5):1015-1024.
[62]. C. Galli, A. Piccini, M.T. Ciotti, et al., Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proceedings of the National Academy of Sciences of the United States of America,1998.95(3):1247-1252.
[63]. R. Regazzi, C.B. Wollheim, J. Lang, et al., VAMP-2 and cellubrevin are expressed in pancreatic beta-cells and are essential for Ca2+—but not for GTP gamma S-induced insulin secretion. Embo Journal,1995.14(12):2723-2730.
[64]. J.E.A. Braun, B.A. Fritz, S.M.E. Wong, et al., Identification of a vesicle-associated membrane protein (VAMP)-like membrane protein in zymogen granules of the rat exocrine pancreas. Journal of Biological Chemistry,1994.269(7):5328-5335.
[65]. R.J. Advani, H.R. Bae, J.B. Bock, et al., Seven novel mammalian SNARE proteins localize to distinct membrane compartments. Journal of Biological Chemistry, 1998.273(17):10317-10324.
[66]. S.H. Wong, T. Zhang, Y. Xu, et al., Endobrevin, a novel synaptobrevin/VAMP-like protein preferentially associated with the early endosome. Molecular Biology of the Cell,1998.9(6):1549-1563.
[67]. Q. Zeng, V.N. Subramaniam, S.H. Wong, et al., A novel synaptobrevin/VAMP homologous protein (VAMP5) is increased during in vitro myogenesis and present in the plasma membrane. Molecular Biology of the Cell,1998.9(9):2423-2437.
[68]. J.E. Gerst, L. Rodgers, M. Riggs, et al., SNC1, a yeast homolog of the synaptic vesicle-associated membrane protein/synaptobrevin gene family:genetic interactions with the RAS and CAP genes. Proceedings of the National Academy of Sciences of the United States of America,1992.89(10):4338-4342.
[69]. V. Protopopov, B. Govindan, P. Novick, et al., Homologs of the synaptobrevin/VAMP family of synaptic vesicle proteins function on the late secretory pathway in S. cerevisiae. Cell,1993.74(5):855-61.
[70]. G. Rossi, A. Salminen, L.M. Rice, et al., Analysis of a yeast SNARE complex reveals remarkable similarity to the neuronal SNARE complex and a novel function for the C terminus of the SNAP-25 homolog, Sec9. Journal of Biological Chemistry,1997.272(26):16610-16617.
[71]. P. Brennwald, B. Kearns, K. Champion, et al., Sec9 is a SNAP-25-like component of a yeast SNARE complex that may be the effector of Sec4 function in exocytosis. Cell,1994.79(2):245-258.
[72]. M.K. Aalto, H. Ronne, and S. Keranen, Yeast syntaxins Ssolp and Sso2p belong to a family of related membrane proteins that function in vesicular transport Embo Journal,1993.12(11):4095-4104.
[73]. A. Couve and J.E. Gerst, Yeast Snc proteins complex with Sec9. Functional interactions between putative SNARE proteins. Journal of Biological Chemistry, 1994.269(38):23391-23394.
[74]. J.E. Gerst, Conserved alpha-helical segments on yeast homologs of the synaptobrevin/VAMP family of V-SNAREs mediate exocytic function. Journal of Biological Chemistry,1997.272(26):16591-16598.
[75]. D. David, S. Sundarababu, and J.E. Gerst, Involvement of long chain fatty acid elongation in the trafficking of secretory vesicles in yeast Journal of Cell Biology, 1998.143(5):1167-1182.
[76]. K.G. Miller, A. Alfonso, M. Nguyen, et al., A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc Natl Acad Sci U S A,1996.93(22): 12593-8.
[77]. P. Novick, C. Field, and R. Schekman, Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell, 1980.21(1):205-215.
[78]. R.R Toonen and M. Verhage, Vesicle trafficking:pleasure and pain from SM genes. Trends Cell Biol,2003.13(4):177-86.
[79]. A. Bracher and W. Weissenhorn, Structural basis for the Golgi membrane recruitment of Sly1p by Sed5p. Embo Journal,2002.21(22):6114-6124.
[80]. K.M.S. Misura, R.H. Scheller, and W.I. Weis, Three-dimensional structure of the neuronal-Secl-syntaxin 1a complex Nature,2000.404(6776):355-362.
[81]. M. Verhage, A.S. Maia, J.J. Plomp, et al., Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science,2000.287(5454):864-869.
[82]. D. Gallwitz and R. Jahn, The riddle of the Sec1/Munc-18 proteins - new twists added to their interactions with SNAREs. Trends Biochem Sci,2003.28(3):113-6.
[83]. Y. Hata, C.A. Slaughter, and T.C. Sudhof, Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature,1993.366(6453):347-351.
[84]. J. Pevsner, S.C. Hsu, and R.H. Scheller, n-Secl:a neural-specific syntaxin-binding protein. Proceedings of the National Academy of Sciences of the United States of America,1994.91(4):1445-1449.
[85]. I. Dulubova, M. Khvotchev, S.Q. Liu, et al., Munc18-1 binds directly to the neuronal SNARE complex. Proceedings of the National Academy of Sciences of the United States of America,2007.104:2697-2702.
[86]. C.M. Carr, E. Grote, M. Munson, et al., Seclp binds to SNARE complexes and concentrates at sites of secretion. Journal of Cell Biology,1999.146(2):333-344.
[87]. I. Dulubova, S. Sugita, S. Hill, et al., A conformational switch in syntaxin during exocytosis:role of muncl8. Embo Journal,1999.18(16):4372-4382.
[88]. P. Burkhardt, D.A. Hattendorf, W.I. Weis, et al., Muncl8a controls SNARE assembly through its interaction with the syntaxin N-peptid. Embo Journal,2008. 27(7):923-933.
[89]. J.E. Richmond, R.M. Weimer, and E.M. Jorgensen, An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature,2001.412(6844): 338-341.
[90]. M. Hammarlund, M.T. Palfreyman, S. Watanabe, et al., Open syntaxin docks synaptic vesicles. PLoS Biol,2007.5(8):e198.
[91]. F.E. Zilly, J.B. Sorensen, R. Jahn, et al., Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes. PLoS Biol, 2006.4(10):e330.
[92]. J. Shen, D.C. Tareste, F. Paumet, et al., Selective activation of cognate SNAREpins by Secl/Munc18 proteins. Cell,2007.128(1):183-95.
[93]. I. Dulubova, M. Khvotchev, S. Liu, et al., Munc18-1 binds directly to the neuronal SNARE complex. Proc Natl Acad Sci U S A,2007.104(8):2697-702.
[94]. H. Shu-Hong, C.F. Latham, C.L. Gee, et al., Structure of the Muncl8c/Syntaxin4 N-peptide complex defines universal features of the N-peptide binding mode of Sec1/Munc18 proteins. Proceedings of the National Academy of Sciences of the United States of America,2007:8773-8.
[95]. C.F. Latham, J.A. Lopez, S.H. Hu, et al., Molecular dissection of the Muncl8c/syntaxin4 interaction:Implications for regulation of membrane trafficking. Traffic,2006.7(10):1408-1419.
[96]. T. Yamaguchi, I. Dulubova, S.W. Min, et al., Slyl binds to Golgi and ER syntaxins via a conserved N-terminal peptide motif Developmental Cell,2002.2(3): 295-305.
[97]. M. D'Andrea-Merrins, L. Chang, A.D. Lam, et al., Muncl8c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. Journal of Biological Chemistry,2007.282(22):16553-16566.
[98]. M. Khvotchev, I. Dulubova, J. Sun, et al., Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 n terminus. Journal of Neuroscience,2007.27:12147-12155.
[99]. L.N. Carpp, L.F. Ciufo, S.G. Shanks, et al., The Sec1p/Munc18 protein Vps45p binds its cognate SNARE proteins via two distinct modes. Journal of Cell Biology, 2006.173(6):927-936.
[100]. I. Dulubova, T. Yamaguchi, Y. Gao, et al., How Tlg2p/syntaxin 16 'snares' Vps45. Embo Journal,2002.21(14):3620-3631.
[101]. Y. Kosodo, Y. Noda, H. Adachi, et al., Binding of Slyl to Sed5 enhances formation of the yeast early Golgi SNARE complex. Journal of Cell Science,2002.115(18): 3683-3691.
[102]. R.W. Peng and D. Gallwitz, Slyl protein bound to Golgi syntaxin Sed5p allows assembly and contributes to specificity of SNARE fusion complexes. Journal of Cell Biology,2002.157(4):645-655.
[103]. N.J. Bryant and D.E. James, The Seclp/Munc18 (SM) protein, Vps45p, cycles on and off membranes during vesicle transport Journal of Cell Biology,2003.161(4): 691-696.
[104]. J.GS. Coe, A.C.B. Lim, J. Xu, et al., A role for T1g1p in the transport of proteins within the Golgi apparatus of Saccharomyces cerevisiae. Molecular Biology of the Cell,1999.10(7):2407-2423.
[105]. J. Togneri, Y.S. Cheng, M. Munson, et al., Specific SNARE complex binding mode of the Sec1/Munc-18 protein, Sec1p. Proceedings of the National Academy of Sciences of the United States of America,2006.103(47):17730-17735.
[106]. B.L. Scott, J.S. Van Komen, H. Irshad, et al., Seclp directly stimulates SNARE-mediated membrane fusion in vitro. Journal of Cell Biology,2004.167(1): 75-85.
[107]. J.S. Shen, D.C. Tareste, F. Paumet, et al., Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell,2007.128:183-195.
[108]. A.L. Williams, S. Ehm, N.C. Jacobson, et al., rslyl binding to syntaxin 5 is required for endoplasmic reticulum-to-Golgi transport but does not promote SNARE motif accessibility. Molecular Biology of the Cell,2004.15(1):162-175.
[109]. D. Arac, I. Dulubova, J.M. Pei, et al., Three-dimensional structure of the rSly1 N-terminal domain reveals a conformational change induced by binding to syntaxin 5. Journal of Molecular Biology,2005.346(2):589-601.
[110]. R.F.G Toonen and M. Verhage, Munc18-1 in secretion:lonely Munc joins SNARE team and takes control. Trends in Neurosciences,2007.30(11):564-572.
[111]. S. Braun and S. Jentsch, SM-protein-controlled ER-associated degradation discriminates between different SNAREs. Embo Reports,2007.8(12):1176-1182.
[112]. N.J. Bryant and D.E. James, Vps45p stabilizes the syntaxin homologue Tlg2p and positively regulates SNARE complex formation. Embo Journal,2001.20(13): 3380-3388.
[113]. R.F.G Toonen, K.J. de Vries, R. Zalm, et al., Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation. Journal of Neurochemistry,2005.93(6):1393-1400.
[114]. L. Arunachalam, L. Han, N.G. Tassew, et al., Munc18-1 is critical for plasma membrane localization of syntaxinl but not of SNAP-25 in PC12 cells. Molecular Biology of the Cell,2008.19(2):722-734.
[115]. T. Voets, R.F. Toonen, E.C. Brian, et al., Munc18-1 promotes large dense-core vesicle docking. Neuron,2001.31(4):581-591.
[116]. E. Nielsen, S. Christoforidis, S. Uttenweiler-Joseph, et al., Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. Journal of Cell Biology,2000.151(3):601-612.
[117]. D.F. Seals, G. Eitzen, N. Margolis, et al., A Ypt/Rab effector complex containing the See1 homolog Vps33p is required for homotypic vacuole fusion. Proceedings of the National Academy of Sciences of the United States of America,2000. 97(17):9402-9407.
[118]. J.R.T. van Weering, R.F. Toonen, and M. Verhage, The Role of Rab3a in Secretory Vesicle Docking Requires Association/Dissociation of Guanidine Phosphates and Munc18-1. PLoS One,2007.2(7):Article No.:e616.
[119]. K.M. Zhou, Y.M. Dong, Q. Ge, et al., PKA activation bypasses the requirement for UNC-31 in the docking of dense core vesicles from C. elegans neurons. Neuron, 2007.56(4):657-69.
[120]. M. Craxton, Synaptotagmin gene content of the sequenced genomes. BMC Genomics,2004.5(1):43.
[121]. T.C. Sudhof, Synaptotagmins:why so many? J Biol Chem,2002.277(10): 7629-32.
[122]. J. Ubach, X.Y. Zhang, X.G Shao, et al., Ca2+ binding to synaptotagmin:how many Ca2+ ions bind to the tip of a C-2-domain? Embo Journal,1998.17(14): 3921-3930.
[123]. W.D. Matthew, L. Tsavaler, and L.F. Reichardt, Identification of a synaptic vesicle-specificmembrane protein with a wide distribution in neuronal and neurosecretory tissue. Journal of Cell Biology,1981.91(1):257-269.
[124]. S. Takamori, M. Holt, K. Stenius, et al., Molecular anatomy of a trafficking organelle. Cell,2006.127(4):831-846.
[125]. M.S. Perin, V.A. Fried, G.A. Mignery, et al., Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature, 1990.345(6272):260-3.
[126]. N. Brose, A.G Petrenko, T.C. Sudhof, et al., Synaptotagmin:a calcium sensor on the synaptic vesicle surface. Science,1992.256(5059):1021-1025.
[127]. S. Sugita, O.H. Shin, W.P. Han, et al., Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities. Embo Journal,2002.21(3): 270-280.
[128]. R. Llinas, M. Sugimori, and R.B. Silver, Microdomains of high calcium concentration in a presynaptic terminal. Science,1992.256(5057):677-9.
[129]. N. Charvin, C. Leveque, D. Walker, et al., Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the alpha(1)A subunit of the P/Q-type calcium channel. Embo Journal,1997.16(15):4591-4596.
[130]. D.K. Kim and W.A. Catterall, Ca2+-dependent and -independent interactions of the isoforms of the alphalA subunit of brain Ca2+ channels with presynaptic SNARE proteins. Proceedings of the National Academy of Sciences of the United States of America,1997.94(26):14782-14786.
[131]. E.R. Chapman, How does synaptotagmin trigger neurotransmitter release? Annual Review of Biochemistry,2008.77:615-641.
[132]. E.R. Chapman, Synaptotagmin:A Ca2+ sensor that triggers exocytosis? Nature Reviews Molecular Cell Biology,2002.3(7):498-508.
[133]. M. Geppert, Y. Goda, R.E. Hammer, et al., Synaptotagmin Ⅰ:a major Ca2+ sensor for transmitter release at a central synapse. Cell,1994.79(4):717-727.
[134]. R. Fernandez-Chacon, A. Konigstorfer, S.H. Gerber, et al., Synaptotagmin I functions as a calcium regulator of release probability. Nature,2001.410(6824): 41-49.
[135]. J.M. Mackler, J.A. Drummond, C.A. Loewen, et al., The C2BCa2+-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature,2002. 418(6895):340-344.
[136]. Z.P. Pang, J.Y. Sun, J. Rizo, et al., Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+-triggered neurotransmitter release. Embo Journal,2006. 25(10):2039-2050.
[137]. J.T. Littleton, M. Stern, M. Perin, et al., Calcium dependence of neurotransmitter release and rate of spontaneous vesicle fusions are altered in Drosophila synaptotagmin mutants. Proceedings of the National Academy of Sciences of the United States of America,1994.91(23):10888-10892.
[138]. T. Nishiki and GJ. Augustine, Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. Journal of Neuroscience,2004.24(27):6127-6132.
[139]. J.R. Schaub, X.B. Lu, B. Doneske, et al., Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nature Structural & Molecular Biology,2006. 13(8):748-750.
[140]. C.G. Giraudo, W.S. Eng, T.J. Melia, et al., A clamping mechanism involved in SNARE-dependent exocytosis. Science,2006.313(5787):676-680.
[141]. J.H. Bai, C.A. Earles, J.L. Lewis, et al., Membrane-embedded synaptotagmin penetrates cis or trans target membranes and clusters via a novel mechanism. Journal of Biological Chemistry,2000.275(33):25427-25435.
[142]. D.Z. Herrick, S. Sterbling, K.A. Rasch, et al., Position of synaptotagmin I at the membrane interface:Cooperative interactions of tandem C2 domains. Biochemistry,2006.45(32):9668-9674.
[143]. S. Martens, M.M. Kozlov, and H.T. McMahon, How synaptotagmin promotes membrane fusion. Science,2007.316(5828):1205-1208.
[144]. G Schiavo, Q.M. Gu, GD. Prestwich, et al., Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. Proceedings of the National Academy of Sciences of the United States of America,1996.93(23): 13327-13332.
[145]. K. Aoyagi, T. Sugaya, M. Umeda, et al., The activation of exocytotic sites by the formation of phosphatidylinositol 4,5-bisphosphate microdomains at syntaxin clusters. Journal of Biological Chemistry,2005.280(17):17346-17352.
[146]. J.H. Bai, W.C. Tucker, and E.R. Chapman, PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nature Structural & Molecular Biology,2004.11(1):36-44.
[147]. A.F. Davis, J.H. Bai, D. Fasshauer, et al., Kinetics of synaptotagmin responses to Ca2+ and assembly with the core SNARE complex onto membranes. Neuron,1999. 24(2):363-376.
[148]. A. Bhalla, M.C. Chicka, W.C. Tucker, et al., Ca2+-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion. Nature Structural & Molecular Biology,2006.13(4):323-330.
[149]. Z.P.P. Pang, O.H. Shin, A.C. Meyer, et al., 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. Journal of Neuroscience,2006.26(48):12556-12565.
[150]. X.G. Shao, I. Fernandez, X.Y. Zhang, et al., Synaptotagmin-syntaxin interaction: The C-2 domain as a Ca2+-dependent electrostatic switch. Neuron,1997.18(1): 133-142.
[151]. E.R. Chapman, How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem,2008.77:615-41.
[152]. J.H. Bai, P. Wang, and E.R. Chapman, C2A activates a cryptic Ca2+-triggered membrane penetration activity within the C2B domain of synaptotagmin Ⅰ. Proceedings of the National Academy of Sciences of the United States of America, 2002.99(3):1665-1670.
[153]. C.T. Wang, J.H. Bai, P.Y. Chang, et al., Synaptotagmin-Ca2+ triggers two sequential steps in regulated exocytosis in rat PC12 cells:fusion pore opening and fusion pore dilation. Journal of Physiology-London,2006.570(2):295-307.
[154]. C. Li, B. Ullrich, J.Z. Zhang, et al., Ca+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature,1995.375(6532):594-599.
[155]. I. Martinez, S. Chakrabarti, T. Hellevik, et al., Synaptotagmin Ⅶ regulates Ca2+-dependent exocytosis of lysosomes in fibroblasts. Journal of Cell Biology, 2000.148(6):1141-1149.
[156]. Z.Y. Gao, J. Reavey-Cantwell, R.A. Young, et al., Synaptotagmin Ⅲ/Ⅶ isoforms mediate Ca2+-induced insulin secretion in pancreatic islet beta-cells. Journal of Biological Chemistry,2000.275(46):36079-36085.
[157]. C. Li, B. Ullrich, J.Z. Zhang, et al., Ca2+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature,1995.375(6532):594-599.
[158]. E.V. Caler, S. Chakrabarti, K.T. Fowler, et al., The exocytosis-regulatory protein synaptotagminVII mediates cell invasion by Trypanosoma cruzi. Journal of Experimental Medicine,2001.193(9):1097-1104.
[159]. M. Fukuda, E. Kanno, M. Satoh, et al., Synaptotagmin Ⅶ is targeted to dense-core vesicles and regulates their Ca2+-dependent exocytosis in PC12 cells. Journal of Biological Chemistry,2004.279(50):52677-52684.
[160]. M. Fukuda, Y. Ogata, C. Saegusa, et al., Alternative splicing isoforms of synaptotagmin VII in the mouse, rat and human. Biochemical Journal,2002.365: 173-180.
[161]. S. Chakrabarti, K.S. Kobayashi, R.A. Flavell, et al., Impaired membrane resealing and autoimmune myositis in synaptotagmin Ⅶ-deficient mice. Journal of Cell Biology,2003.162(4):543-549.
[162]. D. Roy, D.R. Liston, V.J. Idone, et al., A process for controlling intracellular bacterial infections induced by membrane injury. Science,2004.304(5676): 1515-1518.
[163]. A. Gut, C.E. Kiraly, M. Fukuda, et al., Expression and localisation of synaptotagmin isoforms in endocrine beta-cells:their function in insulin exocytosis. Journal of Cell Science,2001.114(9):1709-1716.
[164]. W.C. Tucker, J.M. Edwardson, J.H. Bai, et al., Identification of synaptotagmin effectors via acute inhibition of secretion from cracked PC12 cells. Journal of Cell Biology,2003.162(2):199-209.
[165]. J. Schultz, T. Doerks, C.P. Ponting, et al., More than 1,000 putative new human signalling proteins revealed by EST data mining. Nature Genetics,2000.25(2): 201-204.
[166]. B.L. Grosshans, D. Ortiz, and P. Novick, Rabs and their effectors:achieving specificity in membrane traffic Proc Natl Acad Sci U S A,2006.103(32): 11821-7.
[167]. T.C. Sudhof, The synaptic vesicle cycle. Annu Rev Neurosci,2004.27:509-47.
[168]. H. Stenmark, Rab GTPases as coordinators of vesicle traffic Nature Reviews Molecular Cell Biology,2009.10(8):513-525.
[169]. Y. Wang, M. Okamoto, F. Schmitz, et al., Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature,1997.388(6642):593-598.
[170]. M. Fukuda, Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2 -Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2. Journal of Biological Chemistry,2003.278(17):15373-15380.
[171]. Y. Wang and T.C. Sudhof, Genomic definition of RIM proteins:evolutionary amplification of a family of synaptic regulatory proteins. Genomics,2003.81(2): 126-137.
[172]. C.M. Powell, S. Schoch, L. Monteggia, et al., The presynaptic active zone protein RIM1 alpha is critical for normal learning and memory. Neuron,2004.42(1): 143-153.
[173]. S. Schoch, P.E. Castillo, T. Jo, et al., RIM1 alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature,2002.415(6869): 321-326.
[174]. L. Sun, M.A. Bittner, and R.W. Holz, Rab3a binding and secretion-enhancing domains in Riml are separate and unique - Studies in adrenal chromaffin cells. Journal of Biological Chemistry,2001.276(16):12911-12917.
[175]. D.R. Stevens, Z.X. Wu, U. Matti, et al., Identification of the minimal protein domain required for priming activity of Munc13-1. Curr Biol,2005.15(24): 2243-8.
[176]. B. Aravamudan, T. Fergestad, W.S. Davis, et al., Drosophila Unc-13 is essential for synaptic transmission. Nature Neuroscience,1999.2(11):965-971.
[177]. I. Augustin, C. Rosenmund, T.C. Sudhof, et al., Munc13-1 is essential for fusion competence of glutamatergic synoptic vesicles. Nature,1999.400(6743):457-461.
[178]. F. Varoqueaux, A. Sigler, J.S. Rhee, et al., Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proceedings of the National Academy of Sciences of the United States of America,2002.99(13):9037-9042.
[179]. A. Betz, M. Okamoto, F. Benseler, et al., Direct interaction of the rat unc-13 homologue Munc 13-1 with the N-terminus of syntaxin. European Journal of Cell Biology,1997.72(SUPPL.43):30.
[180]. R. Guan, H. Dai, and J. Rizo, Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes. Biochemistry,2008.47(6):1474-1481.
[181]. T. Sassa, S. Harada, H. Ogawa, et al., Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. Journal of Neuroscience,1999.19(12): 4772-4777.
[182]. R.R. Duncan, M.J. Shipston, and R.H. Chow, Double C2 protein. A review. Biochimie,2000.82(5):421-426.
[183]. AJ.A. Groffen, R. Friedrich, E.C. Brian, et al., DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties. Journal of Neurochemistry,2006.97(3):818-833.
[184]. M. Verhage, K.J. deVries, H. Roshol, et al., DOC2 proteins in rat brain: Complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion. Neuron,1997.18(3):453-461.
[185]. J.H. Walent, B.W. Porter, and T.F. Martin, A novel 145 kd brain cytosolic protein reconstitutes Ca2+-regulated secretion in permeable neuroendocrine cells. Cell, 1992.70(5):765-75.
[186]. B. Berwin, E. Floor, and T.F. Martin, CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis. Neuron,1998. 21(1):137-45.
[187]. A. Tandon, S. Bannykh, J.A. Kowalchyk, et al., Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes. Neuron,1998. 21(1):147-54.
[188]. A. Elhamdani, T.F. Martin, J.A. Kowalchyk, et al., Ca2+-dependent activator protein for secretion is critical for the fusion of dense-core vesicles with the membrane in calf adrenal chromaffin cells. J Neurosci,1999.19(17):7375-83.
[189]. R.N. Grishanin, J.A. Kowalchyk, V.A. Klenchin, et al., CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron,2004. 43(4):551-62.
[190]. Y. Fujita, A. Xu, L. Xie, et al., Ca2+-dependent activator protein for secretion 1 is critical for constitutive and regulated exocytosis but not for loading of transmitters into dense core vesicles. J Biol Chem,2007.282(29):21392-403.
[191]. S. Speese, M. Petrie, K. Schuske, et al., UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans. Journal of Neuroscience,2007.27(23):6150-6162.
[192]. M. Hammarlund, S. Watanabe, K. Schuske, et al., CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons. J Cell Biol,2008.180(3): 483-91.
[193]. R. Renden, B. Berwin, W. Davis, et al., Drosophila CAPS is an essential gene that regulates dense-core vesicle release and synaptic vesicle fusion. Neuron,2001. 31(3):421-37.
[194]. W.J. Jockusch, D. Speidel, A. Sigler, et al., CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins. Cell,2007.131(4):796-808.
[195]. D. Stevens and J. Rettig, The Ca2+-dependent Activator Protein for Secretion CAPS:Do I Dock or do I Prime? Molecular Neurobiology,2009.39(1):62-72.
[196]. T. Sadakata, M. Washida, Y. Iwayama, et al., Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. Journal of Clinical Investigation,2007.117(4):931-943.
[197]. R.N. Grishanin, V.A. Klenchin, K.M. Loyet, et al., Membrane association domains in Ca2+-dependent activator protein for secretion mediate plasma membrane and dense-core vesicle binding required for Ca2+-dependent exocytosis. Journal of Biological Chemistry,2002.277(24):22025-22034.
[198]. M.A. Lemmon, Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol,2008.9(2):99-111.
[199]. D.J. James, J. Kowalchyk, N. Daily, et al., CAPS drives trans-SNARE complex formation and membrane fusion through syntaxin interactions. Proc Natl Acad Sci U S A,2009.106(41):17308-13.
[200]. J. Basu, N. Shen, I. Dulubova, et al., A minimal domain responsible for Munc13 activity. Nat Struct Mol Biol,2005.12(11):1017-8.
[201]. M. Christensen, A. Estevez, X. Yin, et al., A primary culture system for functional analysis of C. elegans neurons and muscle cells. Neuron,2002.33(4):503-14.
[202]. K. Strange, M. Christensen, and R. Morrison, Primary culture of Caenorhabditis elegans developing embryo cells for electrophysiological, cell biological and molecular studies. Nat Protoc,2007.2(4):1003-12.
[203], J. Kimble, J. Hodgkin, T. Smith, et al., Suppression of an amber mutation by microinjection of suppressor tRNA in C. elegans. Nature,1982.299(5882):456-8.
[204]. Y.M. Jiu, R.Y. Zhang, and Z.X. Wu, Gene Microinjection and Integration in C. elegans:Equipments, Processes and Guidance. Progress in Biochemistry and Biophysics,2009.36(5):648-652.
[205]. E. Neher and B. Sakmann, Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature,1976.260(5554):799-802.
[206]. A. Minta, J.P. Kao, and R.Y. Tsien, Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Biol Chem,1989.264(14): 8171-8.
[207]. G. Grynkiewicz, M. Poenie, and R.Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem,1985.260(6): 3440-50.
[208]. T. Voets, Dissection of three Ca2+-dependent steps leading to secretion in chromaffin cells from mouse adrenal slices. Neuron,2000.28(2):537-45.
[209]. M.B. Goodman and S.R. Lockery, Pressure polishing:a method for re-shaping patch pipettes during fire polishing. J Neurosci Methods,2000.100(1-2):13-5.
[210]. L. Avery, The genetics of feeding in Caenorhabditis elegans. Genetics,1993. 133(4):897-917.
[211]. M. Doi and K. Iwasaki, Regulation of retrograde signaling at neuromuscular junctions by the novel C2 domain protein AEX-1. Neuron,2002.33(2):249-59.
[212]. M.R. Lackner, S.J. Nurrish, and J.M. Kaplan, Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta:DAG binding to UNC-13 is required to stimulate acetylcholine release. Neuron,1999.24(2):335-46.
[213]. Y. Sako and T. Uyemura, Total internal reflection fluorescence microscopy for single-molecule imaging in living cells. Cell Struct Funct,2002.27(5):357-65.
[214]. T. Cai, T. Fukushige, A.L. Notkins, et al., Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion in Caenorhabditis elegans. J Neurosci,2004.24(12): 3115-24.
[215]. N.K. Charlie, M.A. Schade, A.M. Thomure, et al., Presynaptic UNC-31 (CAPS) is required to activate the G s pathway of the Caenorhabditis elegans synaptic signaling network. Genetics,2006.172(2):943-61.
[216]. A. Betz, M. Okamoto, F. Benseler, et al., Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem,1997.272(4): 2520-6.
[217]. E.O. Gracheva, A.O. Burdina, D. Touroutine, et al., Tomosyn negatively regulates CAPS-dependent peptide release at Caenorhabditis elegans synapses. Journal of Neuroscience,2007.27(46):12755-12755.
[218]. S.A. Daniels, M. Ailion, J.H. Thomas, et al., egl-4 acts through a transforming growth factor-beta/SMAD pathway in Caenorhabditis elegans to regulate multiple neuronal circuits in response to sensory cues. Genetics,2000.156(1):123-41.
[219]. H. Fares and I. Greenwald, Genetic analysis of endocytosis in Caenorhabditis elegans:coelomocyte uptake defective mutants. Genetics,2001.159(1):133-45.
[220]. H. Fares and B. Grant, Deciphering endocytosis in Caenorhabditis elegans. Traffic, 2002.3(1):11-9.
[221]. J.J. Ewbank, Tackling both sides of the host-pathogen equation with Caenorhabditis elegans. Microbes and Infection,2002.4(2):247-256.
[222]. N.V. Burke, W.P. Han, D.Q. Li, et al., Neuronal peptide release is limited by secretory granule mobility. Neuron,1997.19(5):1095-1102.
[223]. D. Shakiryanova, A. Tully, R.S. Hewes, et al., Activity-dependent liberation of synaptic neuropeptide vesicles. Nature Neuroscience,2005.8(2):173-178.
[224]. D. Shakiryanova, A. Tully, and E.S. Levitan, Activity-dependent synaptic capture of transiting peptidergic vesicles. Nature Neuroscience,2006.9(7):896-900.
[225]. J.C. Olivo-Marin, Extraction of spots in biological images using multiscale products. Pattern Recognition,2002.35(9):1989-1996.
[226]. K. Jaqaman, D. Loerke, M. Mettlen, et al., Robust single-particle tracking in live-cell time-lapse sequences. Nature Methods,2008.5(8):695-702.
[227]. Y. Liu, C. Schirra, D.R. Stevens, et al., CAPS facilitates filling of the rapidly releasable pool of large dense-core vesicles. J Neurosci,2008.28(21):5594-601.
[228]. D.J. James, C. Khodthong, J.A. Kowalchyk, et al., Phosphatidylinositol 4,5-bisphosphate regulation of SNARE function in membrane fusion mediated by CAPS. Adv Enzyme Regul,2009.
[2]. C. Kenyon, The nematode Caenorhabditis elegans. Science,1988.240(4858): 1448-53.
[3]. S. Guo and K.J. Kemphues, par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed Cell,1995.81(4):611-20.
[4]. A. Fire, S. Xu, M.K. Montgomery, et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature,1998.391(6669): 806-11.
[5]. T. Kim, M.C. Gondre-Lewis, I. Arnaoutova, et al., Dense-core secretory granule biogenesis. Physiology,2006.21:124-133.
[6]. T.C. Suedof, Neurotransmitter release, in Handbook of Experimental Pharmacology, T.C. Sudhof and K. Starke, Editors.2008, Springer-Verlag Berlin. p. 1-21.
[7]. S. Sugita, Mechanisms of exocytosis. Acta Physiologica,2008.192(2):185-193.
[8]. J.C. Hay and T.F. Martin, Resolution of regulated secretion into sequential MgATP-dependent and calcium-dependent stages mediated by distinct cytosolic proteins. J Cell Biol,1992.119(1):139-51.
[9]. S.P. Gandhi and C.F. Stevens, Three modes of synaptic vesicular recycling revealed by single-vesicle imaging. Nature,2003.423(6940):607-13.
[10]. D.L. Baillie, K.A. Beckenbach, and A.M. Rose, Cloning within the unc-43 to unc-31 interval (linkage group IV) of the Caenorhabditis elegans genome using Tcl linkage selection. Can J Genet Cytol,1985.27(4):457-66.
[11]. J. Malsam, S. Kreye, and T.H. Sollner, Membrane fusion:SNAREs and regulation. Cell Mol Life Sci,2008.65(18):2814-32.
[12]. R. Jahn and R.H. Scheller, SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol,2006.7(9):631-43.
[13]. W. Hong, SNAREs and traffic Biochim Biophys Acta,2005.1744(3):493-517.
[14]. T. Lang and R. Jahn, Core proteins of the secretory machinery. Handb Exp Pharmacol,2008(184):107-27.
[15]. R.B. Sutton, D. Fasshauer, R. Jahn, et al., Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 angstrom resolution. Nature,1998. 395(6700):347-353.
[16]. F. Li, F. Pincet, E. Perez, et al., Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat Struct Mol Biol,2007.14(10):890-6.
[17]. F.S. Cohen and GB. Melikyan, The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement J Membr Biol,2004. 199(1):1-14.
[18]. Y. Hua and R.H. Scheller, Three SNARE complexes cooperate to mediate membrane fusion. Proc Natl Acad Sci U S A,2001.98(14):8065-70.
[19]. P.I. Hanson, R. Roth, H. Morisaki, et al., Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep-etch electron microscopy. Cell,1997.90(3):523-35.
[20]. T.M. Hohl, F. Parlati, C. Wimmer, et al., Arrangement of subunits in 20 S particles consisting of NSF, SNAPs, and SNARE complexes. Mol Cell,1998.2(5):539-48.
[21]. T. Sollner, M.K. Bennett, S.W. Whiteheart, et al., A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell,1993.75(3):409-18.
[22]. A. Mayer, W. Wickner, and A. Haas, Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell,1996.85(1): 83-94.
[23]. J.T. Littleton, R.J. Barnard, S.A. Titus, et al., SNARE-complex disassembly by NSF follows synaptic-vesicle fusion. Proc Natl Acad Sci U S A,2001.98(21): 12233-8.
[24]. M.K. Bennett, N. Calakos, and R.H. Scheller, Syntaxin:a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science, 1992.257(5067):255-9.
[25]. M.K. Bennett, J.E. Garcia-Arraras, L.A. Elferink, et al., The syntaxin family of vesicular transport receptors. Cell,1993.74(5):863-73.
[26]. F.Y. Teng, Y. Wang, and B.L. Tang, The syntaxins. Genome Biol,2001.2(11): REVIEWS3012.
[27]. T. Weimbs, S.H. Low, S.J. Chapin, et al., A conserved domain is present in different families of vesicular fusion proteins:A new superfamily. Proceedings of the National Academy of Sciences of the United States of America,1997.94(7): 3046-3051.
[28]. J.C. Lerman, J. Robblee, R. Fairman, et al., Structural analysis of the neuronal SNARE protein syntaxin-1A Biochemistry,2000.39(29):8470-9.
[29]. O. Saifee, L.P. Wei, and M.L. Nonet, The Caenorhabditis elegans unc-64 locus encodes a syntaxin that interacts genetically with synaptobrevin. Molecular Biology of the Cell,1998.9(6):1235-1252.
[30]. H. Ogawa, S. Harada, T. Sassa, et al., Functional properties of the unc-64 gene encoding a Caenorhabditis elegans syntaxin. Journal of Biological Chemistry,1998. 273(4):2192-2198.
[31]. M.C. Wilson, P.P. Mehta, and E.J. Hess, SNAP-25, enSNAREd in neurotransmission and regulation of behaviour. Biochem Soc Trans,1996.24(3): 670-76.
[32]. A. Hodel, Snap-25. Int J Biochem Cell Biol,1998.30(10):1069-73.
[33]. D. Fasshauer, D. Bruns, B. Shen, et al., A structural change occurs upon binding of syntaxin to SNAP-25. Journal of Biological Chemistry,1997.272(7):4582-4590.
[34]. G.Y. Wang, J.W. Witkin, GM. Hao, et al., Syndet is a novel SNAP-25 related protein expressed in many tissues. Journal of Cell Science,1997.110:505-513.
[35]. P.I. Hanson, J.E. Heuser, and R. Jahn, Neurotransmitter release - four years of SNARE complexes. Current Opinion in Neurobiology,1997.7(3):310-315.
[36]. L.M. Gutierrez, S. Viniegra, J. Rueda, et al., A peptide that mimics the C-terminal sequence of SNAP-25 inhibits secretory vesicle docking in chromaffin cells. Journal of Biological Chemistry,1997.272(5):2634-2639.
[37]. G.W. Lawrence, P. Foran, N. Mohammed, et al., Importance of two adjacent C-terminal sequences of SNAP-25 in exocytosis from intact and permeabilized chromaffin cells revealed by inhibition with botulinum neurotoxins A and E Biochemistry,1997.36(11):3061-3067.
[38]. P.P. Mehta, E. Battenberg, and M.C. Wilson, SNAP-25 and synaptotagmin involvement in the final Ca2+-dependent triggering of neurotransmitter exocytosis. Proceedings of the National Academy of Sciences of the United States of America, 1996.93(19):10471-10476.
[39]. W.S. Trimble, D.M. Cowan, and R.H. Scheller, VAMP-1 - a synaptic vesicle associated integral membrane proten. Proceedings of the National Academy of Sciences of the United States of America,1988.85(12):4538-4542.
[40]. M. Baumert, P.R. Maycox, F. Navone, et al., Synaptobrevin:an integral membrane protein of 18000 daltons present in small synaptic vesicles of rat brain Embo Journal,1989.8(2):379-384.
[41]. J.E. Gerst, SNAREs and SNARE regulators in membrane fusion and exocytosis. Cellular and Molecular Life Sciences,1999.55(5):707-734.
[42]. D. Fasshauer, H. Otto, W.K. Eliason, et al., Structural changes are associated with soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complex formation. Journal of Biological Chemistry,1997.272(44):28036-28041.
[43]. L.M. Rice, P. Brennwald, and A.T. Brunger, Formation of a yeast SNARE complex is accompanied by significant structural changes. Febs Letters,1997.415(1): 49-55.
[44]. D. Fasshauer, W.K. Eliason, A.T. Brunger, et al., Identification of a minimal core of the synaptic SNARE complex sufficient for reversible assembly and disassembly. Biochemistry,1998.37(29):10354-10362.
[45]. T. Weber, B.V. Zemelman, J.A. McNew, et al., SNAREpins:Minimal machinery for membrane fusion. Cell,1998.92(6):759-772.
[46]. H.Y. Gaisano, L. Sheu, J.K. Foskett, et al., Tetanus toxin light chain cleaves a vesicle-associated membrane protein (VAMP) isoform 2 in rat pancreatic zymogen granules and inhibits enzyme secretion. Journal of Biological Chemistry,1994. 269(25):17062-17066.
[47]. H. Misonou, M. OharaImaizumi, and K. Kumakura, Regulation of the priming of exocytosis and the dissociation of SNAP-25 and VAMP-2 in adrenal chromaffin cells. Neuroscience Letters,1997.232(3):182-184.
[48]. A.L. Olson, J.B. Knight, and J.E. Pessin, Syntaxin 4, VAMP2, and/or VAMP3/cellubrevin are functional target membrane and vesicle SNAP receptors for insulin-stimulated GLUT4 translocation in adipocytes. Molecular and Cellular Biology,1997.17(5):2425-2435.
[49]. O. Rossetto, L. Gorza, G. Schiavo, et al., VAMP synaptobrevin isoforms 1 and 2 are widely and differentially expressed in nonneuronal tissues. Journal of Cell Biology,1996.132(1-2):167-179.
[50]. Y. Tamori, M. Hashiramoto, S. Araki, et al., Cleavage of vesicle-associated membrane protein (VAMP)-2 and cellubrevin on GLUT4-containing vesicles inhibits the translocation of GLUT4 in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications,1996.220(3):740-745.
[51]. L.A. Elferink, W.S. Trimble, and R.H. Scheller, Two vesicle-associated membrane protein genes are differentially expressed in the rat central nervous system. Journal of Biological Chemistry,1989.264(19):11061-11064.
[52]. S. Nielsen, D. Marples, H. Birn, et al., Expression of VAMP-2-like protein in kidney collecting duct intracellular vesicles. Colocalization with Aquaporin-2 water channels. Journal of Clinical Investigation,1995.96(4):1834-1844.
[53]. R. Mandic, W.S. Trimble, and A.W. Lowe, Tissue-specific alternative RNA splicing of rat vesicle-associated membrane protein-1 (VAMP-1). Gene,1997. 199(1-2):173-179.
[54]. S. Isenmann, Y. Khew-Goodall, J. Gamble, et al., A splice-isoform of vesicle-associated membrane protein-1 (VAMP-1) contains a mitochondrial targeting signal. Molecular Biology of the Cell,1998.9(7):1649-1660.
[55]. H.T. McMahon, Y.A. Ushkaryov, L. Edelmann, et al., Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein. Nature,1993.364(6435):346-349.
[56]. T. Galli, A. Zahraoui, V.V. Vaidyanathan, et al., A novel tetanus neurotoxin-insensitive vesicle-associated membrane protein in SNARE complexes of the apical plasma membrane of epithelial cells. Molecular Biology of the Cell, 1998.9(6):1437-1448.
[57]. J.C. Aledo, E. Hajduch, F. Darakhshan, et al., Analyses of the co-localization of cellubrevin and the GLUT4 glucose transporter in rat and human insulin-responsive tissues. Febs Letters,1996.395(2-3):211-216.
[58]. A. Volchuk, Y. Mitsumoto, L.J. He, et al., Expression of vesicle-associated membrane protein 2 (VAMP-2)/synaptobrevin Ⅱ and cellubrevin in rat skeletal muscle and in a muscle cell line. Biochemical Journal,1994.304:139-145.
[59]. D. Sengupta, F.D. Gumkowski, L.H. Tang, et al., Localization of cellubrevin to the Golgi complex in pancreatic acinar cells. European Journal of Cell Biology,1996. 70(4):306-314.
[60]. T.J. Chilcote, T. Galli,O. Mundigl, et al., Cellubrevin and synaptobrevins:similar subcellular localization and biochemical properties in PC12 cells. Journal of Cell Biology,1995.129(1):219-231.
[61]. T. Galli, T. Chilcote,O. Mundigl, et al., Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. Journal of Cell Biology,1994.125(5):1015-1024.
[62]. C. Galli, A. Piccini, M.T. Ciotti, et al., Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proceedings of the National Academy of Sciences of the United States of America,1998.95(3):1247-1252.
[63]. R. Regazzi, C.B. Wollheim, J. Lang, et al., VAMP-2 and cellubrevin are expressed in pancreatic beta-cells and are essential for Ca2+—but not for GTP gamma S-induced insulin secretion. Embo Journal,1995.14(12):2723-2730.
[64]. J.E.A. Braun, B.A. Fritz, S.M.E. Wong, et al., Identification of a vesicle-associated membrane protein (VAMP)-like membrane protein in zymogen granules of the rat exocrine pancreas. Journal of Biological Chemistry,1994.269(7):5328-5335.
[65]. R.J. Advani, H.R. Bae, J.B. Bock, et al., Seven novel mammalian SNARE proteins localize to distinct membrane compartments. Journal of Biological Chemistry, 1998.273(17):10317-10324.
[66]. S.H. Wong, T. Zhang, Y. Xu, et al., Endobrevin, a novel synaptobrevin/VAMP-like protein preferentially associated with the early endosome. Molecular Biology of the Cell,1998.9(6):1549-1563.
[67]. Q. Zeng, V.N. Subramaniam, S.H. Wong, et al., A novel synaptobrevin/VAMP homologous protein (VAMP5) is increased during in vitro myogenesis and present in the plasma membrane. Molecular Biology of the Cell,1998.9(9):2423-2437.
[68]. J.E. Gerst, L. Rodgers, M. Riggs, et al., SNC1, a yeast homolog of the synaptic vesicle-associated membrane protein/synaptobrevin gene family:genetic interactions with the RAS and CAP genes. Proceedings of the National Academy of Sciences of the United States of America,1992.89(10):4338-4342.
[69]. V. Protopopov, B. Govindan, P. Novick, et al., Homologs of the synaptobrevin/VAMP family of synaptic vesicle proteins function on the late secretory pathway in S. cerevisiae. Cell,1993.74(5):855-61.
[70]. G. Rossi, A. Salminen, L.M. Rice, et al., Analysis of a yeast SNARE complex reveals remarkable similarity to the neuronal SNARE complex and a novel function for the C terminus of the SNAP-25 homolog, Sec9. Journal of Biological Chemistry,1997.272(26):16610-16617.
[71]. P. Brennwald, B. Kearns, K. Champion, et al., Sec9 is a SNAP-25-like component of a yeast SNARE complex that may be the effector of Sec4 function in exocytosis. Cell,1994.79(2):245-258.
[72]. M.K. Aalto, H. Ronne, and S. Keranen, Yeast syntaxins Ssolp and Sso2p belong to a family of related membrane proteins that function in vesicular transport Embo Journal,1993.12(11):4095-4104.
[73]. A. Couve and J.E. Gerst, Yeast Snc proteins complex with Sec9. Functional interactions between putative SNARE proteins. Journal of Biological Chemistry, 1994.269(38):23391-23394.
[74]. J.E. Gerst, Conserved alpha-helical segments on yeast homologs of the synaptobrevin/VAMP family of V-SNAREs mediate exocytic function. Journal of Biological Chemistry,1997.272(26):16591-16598.
[75]. D. David, S. Sundarababu, and J.E. Gerst, Involvement of long chain fatty acid elongation in the trafficking of secretory vesicles in yeast Journal of Cell Biology, 1998.143(5):1167-1182.
[76]. K.G. Miller, A. Alfonso, M. Nguyen, et al., A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc Natl Acad Sci U S A,1996.93(22): 12593-8.
[77]. P. Novick, C. Field, and R. Schekman, Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell, 1980.21(1):205-215.
[78]. R.R Toonen and M. Verhage, Vesicle trafficking:pleasure and pain from SM genes. Trends Cell Biol,2003.13(4):177-86.
[79]. A. Bracher and W. Weissenhorn, Structural basis for the Golgi membrane recruitment of Sly1p by Sed5p. Embo Journal,2002.21(22):6114-6124.
[80]. K.M.S. Misura, R.H. Scheller, and W.I. Weis, Three-dimensional structure of the neuronal-Secl-syntaxin 1a complex Nature,2000.404(6776):355-362.
[81]. M. Verhage, A.S. Maia, J.J. Plomp, et al., Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science,2000.287(5454):864-869.
[82]. D. Gallwitz and R. Jahn, The riddle of the Sec1/Munc-18 proteins - new twists added to their interactions with SNAREs. Trends Biochem Sci,2003.28(3):113-6.
[83]. Y. Hata, C.A. Slaughter, and T.C. Sudhof, Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature,1993.366(6453):347-351.
[84]. J. Pevsner, S.C. Hsu, and R.H. Scheller, n-Secl:a neural-specific syntaxin-binding protein. Proceedings of the National Academy of Sciences of the United States of America,1994.91(4):1445-1449.
[85]. I. Dulubova, M. Khvotchev, S.Q. Liu, et al., Munc18-1 binds directly to the neuronal SNARE complex. Proceedings of the National Academy of Sciences of the United States of America,2007.104:2697-2702.
[86]. C.M. Carr, E. Grote, M. Munson, et al., Seclp binds to SNARE complexes and concentrates at sites of secretion. Journal of Cell Biology,1999.146(2):333-344.
[87]. I. Dulubova, S. Sugita, S. Hill, et al., A conformational switch in syntaxin during exocytosis:role of muncl8. Embo Journal,1999.18(16):4372-4382.
[88]. P. Burkhardt, D.A. Hattendorf, W.I. Weis, et al., Muncl8a controls SNARE assembly through its interaction with the syntaxin N-peptid. Embo Journal,2008. 27(7):923-933.
[89]. J.E. Richmond, R.M. Weimer, and E.M. Jorgensen, An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature,2001.412(6844): 338-341.
[90]. M. Hammarlund, M.T. Palfreyman, S. Watanabe, et al., Open syntaxin docks synaptic vesicles. PLoS Biol,2007.5(8):e198.
[91]. F.E. Zilly, J.B. Sorensen, R. Jahn, et al., Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes. PLoS Biol, 2006.4(10):e330.
[92]. J. Shen, D.C. Tareste, F. Paumet, et al., Selective activation of cognate SNAREpins by Secl/Munc18 proteins. Cell,2007.128(1):183-95.
[93]. I. Dulubova, M. Khvotchev, S. Liu, et al., Munc18-1 binds directly to the neuronal SNARE complex. Proc Natl Acad Sci U S A,2007.104(8):2697-702.
[94]. H. Shu-Hong, C.F. Latham, C.L. Gee, et al., Structure of the Muncl8c/Syntaxin4 N-peptide complex defines universal features of the N-peptide binding mode of Sec1/Munc18 proteins. Proceedings of the National Academy of Sciences of the United States of America,2007:8773-8.
[95]. C.F. Latham, J.A. Lopez, S.H. Hu, et al., Molecular dissection of the Muncl8c/syntaxin4 interaction:Implications for regulation of membrane trafficking. Traffic,2006.7(10):1408-1419.
[96]. T. Yamaguchi, I. Dulubova, S.W. Min, et al., Slyl binds to Golgi and ER syntaxins via a conserved N-terminal peptide motif Developmental Cell,2002.2(3): 295-305.
[97]. M. D'Andrea-Merrins, L. Chang, A.D. Lam, et al., Muncl8c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. Journal of Biological Chemistry,2007.282(22):16553-16566.
[98]. M. Khvotchev, I. Dulubova, J. Sun, et al., Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 n terminus. Journal of Neuroscience,2007.27:12147-12155.
[99]. L.N. Carpp, L.F. Ciufo, S.G. Shanks, et al., The Sec1p/Munc18 protein Vps45p binds its cognate SNARE proteins via two distinct modes. Journal of Cell Biology, 2006.173(6):927-936.
[100]. I. Dulubova, T. Yamaguchi, Y. Gao, et al., How Tlg2p/syntaxin 16 'snares' Vps45. Embo Journal,2002.21(14):3620-3631.
[101]. Y. Kosodo, Y. Noda, H. Adachi, et al., Binding of Slyl to Sed5 enhances formation of the yeast early Golgi SNARE complex. Journal of Cell Science,2002.115(18): 3683-3691.
[102]. R.W. Peng and D. Gallwitz, Slyl protein bound to Golgi syntaxin Sed5p allows assembly and contributes to specificity of SNARE fusion complexes. Journal of Cell Biology,2002.157(4):645-655.
[103]. N.J. Bryant and D.E. James, The Seclp/Munc18 (SM) protein, Vps45p, cycles on and off membranes during vesicle transport Journal of Cell Biology,2003.161(4): 691-696.
[104]. J.GS. Coe, A.C.B. Lim, J. Xu, et al., A role for T1g1p in the transport of proteins within the Golgi apparatus of Saccharomyces cerevisiae. Molecular Biology of the Cell,1999.10(7):2407-2423.
[105]. J. Togneri, Y.S. Cheng, M. Munson, et al., Specific SNARE complex binding mode of the Sec1/Munc-18 protein, Sec1p. Proceedings of the National Academy of Sciences of the United States of America,2006.103(47):17730-17735.
[106]. B.L. Scott, J.S. Van Komen, H. Irshad, et al., Seclp directly stimulates SNARE-mediated membrane fusion in vitro. Journal of Cell Biology,2004.167(1): 75-85.
[107]. J.S. Shen, D.C. Tareste, F. Paumet, et al., Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell,2007.128:183-195.
[108]. A.L. Williams, S. Ehm, N.C. Jacobson, et al., rslyl binding to syntaxin 5 is required for endoplasmic reticulum-to-Golgi transport but does not promote SNARE motif accessibility. Molecular Biology of the Cell,2004.15(1):162-175.
[109]. D. Arac, I. Dulubova, J.M. Pei, et al., Three-dimensional structure of the rSly1 N-terminal domain reveals a conformational change induced by binding to syntaxin 5. Journal of Molecular Biology,2005.346(2):589-601.
[110]. R.F.G Toonen and M. Verhage, Munc18-1 in secretion:lonely Munc joins SNARE team and takes control. Trends in Neurosciences,2007.30(11):564-572.
[111]. S. Braun and S. Jentsch, SM-protein-controlled ER-associated degradation discriminates between different SNAREs. Embo Reports,2007.8(12):1176-1182.
[112]. N.J. Bryant and D.E. James, Vps45p stabilizes the syntaxin homologue Tlg2p and positively regulates SNARE complex formation. Embo Journal,2001.20(13): 3380-3388.
[113]. R.F.G Toonen, K.J. de Vries, R. Zalm, et al., Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation. Journal of Neurochemistry,2005.93(6):1393-1400.
[114]. L. Arunachalam, L. Han, N.G. Tassew, et al., Munc18-1 is critical for plasma membrane localization of syntaxinl but not of SNAP-25 in PC12 cells. Molecular Biology of the Cell,2008.19(2):722-734.
[115]. T. Voets, R.F. Toonen, E.C. Brian, et al., Munc18-1 promotes large dense-core vesicle docking. Neuron,2001.31(4):581-591.
[116]. E. Nielsen, S. Christoforidis, S. Uttenweiler-Joseph, et al., Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. Journal of Cell Biology,2000.151(3):601-612.
[117]. D.F. Seals, G. Eitzen, N. Margolis, et al., A Ypt/Rab effector complex containing the See1 homolog Vps33p is required for homotypic vacuole fusion. Proceedings of the National Academy of Sciences of the United States of America,2000. 97(17):9402-9407.
[118]. J.R.T. van Weering, R.F. Toonen, and M. Verhage, The Role of Rab3a in Secretory Vesicle Docking Requires Association/Dissociation of Guanidine Phosphates and Munc18-1. PLoS One,2007.2(7):Article No.:e616.
[119]. K.M. Zhou, Y.M. Dong, Q. Ge, et al., PKA activation bypasses the requirement for UNC-31 in the docking of dense core vesicles from C. elegans neurons. Neuron, 2007.56(4):657-69.
[120]. M. Craxton, Synaptotagmin gene content of the sequenced genomes. BMC Genomics,2004.5(1):43.
[121]. T.C. Sudhof, Synaptotagmins:why so many? J Biol Chem,2002.277(10): 7629-32.
[122]. J. Ubach, X.Y. Zhang, X.G Shao, et al., Ca2+ binding to synaptotagmin:how many Ca2+ ions bind to the tip of a C-2-domain? Embo Journal,1998.17(14): 3921-3930.
[123]. W.D. Matthew, L. Tsavaler, and L.F. Reichardt, Identification of a synaptic vesicle-specificmembrane protein with a wide distribution in neuronal and neurosecretory tissue. Journal of Cell Biology,1981.91(1):257-269.
[124]. S. Takamori, M. Holt, K. Stenius, et al., Molecular anatomy of a trafficking organelle. Cell,2006.127(4):831-846.
[125]. M.S. Perin, V.A. Fried, G.A. Mignery, et al., Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature, 1990.345(6272):260-3.
[126]. N. Brose, A.G Petrenko, T.C. Sudhof, et al., Synaptotagmin:a calcium sensor on the synaptic vesicle surface. Science,1992.256(5059):1021-1025.
[127]. S. Sugita, O.H. Shin, W.P. Han, et al., Synaptotagmins form a hierarchy of exocytotic Ca2+ sensors with distinct Ca2+ affinities. Embo Journal,2002.21(3): 270-280.
[128]. R. Llinas, M. Sugimori, and R.B. Silver, Microdomains of high calcium concentration in a presynaptic terminal. Science,1992.256(5057):677-9.
[129]. N. Charvin, C. Leveque, D. Walker, et al., Direct interaction of the calcium sensor protein synaptotagmin I with a cytoplasmic domain of the alpha(1)A subunit of the P/Q-type calcium channel. Embo Journal,1997.16(15):4591-4596.
[130]. D.K. Kim and W.A. Catterall, Ca2+-dependent and -independent interactions of the isoforms of the alphalA subunit of brain Ca2+ channels with presynaptic SNARE proteins. Proceedings of the National Academy of Sciences of the United States of America,1997.94(26):14782-14786.
[131]. E.R. Chapman, How does synaptotagmin trigger neurotransmitter release? Annual Review of Biochemistry,2008.77:615-641.
[132]. E.R. Chapman, Synaptotagmin:A Ca2+ sensor that triggers exocytosis? Nature Reviews Molecular Cell Biology,2002.3(7):498-508.
[133]. M. Geppert, Y. Goda, R.E. Hammer, et al., Synaptotagmin Ⅰ:a major Ca2+ sensor for transmitter release at a central synapse. Cell,1994.79(4):717-727.
[134]. R. Fernandez-Chacon, A. Konigstorfer, S.H. Gerber, et al., Synaptotagmin I functions as a calcium regulator of release probability. Nature,2001.410(6824): 41-49.
[135]. J.M. Mackler, J.A. Drummond, C.A. Loewen, et al., The C2BCa2+-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature,2002. 418(6895):340-344.
[136]. Z.P. Pang, J.Y. Sun, J. Rizo, et al., Genetic analysis of synaptotagmin 2 in spontaneous and Ca2+-triggered neurotransmitter release. Embo Journal,2006. 25(10):2039-2050.
[137]. J.T. Littleton, M. Stern, M. Perin, et al., Calcium dependence of neurotransmitter release and rate of spontaneous vesicle fusions are altered in Drosophila synaptotagmin mutants. Proceedings of the National Academy of Sciences of the United States of America,1994.91(23):10888-10892.
[138]. T. Nishiki and GJ. Augustine, Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. Journal of Neuroscience,2004.24(27):6127-6132.
[139]. J.R. Schaub, X.B. Lu, B. Doneske, et al., Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nature Structural & Molecular Biology,2006. 13(8):748-750.
[140]. C.G. Giraudo, W.S. Eng, T.J. Melia, et al., A clamping mechanism involved in SNARE-dependent exocytosis. Science,2006.313(5787):676-680.
[141]. J.H. Bai, C.A. Earles, J.L. Lewis, et al., Membrane-embedded synaptotagmin penetrates cis or trans target membranes and clusters via a novel mechanism. Journal of Biological Chemistry,2000.275(33):25427-25435.
[142]. D.Z. Herrick, S. Sterbling, K.A. Rasch, et al., Position of synaptotagmin I at the membrane interface:Cooperative interactions of tandem C2 domains. Biochemistry,2006.45(32):9668-9674.
[143]. S. Martens, M.M. Kozlov, and H.T. McMahon, How synaptotagmin promotes membrane fusion. Science,2007.316(5828):1205-1208.
[144]. G Schiavo, Q.M. Gu, GD. Prestwich, et al., Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. Proceedings of the National Academy of Sciences of the United States of America,1996.93(23): 13327-13332.
[145]. K. Aoyagi, T. Sugaya, M. Umeda, et al., The activation of exocytotic sites by the formation of phosphatidylinositol 4,5-bisphosphate microdomains at syntaxin clusters. Journal of Biological Chemistry,2005.280(17):17346-17352.
[146]. J.H. Bai, W.C. Tucker, and E.R. Chapman, PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nature Structural & Molecular Biology,2004.11(1):36-44.
[147]. A.F. Davis, J.H. Bai, D. Fasshauer, et al., Kinetics of synaptotagmin responses to Ca2+ and assembly with the core SNARE complex onto membranes. Neuron,1999. 24(2):363-376.
[148]. A. Bhalla, M.C. Chicka, W.C. Tucker, et al., Ca2+-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion. Nature Structural & Molecular Biology,2006.13(4):323-330.
[149]. Z.P.P. Pang, O.H. Shin, A.C. Meyer, et al., 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. Journal of Neuroscience,2006.26(48):12556-12565.
[150]. X.G. Shao, I. Fernandez, X.Y. Zhang, et al., Synaptotagmin-syntaxin interaction: The C-2 domain as a Ca2+-dependent electrostatic switch. Neuron,1997.18(1): 133-142.
[151]. E.R. Chapman, How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem,2008.77:615-41.
[152]. J.H. Bai, P. Wang, and E.R. Chapman, C2A activates a cryptic Ca2+-triggered membrane penetration activity within the C2B domain of synaptotagmin Ⅰ. Proceedings of the National Academy of Sciences of the United States of America, 2002.99(3):1665-1670.
[153]. C.T. Wang, J.H. Bai, P.Y. Chang, et al., Synaptotagmin-Ca2+ triggers two sequential steps in regulated exocytosis in rat PC12 cells:fusion pore opening and fusion pore dilation. Journal of Physiology-London,2006.570(2):295-307.
[154]. C. Li, B. Ullrich, J.Z. Zhang, et al., Ca+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature,1995.375(6532):594-599.
[155]. I. Martinez, S. Chakrabarti, T. Hellevik, et al., Synaptotagmin Ⅶ regulates Ca2+-dependent exocytosis of lysosomes in fibroblasts. Journal of Cell Biology, 2000.148(6):1141-1149.
[156]. Z.Y. Gao, J. Reavey-Cantwell, R.A. Young, et al., Synaptotagmin Ⅲ/Ⅶ isoforms mediate Ca2+-induced insulin secretion in pancreatic islet beta-cells. Journal of Biological Chemistry,2000.275(46):36079-36085.
[157]. C. Li, B. Ullrich, J.Z. Zhang, et al., Ca2+-dependent and -independent activities of neural and non-neural synaptotagmins. Nature,1995.375(6532):594-599.
[158]. E.V. Caler, S. Chakrabarti, K.T. Fowler, et al., The exocytosis-regulatory protein synaptotagminVII mediates cell invasion by Trypanosoma cruzi. Journal of Experimental Medicine,2001.193(9):1097-1104.
[159]. M. Fukuda, E. Kanno, M. Satoh, et al., Synaptotagmin Ⅶ is targeted to dense-core vesicles and regulates their Ca2+-dependent exocytosis in PC12 cells. Journal of Biological Chemistry,2004.279(50):52677-52684.
[160]. M. Fukuda, Y. Ogata, C. Saegusa, et al., Alternative splicing isoforms of synaptotagmin VII in the mouse, rat and human. Biochemical Journal,2002.365: 173-180.
[161]. S. Chakrabarti, K.S. Kobayashi, R.A. Flavell, et al., Impaired membrane resealing and autoimmune myositis in synaptotagmin Ⅶ-deficient mice. Journal of Cell Biology,2003.162(4):543-549.
[162]. D. Roy, D.R. Liston, V.J. Idone, et al., A process for controlling intracellular bacterial infections induced by membrane injury. Science,2004.304(5676): 1515-1518.
[163]. A. Gut, C.E. Kiraly, M. Fukuda, et al., Expression and localisation of synaptotagmin isoforms in endocrine beta-cells:their function in insulin exocytosis. Journal of Cell Science,2001.114(9):1709-1716.
[164]. W.C. Tucker, J.M. Edwardson, J.H. Bai, et al., Identification of synaptotagmin effectors via acute inhibition of secretion from cracked PC12 cells. Journal of Cell Biology,2003.162(2):199-209.
[165]. J. Schultz, T. Doerks, C.P. Ponting, et al., More than 1,000 putative new human signalling proteins revealed by EST data mining. Nature Genetics,2000.25(2): 201-204.
[166]. B.L. Grosshans, D. Ortiz, and P. Novick, Rabs and their effectors:achieving specificity in membrane traffic Proc Natl Acad Sci U S A,2006.103(32): 11821-7.
[167]. T.C. Sudhof, The synaptic vesicle cycle. Annu Rev Neurosci,2004.27:509-47.
[168]. H. Stenmark, Rab GTPases as coordinators of vesicle traffic Nature Reviews Molecular Cell Biology,2009.10(8):513-525.
[169]. Y. Wang, M. Okamoto, F. Schmitz, et al., Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature,1997.388(6642):593-598.
[170]. M. Fukuda, Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2 -Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2. Journal of Biological Chemistry,2003.278(17):15373-15380.
[171]. Y. Wang and T.C. Sudhof, Genomic definition of RIM proteins:evolutionary amplification of a family of synaptic regulatory proteins. Genomics,2003.81(2): 126-137.
[172]. C.M. Powell, S. Schoch, L. Monteggia, et al., The presynaptic active zone protein RIM1 alpha is critical for normal learning and memory. Neuron,2004.42(1): 143-153.
[173]. S. Schoch, P.E. Castillo, T. Jo, et al., RIM1 alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature,2002.415(6869): 321-326.
[174]. L. Sun, M.A. Bittner, and R.W. Holz, Rab3a binding and secretion-enhancing domains in Riml are separate and unique - Studies in adrenal chromaffin cells. Journal of Biological Chemistry,2001.276(16):12911-12917.
[175]. D.R. Stevens, Z.X. Wu, U. Matti, et al., Identification of the minimal protein domain required for priming activity of Munc13-1. Curr Biol,2005.15(24): 2243-8.
[176]. B. Aravamudan, T. Fergestad, W.S. Davis, et al., Drosophila Unc-13 is essential for synaptic transmission. Nature Neuroscience,1999.2(11):965-971.
[177]. I. Augustin, C. Rosenmund, T.C. Sudhof, et al., Munc13-1 is essential for fusion competence of glutamatergic synoptic vesicles. Nature,1999.400(6743):457-461.
[178]. F. Varoqueaux, A. Sigler, J.S. Rhee, et al., Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proceedings of the National Academy of Sciences of the United States of America,2002.99(13):9037-9042.
[179]. A. Betz, M. Okamoto, F. Benseler, et al., Direct interaction of the rat unc-13 homologue Munc 13-1 with the N-terminus of syntaxin. European Journal of Cell Biology,1997.72(SUPPL.43):30.
[180]. R. Guan, H. Dai, and J. Rizo, Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes. Biochemistry,2008.47(6):1474-1481.
[181]. T. Sassa, S. Harada, H. Ogawa, et al., Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. Journal of Neuroscience,1999.19(12): 4772-4777.
[182]. R.R. Duncan, M.J. Shipston, and R.H. Chow, Double C2 protein. A review. Biochimie,2000.82(5):421-426.
[183]. AJ.A. Groffen, R. Friedrich, E.C. Brian, et al., DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties. Journal of Neurochemistry,2006.97(3):818-833.
[184]. M. Verhage, K.J. deVries, H. Roshol, et al., DOC2 proteins in rat brain: Complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion. Neuron,1997.18(3):453-461.
[185]. J.H. Walent, B.W. Porter, and T.F. Martin, A novel 145 kd brain cytosolic protein reconstitutes Ca2+-regulated secretion in permeable neuroendocrine cells. Cell, 1992.70(5):765-75.
[186]. B. Berwin, E. Floor, and T.F. Martin, CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis. Neuron,1998. 21(1):137-45.
[187]. A. Tandon, S. Bannykh, J.A. Kowalchyk, et al., Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes. Neuron,1998. 21(1):147-54.
[188]. A. Elhamdani, T.F. Martin, J.A. Kowalchyk, et al., Ca2+-dependent activator protein for secretion is critical for the fusion of dense-core vesicles with the membrane in calf adrenal chromaffin cells. J Neurosci,1999.19(17):7375-83.
[189]. R.N. Grishanin, J.A. Kowalchyk, V.A. Klenchin, et al., CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron,2004. 43(4):551-62.
[190]. Y. Fujita, A. Xu, L. Xie, et al., Ca2+-dependent activator protein for secretion 1 is critical for constitutive and regulated exocytosis but not for loading of transmitters into dense core vesicles. J Biol Chem,2007.282(29):21392-403.
[191]. S. Speese, M. Petrie, K. Schuske, et al., UNC-31 (CAPS) is required for dense-core vesicle but not synaptic vesicle exocytosis in Caenorhabditis elegans. Journal of Neuroscience,2007.27(23):6150-6162.
[192]. M. Hammarlund, S. Watanabe, K. Schuske, et al., CAPS and syntaxin dock dense core vesicles to the plasma membrane in neurons. J Cell Biol,2008.180(3): 483-91.
[193]. R. Renden, B. Berwin, W. Davis, et al., Drosophila CAPS is an essential gene that regulates dense-core vesicle release and synaptic vesicle fusion. Neuron,2001. 31(3):421-37.
[194]. W.J. Jockusch, D. Speidel, A. Sigler, et al., CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins. Cell,2007.131(4):796-808.
[195]. D. Stevens and J. Rettig, The Ca2+-dependent Activator Protein for Secretion CAPS:Do I Dock or do I Prime? Molecular Neurobiology,2009.39(1):62-72.
[196]. T. Sadakata, M. Washida, Y. Iwayama, et al., Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. Journal of Clinical Investigation,2007.117(4):931-943.
[197]. R.N. Grishanin, V.A. Klenchin, K.M. Loyet, et al., Membrane association domains in Ca2+-dependent activator protein for secretion mediate plasma membrane and dense-core vesicle binding required for Ca2+-dependent exocytosis. Journal of Biological Chemistry,2002.277(24):22025-22034.
[198]. M.A. Lemmon, Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol,2008.9(2):99-111.
[199]. D.J. James, J. Kowalchyk, N. Daily, et al., CAPS drives trans-SNARE complex formation and membrane fusion through syntaxin interactions. Proc Natl Acad Sci U S A,2009.106(41):17308-13.
[200]. J. Basu, N. Shen, I. Dulubova, et al., A minimal domain responsible for Munc13 activity. Nat Struct Mol Biol,2005.12(11):1017-8.
[201]. M. Christensen, A. Estevez, X. Yin, et al., A primary culture system for functional analysis of C. elegans neurons and muscle cells. Neuron,2002.33(4):503-14.
[202]. K. Strange, M. Christensen, and R. Morrison, Primary culture of Caenorhabditis elegans developing embryo cells for electrophysiological, cell biological and molecular studies. Nat Protoc,2007.2(4):1003-12.
[203], J. Kimble, J. Hodgkin, T. Smith, et al., Suppression of an amber mutation by microinjection of suppressor tRNA in C. elegans. Nature,1982.299(5882):456-8.
[204]. Y.M. Jiu, R.Y. Zhang, and Z.X. Wu, Gene Microinjection and Integration in C. elegans:Equipments, Processes and Guidance. Progress in Biochemistry and Biophysics,2009.36(5):648-652.
[205]. E. Neher and B. Sakmann, Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature,1976.260(5554):799-802.
[206]. A. Minta, J.P. Kao, and R.Y. Tsien, Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Biol Chem,1989.264(14): 8171-8.
[207]. G. Grynkiewicz, M. Poenie, and R.Y. Tsien, A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem,1985.260(6): 3440-50.
[208]. T. Voets, Dissection of three Ca2+-dependent steps leading to secretion in chromaffin cells from mouse adrenal slices. Neuron,2000.28(2):537-45.
[209]. M.B. Goodman and S.R. Lockery, Pressure polishing:a method for re-shaping patch pipettes during fire polishing. J Neurosci Methods,2000.100(1-2):13-5.
[210]. L. Avery, The genetics of feeding in Caenorhabditis elegans. Genetics,1993. 133(4):897-917.
[211]. M. Doi and K. Iwasaki, Regulation of retrograde signaling at neuromuscular junctions by the novel C2 domain protein AEX-1. Neuron,2002.33(2):249-59.
[212]. M.R. Lackner, S.J. Nurrish, and J.M. Kaplan, Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta:DAG binding to UNC-13 is required to stimulate acetylcholine release. Neuron,1999.24(2):335-46.
[213]. Y. Sako and T. Uyemura, Total internal reflection fluorescence microscopy for single-molecule imaging in living cells. Cell Struct Funct,2002.27(5):357-65.
[214]. T. Cai, T. Fukushige, A.L. Notkins, et al., Insulinoma-Associated Protein IA-2, a Vesicle Transmembrane Protein, Genetically Interacts with UNC-31/CAPS and Affects Neurosecretion in Caenorhabditis elegans. J Neurosci,2004.24(12): 3115-24.
[215]. N.K. Charlie, M.A. Schade, A.M. Thomure, et al., Presynaptic UNC-31 (CAPS) is required to activate the G s pathway of the Caenorhabditis elegans synaptic signaling network. Genetics,2006.172(2):943-61.
[216]. A. Betz, M. Okamoto, F. Benseler, et al., Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem,1997.272(4): 2520-6.
[217]. E.O. Gracheva, A.O. Burdina, D. Touroutine, et al., Tomosyn negatively regulates CAPS-dependent peptide release at Caenorhabditis elegans synapses. Journal of Neuroscience,2007.27(46):12755-12755.
[218]. S.A. Daniels, M. Ailion, J.H. Thomas, et al., egl-4 acts through a transforming growth factor-beta/SMAD pathway in Caenorhabditis elegans to regulate multiple neuronal circuits in response to sensory cues. Genetics,2000.156(1):123-41.
[219]. H. Fares and I. Greenwald, Genetic analysis of endocytosis in Caenorhabditis elegans:coelomocyte uptake defective mutants. Genetics,2001.159(1):133-45.
[220]. H. Fares and B. Grant, Deciphering endocytosis in Caenorhabditis elegans. Traffic, 2002.3(1):11-9.
[221]. J.J. Ewbank, Tackling both sides of the host-pathogen equation with Caenorhabditis elegans. Microbes and Infection,2002.4(2):247-256.
[222]. N.V. Burke, W.P. Han, D.Q. Li, et al., Neuronal peptide release is limited by secretory granule mobility. Neuron,1997.19(5):1095-1102.
[223]. D. Shakiryanova, A. Tully, R.S. Hewes, et al., Activity-dependent liberation of synaptic neuropeptide vesicles. Nature Neuroscience,2005.8(2):173-178.
[224]. D. Shakiryanova, A. Tully, and E.S. Levitan, Activity-dependent synaptic capture of transiting peptidergic vesicles. Nature Neuroscience,2006.9(7):896-900.
[225]. J.C. Olivo-Marin, Extraction of spots in biological images using multiscale products. Pattern Recognition,2002.35(9):1989-1996.
[226]. K. Jaqaman, D. Loerke, M. Mettlen, et al., Robust single-particle tracking in live-cell time-lapse sequences. Nature Methods,2008.5(8):695-702.
[227]. Y. Liu, C. Schirra, D.R. Stevens, et al., CAPS facilitates filling of the rapidly releasable pool of large dense-core vesicles. J Neurosci,2008.28(21):5594-601.
[228]. D.J. James, C. Khodthong, J.A. Kowalchyk, et al., Phosphatidylinositol 4,5-bisphosphate regulation of SNARE function in membrane fusion mediated by CAPS. Adv Enzyme Regul,2009.