Regulated Secretion

  • Naveen Nagarajan
  • Kenneth L. Custer
  • Sandra Bajjalieh
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Regulated secretion is a defining feature of neurons and endocrine cells. It produces the precisely timed release of chemical messengers that is crucial for the coordina tion of the complex systems that regulate thought, behavior and body homeostasis. The molecular reactions that underlie regulated secretion are an adaptation of constitutive membrane trafficking. Changes in the structure of the proteins that mediate the targeting, attachment and fusion of transmitter-containing vesicles combine with unique regulators to produce secretion that is tightly linked to increases in cytoplasmic calcium concentrations. At neuronal synapses this process is further modified to provide sustained, localized release of transmitters. This chapter surveys the components of regulated secretion that create these distinctive features.


Synaptic Vesicle Endocrine Cell Snare Complex Fusion Pore Neuronal Synapse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schekman R, Novick P. 23 genes, 23 years later. Cell 2004; 116(2 Suppl):S13–5, 1 p following S19.CrossRefGoogle Scholar
  2. 2.
    FerroNovick S, Jahn R. Vesicle fusion from yeast to man. Nature 1994; 370(6486):191–3.CrossRefGoogle Scholar
  3. 3.
    Sollner T, Whiteheart SW, Brunner M et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 1993; 362(6418):318–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Toonen RF, Verhage M. Munc18-1 in secretion: lonely Munc joins SNARE team and takes control. Trends Neurosci 2007; 30(11):564–72.PubMedGoogle Scholar
  5. 5.
    Whiteheart SW, Schraw T, Matveeva EA. N-ethylmaleimide sensitive factor (NSF) structure and function. Int Rev Cytol 2001; 207:71–112.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhao C, Slevin JT, Whiteheart SM. Cellular functions of NSF: not just SNAPs and SNAREs. FEBS Lett 2007; 581(11):2140–9.PubMedCrossRefGoogle Scholar
  7. 7.
    TerBush DR, Maurice T, Roth D et al. The exocyst is a multiprotein complex required for exocytosis in saccharomyces cerevisiae. EMBO Journal 1996; 15:6483–94.PubMedGoogle Scholar
  8. 8.
    Lipschutz JH, Mostov KE. Exocytosis: the many masters of the exocyst. Curr Biol 2002; 12(6):R212–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Hsu SC, TerBush D, Abraham M et al. The exocyst complex in polarized exocytosis. Int Rev Cytol 2004; 233:243–65.PubMedCrossRefGoogle Scholar
  10. 10.
    Murthy M, Schwarz TL. The exocyst component Sec5 is required for membrane traffic and polarity in the Drosophila ovary. Development 2004; 131(2):377–88.PubMedCrossRefGoogle Scholar
  11. 11.
    Vega IE, Hsu SC. The exocyst complex associates with microtubules to mediate vesicle targeting and neurite outgrowth. J Neurosci 2001; 21(11):3839–48.PubMedGoogle Scholar
  12. 12.
    Cerveny KL, Tamura Y, Zhang Z et al. Regulation of mitochondrial fusion and division. Trends Cell Biol 2007; 17(11):563–9.PubMedCrossRefGoogle Scholar
  13. 13.
    McNew JA, Parlati F, Fukuda R et al. Compartmental specificity of cellular membrane fusion encoded in SNARE proteins. Nature 2000; 407(6801):153–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Trimble WS, Cowan DM, Scheller RH. VAMP-1: a synaptic vesicle-associated integral membrane protein. Proc Natl Acad Sci USA 1988; 85(12):4538–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Bennett MK, Calakos N, Scheller RH. Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones. Science 1992; 257(5067):255–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Bennett MK, Garcia-Arraras JE, Elferink LA et al. The syntaxin family of vesicular transport receptors. Cell 1993; 74(5):863–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Oyler GA, Higgins GA, Hart RA et al. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol 1989; 109(6 Pt 1):3039–52.PubMedCrossRefGoogle Scholar
  18. 18.
    Sorensen JB. SNARE complexes prepare for membrane fusion. Trends Neurosci 2005; 28(9):453–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Sutton RB, Fasshauer D, Jahn R et al. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 angstrom resolution. Nature 1998; 395:347–53.PubMedCrossRefGoogle Scholar
  20. 20.
    Weber T, Zemelman BV, McNew JA et al. SNARE-pins: minimal machinery for membrane fusion. Cell 1998; 92:759-72.Google Scholar
  21. 21.
    Nickel W, Weber T, McNew JA et al. Content mixing and membrane integrity during membrane fusion driven by pairing of isolated v-SNAREs and t-SNAREs. Proc Natl Acad Sci USA 1999; 96(22):12571–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Burgoyne RD. Yeast mutants illuminate the secretory pathway. Trends Biochem Sci 1988; 13(7):241–2.PubMedCrossRefGoogle Scholar
  23. 23.
    Dulubova I, Khvotchev M, Liu S et al. Muncl8-1 binds directly to the neuronal SNARE complex. Proc Natl Acad Sci USA 2007; 104(8):2697–702.PubMedCrossRefGoogle Scholar
  24. 24.
    Verhage M, Maia AS, Plomp JJ et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 2000; 287(5454):864–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Garcia EP, Gatti E, Butler M et al. A rat brain Seel homolog related to Rop and UNCI8 interacts with syntaxin. Proceedings of the National Academy of Science, USA 1994; 91:2003–7.CrossRefGoogle Scholar
  26. 26.
    Pevsner J, Hsu SC, Scheller R. n-Secl: A neural-specific syntaxin-binding protein. Proceedings of the National Academy of Science, USA 1994; 91:1445–9.CrossRefGoogle Scholar
  27. 27.
    Misura KM, Scheller RH, Weis Wl. Three-dimensional structure of the neuronal-Secl-syntaxin la complex. Nature 2000; 404(6776):355–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Medine CN, Rickman C, Chamberlain LH et al. Munc18-1 prevents the formation of ectopic SNARE complexes in living cells. J Cell Sci 2007; 120(Pt 24):4407–15.PubMedCrossRefGoogle Scholar
  29. 29.
    Block MR, Glick BS, Wilcox CA et al. Purification of an N-ethylmaleimide-sensitive protein catalyzing vesicular transport. Proc Natl Acad Sci USA 1988; 85(21):7852–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Hanson PI, Roth R, Morisake H et al. Structure and conformational changes in NSF and its membrane receptor complexes visualized by quick-freeze/deep etch electron microscopy. Cell 1997; 90:523–35.PubMedCrossRefGoogle Scholar
  31. 31.
    Weidman PJ, Melancon P, Block MR et al. Binding of an N-ethylmaleimide-sensitive fusion protein to Golgi membranes requires both a soluble protein(s) and an integral membrane receptor. J Cell Biol 1989; 108(5):1589–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Marz KE, Lauer JM, Hanson PI. Defining the SNARE complex binding surface of alpha-SNAP: implications for SNARE complex disassembly. J Biol Chem 2003; 278(29):27000–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Hanson PI, Otto H, Barton N et al. The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin. J Biol Chem 1995; 270(28):16955–61.PubMedCrossRefGoogle Scholar
  34. 34.
    Kuner T, Li Y, Gee KR et al. Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release. Proc Natl Acad Sci USA 2008; 105(1):347–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Schweizer FE, Dresbach T, DeBello WM et al. Regulation of neurotransmitter release kinetics by NSF. Science 1998; 279:1203–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Breckenridge LJ, Aimers W. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. Nature 1987; 328(6133):8l4–7.CrossRefGoogle Scholar
  37. 37.
    Han X, Wang CT, Bai J et al. Transmembrane segments of syntaxin line the fusion pore of Ca2+-triggered exocytosis. Science 2004; 304(5668):289–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Peters C, Bayer MJ, Buhler S et al. Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 2001; 409(6820):581–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Hiesinger PR, Fayyazuddin A, Mehta SQ et al. The vATPase V0 subunit al is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 2005; 121(4):607–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Chanturiya A, Chernomordik LV, Zimmerberg J. Flickering fusion pores comparable with initial exocytotic pores occur in protein-free phospholipid bilayers. Proc Natl Acad Sci USA 1997; 94(26):14423–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Leventis R, Gagne J, Fuller RP et al. Divalent cation induced fusion and lipid lateral segregation in phosphatidylcholine-phosphatidic acid vesicles. Biochemistry 1986; 25(22):6978–87.PubMedCrossRefGoogle Scholar
  42. 42.
    Hinkovska-Galcheva V, Boxer LA, Kindzelskii A et al. Ceramide 1-phosphate, a mediator of phagocytosis. J Biol Chem 2005; 280(28):26612–21.PubMedCrossRefGoogle Scholar
  43. 43.
    Du G, Altshuller YM, Vitale N et al. Regulation of phospholipase DI subcellular cycling through coordination of multiple membrane association motifs. J Cell Biol 2003; 162(2):305–15.PubMedCrossRefGoogle Scholar
  44. 44.
    Vitale N, Caumont AS, Chasserot-Golaz S et al. Phospholipase DI: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J 2001; 20(10):2424–34.PubMedCrossRefGoogle Scholar
  45. 45.
    Zenio-Meyer M, Zabari N, Ashery U et al. Phospholipase DI production of phosphatidic acid at the plasma membrane promotes exocytosis of large dense-core granules at a late stage. J Biol Chem 2007; 282(30):21746–57.CrossRefGoogle Scholar
  46. 46.
    Choi SY, Huang P, Jenkins GM et al. A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis. Nat Cell Biol 2006; 8(11):1255–62.PubMedCrossRefGoogle Scholar
  47. 47.
    Bajjalieh SM, Martin TF, Floor E. Synaptic vesicle ceramide kinase. A calcium-stimulated lipid kinase that copurifies with brain synaptic vesicles. J Biol Chem 1989; 264(24):14354–60.PubMedGoogle Scholar
  48. 48.
    Mitsutake S, Kim TJ, Inagaki Y et al. Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J Biol Chem 2004; 279(17):17570–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Stevens CF, Williams JH. Discharge of the readily releasable pool with action potentials at hippocampal synapses. J Neurophysiol 2007; 98(6):3221–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Haynes CL, Siff LN, Wightman RM. Temperaturedependent differences between readily releasable and reserve pool vesicles in chromaffin cells. Biochim Biophys Acta 2007; 1773(6):728–35.PubMedCrossRefGoogle Scholar
  51. 51.
    Rosenmund C, Stevens CF. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 1996; 16(6):1197–207.PubMedCrossRefGoogle Scholar
  52. 52.
    Pyle JL, Kavalali ET, Piedras-Renteria ES et al. Rapid reuse of readily releasable pool vesicles at hippocampal synapses. Neuron 2000; 28(1):221–31.PubMedCrossRefGoogle Scholar
  53. 53.
    Rettig J, Neher E. Emerging roles of presynaptic proteins in Ca++-triggered exocytosis. Science 2002; 298(5594):781–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Wadel K, Neher E, Sakaba T. The Coupling between Synaptic Vesicles and Ca(2+) Channels Determines Fast Neurotransmitter Release. Neuron 2007; 53(4):563–75.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang Y, Okamoto M, Schmitz F et al. Rim is a putative rab3 effector in regulating synaptic-vesicle fusion. Nature 1997; 388:593–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Coppola T, Magnin-Luthi S, Perret-Menoud V et al. Direct interaction of the Rab3 effector RIM with Ca2+ channels, SNAP25, and synaptotagmin. J Biol Chem 2001; 276(35):32756–62.PubMedCrossRefGoogle Scholar
  57. 57.
    Betz A, Thakur P, Junge HJ et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 2001; 30(1):183–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Calakos N, Schoch S, Sudhof TC et al. Multiple roles for the active zone protein RIM 1 alpha in late stages of neurotransmitter release. Neuron 2004; 42(6):889–96.PubMedCrossRefGoogle Scholar
  59. 59.
    Kikuchi A, Nakanishi H, Takai Y. Purification and properties of Rab3A. Methods Enzymol 1995; 257:57–70.PubMedCrossRefGoogle Scholar
  60. 60.
    Tsuboi T, Fukuda M. The C2B domain of rabphilin directly interacts with SNAP-25 and regulates the docking step of dense core vesicle exocytosis in PC12 cells. J Biol Chem 2005; 280(47):39253–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Schluter OM, Schnell E, Verhage M et al. Rabphilin knock-out mice reveal that rabphilin is not required for rab3 function in regulating neurotransmitter release. J Neurosci 1999; 19(l4):5834–46.PubMedGoogle Scholar
  62. 62.
    Betz A, Ashery U, Rickmann M et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron 1998; 21(1):123–36.PubMedCrossRefGoogle Scholar
  63. 63.
    Brose N, Hofmann K, Hata Y et al. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem 1995; 270(42):25273–80.PubMedCrossRefGoogle Scholar
  64. 64.
    Aravamudan B, Fergestad T, Davis WS et al. Drosophila UNC-13 is essential for synaptic transmission. Nat Neurosci 1999; 2(11):965–71.PubMedCrossRefGoogle Scholar
  65. 65.
    Richmond JE, Davis WS, Jorgensen EM. UNC-13 is required for synaptic vesicle fusion in C. elegans. Nat Neurosci 1999; 2(11):959–64.PubMedCrossRefGoogle Scholar
  66. 66.
    Augustin I, Rosenmund C, Sudhof TC et al. Muncl3-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 1999; 400(6743):457–61.PubMedCrossRefGoogle Scholar
  67. 67.
    Basu J, Shen N, Dulubova I et al. A minimal domain responsible for Muncl3 activity. Nat Struct Mol Biol 2005; 12(11):1017–8.PubMedGoogle Scholar
  68. 68.
    Stevens DR, Wu ZX, Matti U et al. Identification of the minimal protein domain required for priming activity of Muncl3-1. Curr Biol 2005; 15(24):2243–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Stevens CF, Sullivan JM. The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission. Neuron 2003; 39(2):299–308.PubMedCrossRefGoogle Scholar
  70. 70.
    Rhee JS, Betz A, Pyott S et al. Beta phorbol ester-and diacylglycerol-induced augmentation of transmitter release is mediated by Muncl3s and not by PKCs. Cell 2002; 108(1):121–33.PubMedCrossRefGoogle Scholar
  71. 71.
    Wierda KD, Toonen RF, De Wit H et al. Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 2007; 54(2):275–90.PubMedCrossRefGoogle Scholar
  72. 72.
    Walent JH, Porter BW, Martin TFJ. A novel 145 kd brain cytosolic protein reconstitutes Ca2+-regulated secretion in permeable neuroendocrine cells. Cell 1992; 70:765-75.Google Scholar
  73. 73.
    Grishanin RN, Kowalchyk JA, Klenchin VA et al. CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron 2004; 43(4):551–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Jockusch WJ, Speidel D, Sigler A et al. CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins. Cell 2007; 131(4):796–808.PubMedCrossRefGoogle Scholar
  75. 75.
    Zhou KM, Dong YM, Ge Q et al. PKA activation bypasses the requirement for UNC3-1 in the docking of dense core vesicles from C. tielegans neurons. Neuron 2007; 56(4):657–69.PubMedCrossRefGoogle Scholar
  76. 76.
    Fujita Y, Shirataki H, Sakisaka T et al. Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process. Neuron 1998; 20(5):905–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Scales SJ, Hesser BA, Masuda ES et al. Amisyn, a novel syntaxin-binding protein that may regulate SNARE complex assembly. J Biol Chem 2002; 277(31):28271–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Yizhar O, Matti U, Melamed R et al. Tomosyn inhibits priming of large dense-core vesicles in a calcium-dependent manner. Proc Natl Acad Sci USA 2004; 101(8):2578–83.PubMedCrossRefGoogle Scholar
  79. 79.
    McEwen JM, Madison JM, Dybbs M et al. Antagonistic regulation of synaptic vesicle priming by Tomosyn and UNC-13. Neuron 2006; 51(3):303–15.PubMedCrossRefGoogle Scholar
  80. 80.
    Gracheva EO, Burdina AO, Holgado AM et al. Tomosyn inhibits synaptic vesicle priming in Caenorhabditis elegans. PLoS Biol 2006; 4(8):e261.PubMedCrossRefGoogle Scholar
  81. 81.
    Gracheva EO, Burdina AO, Touroutine D et al. Tomosyn negatively regulates CAPS-dependent peptide release at Caenorhabditis elegans synapses. J Neurosci 2007; 27(38):10176–84.PubMedCrossRefGoogle Scholar
  82. 82.
    Constable JR, Graham ME, Morgan A et al. Amisyn regulates exocytosis and fusion pore stability by both syntaxin-dependent and syntaxin-independent mechanisms. J Biol Chem 2005; 280(36):31615–23.PubMedCrossRefGoogle Scholar
  83. 83.
    Yizhar O, Lipstein N, Gladycheva SE et al. Multiple functional domains are involved in tomosyn regulation of exocytosis. J Neurochem 2007; 103(2):604–16.PubMedCrossRefGoogle Scholar
  84. 84.
    Ilardi JM, Mochida S, Sheng ZH. Snapin: a SNARE-associated protein implicated in synaptic transmission. Nat Neurosci 1999; 2(2):119–24.PubMedCrossRefGoogle Scholar
  85. 85.
    Tian JH, Wu ZX, Unzicker M et al. The role of Snapin in neurosecretion: snapin knock-out mice exhibit impaired calcium-dependent exocytosis of large dense-core vesicles in chromaffin cells. J Neurosci 2005; 25(45):10546–55.PubMedCrossRefGoogle Scholar
  86. 86.
    Chheda MG, Ashery U, Thaker P et al. Phosphorylation of Snapin by PKA modulates its interaction with the SNARE complex. Nat Cell Biol 2001; 3(4):331–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Thakur P, Stevens DR, Sheng ZH et al. Effects of PKA-mediated phosphorylation of Snapin on synaptic transmission in cultured hippocampal neurons. J Neurosci 2004; 24(29):6476–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Chou JL, Huang CL, Lai HL et al. Regulation of type VI adenylyl cyclase by Snapin, a SNAP25-binding protein. J Biol Chem 2004; 279(44):46271–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Chen M, Lucas KG, Akum BF et al. A novel role for snapin in dendrite patterning: interaction with cypin. Mol Biol Cell 2005; 16(11):5103–14.PubMedCrossRefGoogle Scholar
  90. 90.
    Krapivinsky G, Mochida S, Krapivinsky L et al. The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release. Neuron 2006; 52(3):485–96.PubMedCrossRefGoogle Scholar
  91. 91.
    Starcevic M, Dell’Angelica EC. Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J Biol Chem 2004; 279(27):28393–401.PubMedCrossRefGoogle Scholar
  92. 92.
    Zissimopoulos S, West DJ, Williams AJ et al. Ryanodine receptor interaction with the SNARE-associated protein snapin. J Cell Sci 2006; 119(Pt 11):2386–97.PubMedCrossRefGoogle Scholar
  93. 93.
    Talbot K, Cho DS, Ong WY et al. Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum Mol Genet 2006; 15(20):304l–54.CrossRefGoogle Scholar
  94. 94.
    Wolff S, Stoter M, Giamas G et al. Casein kinase 1 delta (CK1 delta) interacts with the SNARE associated protein snapin. FEBS Lett 2006; 580(27):6477–84.PubMedCrossRefGoogle Scholar
  95. 95.
    Mistry AC, Mallick R, Frohlich O et al. The UTA-1 urea transporter interacts with snapin, a SNARE-associated protein. J Biol Chem 2007; 282(4l):30097–106.PubMedCrossRefGoogle Scholar
  96. 96.
    Bao Y, Lopez JA, James DE et al. Snapin interacts with the Exo70 subunit of the exocyst and modulates GLUT4 trafficking. J Biol Chem 2008; 283(1):324–31.PubMedCrossRefGoogle Scholar
  97. 97.
    Vites O, Rhee JS, James DE et al. Reinvestigation of the role of snapin in neurotransmitter release. J Biol Chem 2004; 279(25):26251–6.PubMedCrossRefGoogle Scholar
  98. 98.
    McMahon HT, Missler M, Li C et al. Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 1995; 83:111-9.Google Scholar
  99. 99.
    Reim K, Mansour M, Varoqueaux F et al. Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell 2001; 104(1):71–81.PubMedCrossRefGoogle Scholar
  100. 100.
    Giraudo CG, Eng WS, Melia TJ et al. A clamping mechanism involved in SNARE-dependent exocytosis. Science 2006; 313(5787):676–80.PubMedCrossRefGoogle Scholar
  101. 101.
    Tang J, Maximov A, Shin OH et al. A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis. Cell 2006; 126(6):1175–87.PubMedCrossRefGoogle Scholar
  102. 102.
    Xue M, Reim K, Chen X et al. Distinct domains of complexin I differentially regulate neurotransmitter release. Nat Struct Mol Biol 2007; l4(10):949–58.CrossRefGoogle Scholar
  103. 103.
    Bittner MA, Holz RW. Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components. Journal of Biological Chemistry 1992; 267:16219–25.PubMedGoogle Scholar
  104. 104.
    Hay JC, Martin TFJ. Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion. Nature 1993; 366:572–5.PubMedCrossRefGoogle Scholar
  105. 105.
    Klenchin VA, Martin TF. Priming in exocytosis: attaining fusion-competence after vesicle docking. Biochimie 2000; 82(5):399–407.PubMedCrossRefGoogle Scholar
  106. 106.
    Bankaitis VA, Phillips S, Yanagisawa L et al. Phosphatidylinositol transfer protein function in the yeast Saccharomyces cerevisiae. Adv Enzyme Regul 2005; 45:155–70.PubMedCrossRefGoogle Scholar
  107. 107.
    Hsuan J, Cockcroft S. The PITP family of phosphatidylinositol transfer proteins. Genome Biol 2001; 2(9):REVIEWS3011.Google Scholar
  108. 108.
    Liscovitch M, Cantley LC. Signal transduction and membrane traffic: the PITP/phosphoinositide connection. Cell 1995; 81(5):659–62.PubMedCrossRefGoogle Scholar
  109. 109.
    Hay JC, Fisette PL, Jenkins GH et al. ATP-dependent inositide phosphorylation required for Ca2+-activated secretion. Nature 1995; 374:173–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Buckley K, Kelly RB. Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. Journal of Cell Biology 1985; 100(4): 1284–94.PubMedCrossRefGoogle Scholar
  111. 111.
    Bajjalieh SM, Peterson K, Shinghal R et al. SV2, a brain synaptic vesicle protein homologous to bacterial transporters. Science 1992; 257(5074):1271–3.PubMedCrossRefGoogle Scholar
  112. 112.
    Bajjalieh SM, Peterson K, Linial M et al. Brain contains two forms of synaptic vesicle protein 2. Proceedings of the National Academy of Sciences, USA 1993; 90(6):2150–4.CrossRefGoogle Scholar
  113. 113.
    Janz R, Hofmann K, Sudhof TC. SVOP, an evolutionarily conserved synaptic vesicle protein, suggests novel transport functions of synaptic vesicles. Journal of Neuroscience 1998; 15:9269–81.Google Scholar
  114. 114.
    Crowder KM, Gunther JM, Jones TA et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proceedings of the National Academy of Science, USA 1999; 96:115268–73.Google Scholar
  115. 115.
    Xu T, Bajjalieh SM. SV2 modulates the size of the readily releasable pool of secretory vesicles. Nature Cell Biology 2001; 3:691–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Custer KL, Austin NS, Sullivan JM et al. Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J Neurosci 2006; 26(4): 1303–13.PubMedCrossRefGoogle Scholar
  117. 117.
    Schivell AE, Batchelor RH, Bajjalieh SM. Isoform-specific, calcium-regulated interaction of the synaptic vesicle proteins SV2 and synaptotagmin. J Biol Chem 1996; 271:27770–5.PubMedCrossRefGoogle Scholar
  118. 118.
    Schivell AE, Mochida S, Kensel-Hammes P et al. SV2A and SV2C contain a unique synaptotagmin-binding site. Mol Cell Neurosci 2005; 29(1):56–64.PubMedCrossRefGoogle Scholar
  119. 119.
    Haucke V, De Camilli P. AP-2 recruitment to synaptotamin stimulated by tyrosine-based endocytic motifs. Science 1999; 285:1268–71.PubMedCrossRefGoogle Scholar
  120. 120.
    Dodge FA Jr, Rahamimoff R. Cooperative action a calcium ions in transmitter release at the neu-romuscular junction. J Physiol 1967; 193(2):419–32.PubMedGoogle Scholar
  121. 121.
    Chapman ER. Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nat Rev Mol Cell Biol 2002; 3(7):498–508.PubMedCrossRefGoogle Scholar
  122. 122.
    Rizo J, Sudhof TC. C2-domains, structure and runction of a universal calcium-binding domain. Journal of Biological Chemistry 1998; 273:15879–82.PubMedCrossRefGoogle Scholar
  123. 123.
    Matthew WD, Tsavaler L, Reichardt LF. Identification of a synaptic vesicle-specific membrane protein with a wide distribution in neuronal and neurosecretory tissue. J Cell Biol 1981; 91(1):257–69.PubMedCrossRefGoogle Scholar
  124. 124.
    Brose N, Petrenko AG, Sudhof TC et al. Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 1992; 256(5059):1021–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Geppert M, Goda Y, Hammer RE et al. Synaptotagmin I: a major Ca2+ sensor for transmitter release at a central synapse. Cell 1994; 79:717–27.PubMedCrossRefGoogle Scholar
  126. 126.
    Mackler JM, Drummond JA, Loewen CA et al. The C(2)B Ca(2+)-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature 2002; 418(6895):340–4.PubMedCrossRefGoogle Scholar
  127. 127.
    Fernandez-Chacon R, Konigstorfer A, Gerber SH et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 2001; 410(6824):41–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Borden CR, Stevens CF, Sullivan JM et al. Synaptotagmin mutants Y311N and K326/327A alter the calcium dependence of neurotransmission. Mol Cell Neurosci 2005; 29(3):462–70.PubMedCrossRefGoogle Scholar
  129. 129.
    Nishiki T, Augustine GJ. Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons. J Neurosci 2004; 24(27):6127–32.PubMedCrossRefGoogle Scholar
  130. 130.
    Davletov BA, Sudhof TC. A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. J Biol Chem 1993; 268(35):26386–90.PubMedGoogle Scholar
  131. 131.
    Lynch KL, Gerona RR, Larsen EC et al. Synaptotagmin C2A loop 2 mediates Ca2+-dependent SNARE interactions essential for Ca2+-triggered vesicle exocytosis. Mol Biol Cell 2007; 18_(12):4957–68.CrossRefGoogle Scholar
  132. 132.
    Pang ZP, Melicoff E, Padgett D et al. Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses. J Neurosci 2006; 26(52):13493–504.PubMedCrossRefGoogle Scholar
  133. 133.
    Bhalla A, Chicka MC, Tucker WC et al. Ca(2+)-synaptotagmin directly regulates t-SNARE func-tion during reconstituted membrane fusion. Nat Struct Mol Biol 2006; 13(4):323–30.PubMedCrossRefGoogle Scholar
  134. 134.
    Stein A, Radhakrishnan A, Riedel D et al. Synaptotagmin activates membrane fusion through a Ca2+-dependent trans interaction with phospholipids. Nat Struct Mol Biol 2007; 14(10):904–11.PubMedCrossRefGoogle Scholar
  135. 135.
    Quetglas S, Leveque C, Miquelis R et al. Ca2+-dependent regulation of synaptic SNARE complex assembly via a calmodulin-and phospholipid-binding domain of synaptobrevin. Proc Natl Acad Sci USA 2000; 97(17):9695–700.PubMedCrossRefGoogle Scholar
  136. 136.
    de Haro L, Ferracci G, Opi S et al. Ca2+/calmodulin transfers the membrane-proximal lipid-binding domain of the v-SNARE synaptobrevin from cis to trans bilayers. Proc Natl Acad Sci USA 2004; 101(6):1578–83.PubMedCrossRefGoogle Scholar
  137. 137.
    Schoch S, Deak F, Konigstorfer A et al. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science 2001; 294_(5544): 1117–22.CrossRefGoogle Scholar
  138. 138.
    Greengard P, Benfenati F, Valtorta F. Synapsin I, an actin-binding protein regulating synaptic vesicle traffic in the nerve terminal. Adv Second Messenger Phosphoprotein Res 1994; 29:31–45.PubMedGoogle Scholar
  139. 139.
    Benfenati F, Valtorta F, Greengard P. Computer modeling of synapsin I binding to synaptic vesicles and F-actin: implications for regulation of neurotransmitter release. Proc Nad Acad Sci USA 1991; 88(2):575–9.CrossRefGoogle Scholar
  140. 140.
    Fiumara F, Milanese C, Corradi A et al. Phosphorylation of synapsin domain A is required for post-tetanic potentiation. J Cell Sci 2007; 120(Pt 18):3228–37.PubMedCrossRefGoogle Scholar
  141. 141.
    Onofri F, Messa M, Matafora V et al. Synapsin phosphorylation by SRC tyrosine kinase enhances SRC activity in synaptic vesicles. J Biol Chem 2007; 282_(21):15754–67.CrossRefGoogle Scholar
  142. 142.
    Menegon A, Bonanomi D, Albertinazzi C et al. Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2+-dependent synaptic activity. J Neurosci 2006; 26(45): 11670–81.PubMedCrossRefGoogle Scholar
  143. 143.
    Sun J, Bronk P, Liu X et al. Synapsins regulate use-dependent synaptic plasticity in the calyx of Held by a Ca2+/calmodulin-dependent pathway. Proc Natl Acad Sci USA 2006; 103(8):2880–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Bonanomi D, Menegon A, Miccio A et al. Phosphorylation of synapsin I by cAMP-dependent protein kinase controls synaptic vesicle dynamics in developing neurons. J Neurosci 2005; 25(32):7299–308.PubMedCrossRefGoogle Scholar
  145. 145.
    Chi P, Greengard P, Ryan TA. Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Neuron 2003; 38(1):69–78.PubMedCrossRefGoogle Scholar
  146. 146.
    Gitler D, Takagishi Y, Feng J et al. Different presynaptic roles of synapsins at excitatory and inhibitory synapses. J Neurosci 2004; 24(50): 11368–80.PubMedCrossRefGoogle Scholar
  147. 147.
    Fenster SD, Chung WJ, Zhai R et al. Piccolo, a presynaptic zinc finger protein structurally related to bassoon. Neuron 2000; 25(1):203–14.PubMedCrossRefGoogle Scholar
  148. 148.
    Altrock WD, Tom Dieck S, Sokolov M et al. Functional inactivation of a fraction of excitatory synapses in mice deficient for the active zone protein bassoon. Neuron 2003; 37(5):787–800.PubMedCrossRefGoogle Scholar
  149. 149.
    Duclos F, Koenig M. Comparison of primary structure of a neuron-specific protein, XI1, between human and mouse. Mamm Genome 1995; 6(1):57–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Okamoto M, Sudhof TC. Mint 3: a ubiquitous mint isoform that does not bind to muncl8-l or-2. Eur J Cell Biol 1998; 77(3):161–5.PubMedGoogle Scholar
  151. 151.
    Borg JP, Ooi J, Levy E et al. The phosphotyrosine interaction domains of XI1 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cell Biol 1996; 16(11):6229–41.PubMedGoogle Scholar
  152. 152.
    Borg JP, Yang Y, De Taddeo-Borg M et al. The Xllalpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion. J Biol Chem 1998; 273(24): 14761–6.PubMedCrossRefGoogle Scholar
  153. 153.
    McLoughlin DM, Irving NG, Brownlees J et al. Mint2/Xll-like colocalizes with the Alzheimer’s disease amyloid precursor protein and is associated with neuritic plaques in Alzheimer’s disease. Eur J Neurosci 1999; 11 (6): 1988–94.PubMedCrossRefGoogle Scholar
  154. 154.
    McLoughlin DM, Miller CC. The intracellular cytoplasmic domain of the Alzheimer’s disease amyloid precursor protein interacts with phosphotyrosine-binding domain proteins in the yeast two-hybrid system. FEBS Lett 1996; 397(2–3): 197–200.PubMedCrossRefGoogle Scholar
  155. 155.
    Lau KF, McLoughlin DM, Standen C et al. XI1 alpha and xll beta interact with presenilin-1 via their PDZ domains. Mol Cell Neurosci 2000; 16(5):557–65.PubMedCrossRefGoogle Scholar
  156. 156.
    Zamponi GW. Regulation of presynaptic calcium channels by synaptic proteins. J Pharmacol Sci 2003; 92(2):79–83.PubMedCrossRefGoogle Scholar
  157. 157.
    Tabuchi K, Biederer T, Butz S et al. CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. J Neurosci 2002; 22(11):4264–73.PubMedGoogle Scholar
  158. 158.
    Ho A, Morishita W, Hammer RE et al. A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission. Proc Natl Acad Sci USA 2003; 100(3):1409–14.PubMedCrossRefGoogle Scholar
  159. 159.
    Ho A, Morishita W, Atasoy D et al. Genetic analysis of Mint/Xll proteins: essential presynaptic functions of a neuronal adaptor protein family. J Neurosci 2006; 26(50): 13089–101.PubMedCrossRefGoogle Scholar
  160. 160.
    Spangler SA, Hoogenraad CC. Liprin-alpha proteins: scaffold molecules for synapse maturation. Biochem Soc Trans 2007; 35_(Pt 5): 1278–82.Google Scholar
  161. 161.
    Stryker E, Johnson KG. LAR, liprin alpha and the regulation of active zone morphogenesis. J Cell Sci 2007; 120(Pt 21):3723–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Schoch S, Castillo PE, Jo T et al. RIM 1 alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature 2002; 415(6869):321–6.PubMedCrossRefGoogle Scholar
  163. 163.
    Olsen O, Moore KA, Fukata M et al. Neurotransmitter release regulated by a MALS-liprin-alpha presynaptic complex. J Cell Biol 2005; 170(7): 1127–34.PubMedCrossRefGoogle Scholar
  164. 164.
    Kaufmann N, DeProto J, Ranjan R et al. Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron 2002; 34(1):27–38.PubMedCrossRefGoogle Scholar
  165. 165.
    Zhen M, Jin Y. The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 1999; 401(6751):371–5.PubMedGoogle Scholar
  166. 166.
    Haimann C, Torri-Tarelli F, Fesce R et al. Measurement of quantal secretion induced by ouabain and its correlation with depletion of synaptic vesicles. J Cell Biol 1985; 101(5 Pt 1): 1953–65.PubMedCrossRefGoogle Scholar
  167. 167.
    Chandler DE, Heuser JE. Arrest of membrane fusion events in mast cells by quick-freezing. J Cell Biol 1980; 86(2):666–74.PubMedCrossRefGoogle Scholar
  168. 168.
    Ales E, Tabares L, Poyato JM et al. High calcium concentrations shift the mode of exocytosis to the kiss-and-run mechanism. Nat Cell Biol 1999; 1(1):40–4.PubMedCrossRefGoogle Scholar
  169. 169.
    Artalejo CR, Elhamdani A, Palfrey HC. Sustained stimulation shifts the mechanism of endocytosis from dynamin-1-dependent rapid endocytosis to clathrin-and dynamin-2-mediated slow endocytosis in chromaffin cells. Proc Natl Acad Sci USA 2002; 99(9):6358–63.PubMedCrossRefGoogle Scholar
  170. 170.
    Sontag JM, Fykse EM, Ushkaryov Y et al. Differential expression and regulation of multiple dynamins. J Biol Chem 1994; 269(6):4547–54.PubMedGoogle Scholar
  171. 171.
    Gandhi SP, Stevens CF. Three modes of synaptic vesicular recycling revealed by single-vesicle imaging. Nature 2003; 423(6940):607–13.PubMedCrossRefGoogle Scholar
  172. 172.
    Harata NC, Choi S, Pyle JL et al. Frequency-dependent kinetics and prevalence of kiss-and-run and reuse at hippocampal synapses studied with novel quenching methods. Neuron 2006; 49(2):243–56.PubMedCrossRefGoogle Scholar
  173. 173.
    Granseth B, Odermatt B, Royle SJ et al. Clathrin-mediated endocytosis is the dominant mechanism of vesicle retrieval at hippocampal synapses. Neuron 2006; 51(6):773–86.PubMedCrossRefGoogle Scholar
  174. 174.
    Ferguson SM, Brasnjo G, Hayashi M et al. A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 2007; 316(5824):570–4.PubMedCrossRefGoogle Scholar
  175. 175.
    McPherson PS, Garcia EP, Slepnev VI et al. A presynaptic inositol-5-phosphatase. Nature 1996; 379_(6563):353–7.CrossRefGoogle Scholar
  176. 176.
    Haffner C, Di Paolo G, Rosenthal JA et al. Direct interaction of the 170 kDa isoform of synaptojanin 1 with clathrin and with the clathrin adaptor AP-2. Curr Biol 2000; 10(8):471–4.PubMedCrossRefGoogle Scholar
  177. 177.
    Cremona O, Di Paolo G, Wenk MR et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 1999; 99(2):179–88.PubMedCrossRefGoogle Scholar
  178. 178.
    Kim WT, Chang S, Daniell L et al. Delayed reentry of recycling vesicles into the fusioncompetent synaptic vesicle pool in synaptojanin 1 knockout mice. Proc Natl Acad Sci USA 2002; 99(26):17143–8.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Naveen Nagarajan
    • 2
  • Kenneth L. Custer
    • 3
    • 4
  • Sandra Bajjalieh
    • 1
  1. 1.Department of PharmacologyUniversity of WashingtonSeattleUSA
  2. 2.Eccles Institute of Human Genetics HHMIUniversity of UtahSalt Lake CityUSA
  3. 3.Graduate Program in NeurobiologyUniversity of WashingtonSeatleUSA
  4. 4.Behavior and Department of PharmacologyUniversity of WashingtonSeatleUSA

Personalised recommendations