Skip to main content

The Architecture of the Presynaptic Release Site

  • Chapter
  • First Online:
Molecular Mechanisms of Neurotransmitter Release

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 33))

  • 522 Accesses

Abstract

The architecture of the presynaptic release site is exquisitely designed to facilitate and regulate synaptic vesicle exocytosis. With the identification of some of the building blocks of the active zone and the advent of super resolution imaging techniques, we are beginning to understand the morphological and functional properties of synapses in great detail. Presynaptic release sites consist of the plasma membrane, the cytomatrix, and dense projections. These three components are morphologically distinct but intimately connected with each other and with postsynaptic specializations, ensuring the fidelity of synaptic vesicle tethering, docking, and fusion, as well as signal detection. Although the morphology and molecular compositions of active zones may vary among species, tissues, and cells, global architectural design of the release sites is highly conserved.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sherrington CS. The central nervous system. In: Foster M, editor. A text book of physiology, vol. 3. London: Macmillan and Co.; 1897. p. 929.

    Google Scholar 

  2. Fulton JF. Physiology of the nervous system. London: Oxford University Press; 1938.

    Google Scholar 

  3. Elliott TR. On the action of adrenalin. J Physiol (London). 1904;31:20P.

    Google Scholar 

  4. Loewi O. Ueber humorale uebertragbarkeit der Herznervenwirkung (II. Miteilung). Pflugers Arch Gesamte Physio Menschen Tirer. 1921;193:201–13.

    Article  Google Scholar 

  5. Dale HH. The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol. 1914;6:147–90.

    CAS  Google Scholar 

  6. Tsuji S. Rene Couteaux (1909-1999) and the morphological identification of synapses. Biol Cell. 2006;98:503–9. https://doi.org/10.1042/BC20050036.

    Article  PubMed  Google Scholar 

  7. Couteaux R. Nouvelles observations sur la structure de la plaque motrice et interprétation des rapports myo-neuraux. C R Soc Biol. 1944;138:976–9.

    Google Scholar 

  8. Couteaux R. *Sur Les Gouttieres Synaptiques Du Muscle Strie. Comptes Rendus Des Seances De La Societe De Biologie Et De Ses Filiales. 1946;140:270–1.

    Google Scholar 

  9. De Robertis ED, Bennett HS. Some features of the submicroscopic morphology of synapses in frog and earthworm. J Biophys Biochem Cytol. 1955;1:47–58. https://doi.org/10.1083/jcb.1.1.47.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Palay SL, Palade GE. The fine structure of neurons. J Biophys Biochem Cytol. 1955;1:69–88. https://doi.org/10.1083/jcb.1.1.69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Couteaux R, Pecot-Dechavassine M. Synaptic vesicles and pouches at the level of "active zones" of the neuromuscular junction. C R Acad Sci Hebd Seances Acad Sci D. 1970;271:2346–9.

    CAS  PubMed  Google Scholar 

  12. Heuser JE, Reese TS. Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J Cell Biol. 1973;57:315–44. https://doi.org/10.1083/jcb.57.2.315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Landis DM, Hall AK, Weinstein LA, Reese TS. The organization of cytoplasm at the presynaptic active zone of a central nervous system synapse. Neuron. 1988;1:201–9. https://doi.org/10.1016/0896-6273(88)90140-7.

    Article  CAS  PubMed  Google Scholar 

  14. Matsui K, Jahr CE. Exocytosis unbound. Curr Opin Neurobiol. 2006;16:305–11. https://doi.org/10.1016/j.conb.2006.04.001.

    Article  CAS  PubMed  Google Scholar 

  15. Parsegian VA. Approaches to the cell biology of neurons. In: Cowan WW, Ferrendelli JA, editors. . Bethesda: Society for Neuroscience; 1977. p. 161–71.

    Google Scholar 

  16. Stanley EF. The calcium channel and the organization of the presynaptic transmitter release face. Trends Neurosci. 1997;20:404–9. https://doi.org/10.1016/s0166-2236(97)01091-6.

    Article  CAS  PubMed  Google Scholar 

  17. Bennett MR, Farnell L, Gibson WG. The probability of quantal secretion near a single calcium channel of an active zone. Biophys J. 2000;78:2201–21. https://doi.org/10.1016/S0006-3495(00)76769-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Atwood HL, Karunanithi S. Diversification of synaptic strength: presynaptic elements. Nat Rev Neurosci. 2002;3:497–516. https://doi.org/10.1038/nrn876.

    Article  CAS  PubMed  Google Scholar 

  19. Kawasaki F, Zou B, Xu X, Ordway RW. Active zone localization of presynaptic calcium channels encoded by the cacophony locus of Drosophila. J Neurosci. 2004;24:282–5. https://doi.org/10.1523/JNEUROSCI.3553-03.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Robitaille R, Adler EM, Charlton MP. Strategic location of calcium channels at transmitter release sites of frog neuromuscular synapses. Neuron. 1990;5:773–9. https://doi.org/10.1016/0896-6273(90)90336-e.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang L, Volknandt W, Gundelfinger ED, Zimmermann H. A comparison of synaptic protein localization in hippocampal mossy fiber terminals and neurosecretory endings of the neurohypophysis using the cryo-immunogold technique. J Neurocytol. 2000;29:19–30. https://doi.org/10.1023/a:1007108012667.

    Article  CAS  PubMed  Google Scholar 

  22. Ellisman MH, Rash JE, Staehelin LA, Porter KR. Studies of excitable membranes. II. A comparison of specializations at neuromuscular junctions and nonjunctional sarcolemmas of mammalian fast and slow twitch muscle fibers. J Cell Biol. 1976;68:752–74. https://doi.org/10.1083/jcb.68.3.752.

    Article  CAS  PubMed  Google Scholar 

  23. Heuser JE, Reese TS, Landis DM. Functional changes in frog neuromuscular junctions studied with freeze-fracture. J Neurocytol. 1974;3:109–31. https://doi.org/10.1007/BF01111936.

    Article  CAS  PubMed  Google Scholar 

  24. Walrond JP, Reese TS. Structure of axon terminals and active zones at synapses on lizard twitch and tonic muscle fibers. J Neurosci. 1985;5:1118–31. https://doi.org/10.1523/JNEUROSCI.05-05-01118.1985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cohen MW, Jones OT, Angelides KJ. Distribution of Ca2+ channels on frog motor nerve terminals revealed by fluorescent omega-conotoxin. J Neurosci. 1991;11:1032–9. https://doi.org/10.1523/JNEUROSCI.11-04-01032.1991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pumplin DW, Reese TS, Llinas R. Are the presynaptic membrane particles the calcium channels? Proc Natl Acad Sci U S A. 1981;78:7210–3. https://doi.org/10.1073/pnas.78.11.7210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Haydon PG, Henderson E, Stanley EF. Localization of individual calcium channels at the release face of a presynaptic nerve terminal. Neuron. 1994;13:1275–80. https://doi.org/10.1016/0896-6273(94)90414-6.

    Article  CAS  PubMed  Google Scholar 

  28. Siddig S, Aufmkolk S, Doose S, Jobin ML, Werner C, Sauer M, et al. Super-resolution imaging reveals the nanoscale organization of metabotropic glutamate receptors at presynaptic active zones. Sci Adv. 2020;6:eaay7193. https://doi.org/10.1126/sciadv.aay7193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carvalhais LG, Martinho VC, Ferreiro E, Pinheiro PS. Unraveling the nanoscopic organization and function of central mammalian Presynapses with super-resolution microscopy. Front Neurosci. 2020;14:578409. https://doi.org/10.3389/fnins.2020.578409.

    Article  PubMed  Google Scholar 

  30. Grauel MK, Maglione M, Reddy-Alla S, Willmes CG, Brockmann MM, Trimbuch T, et al. RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses. Proc Natl Acad Sci U S A. 2016;113:11615–20. https://doi.org/10.1073/pnas.1605256113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schneider R, Hosy E, Kohl J, Klueva J, Choquet D, Thomas U, et al. Mobility of calcium channels in the presynaptic membrane. Neuron. 2015;86:672–9. https://doi.org/10.1016/j.neuron.2015.03.050.

    Article  CAS  PubMed  Google Scholar 

  32. Jahn R, Lang T, Sudhof TC. Membrane fusion. Cell. 2003;112:519–33. https://doi.org/10.1016/s0092-8674(03)00112-0.

    Article  CAS  PubMed  Google Scholar 

  33. Rizo J. SNARE function revisited. Nat Struct Biol. 2003;10:417–9. https://doi.org/10.1038/nsb0603-417.

    Article  CAS  PubMed  Google Scholar 

  34. Garcia EP, McPherson PS, Chilcote TJ, Takei K, De Camilli P. rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin. J Cell Biol. 1995;129:105–20. https://doi.org/10.1083/jcb.129.1.105.

    Article  CAS  PubMed  Google Scholar 

  35. Hiesinger PR, Scholz M, Meinertzhagen IA, Fischbach KF, Obermayer K. Visualization of synaptic markers in the optic neuropils of Drosophila using a new constrained deconvolution method. J Comp Neurol. 2001;429:277–88. https://doi.org/10.1002/1096-9861(20000108)429:2<277::aid-cne8>3.0.co;2-8.

    Article  CAS  PubMed  Google Scholar 

  36. Schulze KL, Broadie K, Perin MS, Bellen HJ. Genetic and electrophysiological studies of Drosophila syntaxin-1A demonstrate its role in nonneuronal secretion and neurotransmission. Cell. 1995;80:311–20. https://doi.org/10.1016/0092-8674(95)90414-x.

    Article  CAS  PubMed  Google Scholar 

  37. Jarvis SE, Barr W, Feng ZP, Hamid J, Zamponi GW. Molecular determinants of syntaxin 1 modulation of N-type calcium channels. J Biol Chem. 2002;277:44399–407. https://doi.org/10.1074/jbc.M206902200.

    Article  CAS  PubMed  Google Scholar 

  38. Taverna E, Saba E, Rowe J, Francolini M, Clementi F, Rosa P. Role of lipid microdomains in P/Q-type calcium channel (Cav2.1) clustering and function in presynaptic membranes. J Biol Chem. 2004;279:5127–34. https://doi.org/10.1074/jbc.M308798200.

    Article  CAS  PubMed  Google Scholar 

  39. Catterall WA. Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter release. Ann N Y Acad Sci. 1999;868:144–59. https://doi.org/10.1111/j.1749-6632.1999.tb11284.x.

    Article  CAS  PubMed  Google Scholar 

  40. Martin-Moutot N, Charvin N, Leveque C, Sato K, Nishiki T, Kozaki S, et al. Interaction of SNARE complexes with P/Q-type calcium channels in rat cerebellar synaptosomes. J Biol Chem. 1996;271:6567–70. https://doi.org/10.1074/jbc.271.12.6567.

    Article  CAS  PubMed  Google Scholar 

  41. Wilhelm BG, Mandad S, Truckenbrodt S, Krohnert K, Schafer C, Rammner B, et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014;344:1023–8. https://doi.org/10.1126/science.1252884.

    Article  CAS  PubMed  Google Scholar 

  42. Pertsinidis A, Mukherjee K, Sharma M, Pang ZP, Park SR, Zhang Y, et al. Ultrahigh-resolution imaging reveals formation of neuronal SNARE/Munc18 complexes in situ. Proc Natl Acad Sci U S A. 2013;110:E2812–20. https://doi.org/10.1073/pnas.1310654110.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Japel M, Gerth F, Sakaba T, Bacetic J, Yao L, Koo SJ, et al. Intersectin-mediated clearance of SNARE complexes is required for fast neurotransmission. Cell Rep. 2020;30:409–420 e406. https://doi.org/10.1016/j.celrep.2019.12.035.

    Article  CAS  PubMed  Google Scholar 

  44. Lang T, Bruns D, Wenzel D, Riedel D, Holroyd P, Thiele C, et al. SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 2001;20:2202–13. https://doi.org/10.1093/emboj/20.9.2202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shapiro L, Colman DR. The diversity of cadherins and implications for a synaptic adhesive code in the CNS. Neuron. 1999;23:427–30. https://doi.org/10.1016/s0896-6273(00)80796-5.

    Article  CAS  PubMed  Google Scholar 

  46. Yagi T, Takeichi M. Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev. 2000;14:1169–80. https://doi.org/10.1101/gad.14.10.1169.

    Article  CAS  PubMed  Google Scholar 

  47. Frank M, Kemler R. Protocadherins. Curr Opin Cell Biol. 2002;14:557–62. https://doi.org/10.1016/s0955-0674(02)00365-4.

    Article  CAS  PubMed  Google Scholar 

  48. Mizoguchi A, Nakanishi H, Kimura K, Matsubara K, Ozaki-Kuroda K, Katata T, et al. Nectin: an adhesion molecule involved in formation of synapses. J Cell Biol. 2002;156:555–65. https://doi.org/10.1083/jcb.200103113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takai Y, Shimizu K, Ohtsuka T. The roles of cadherins and nectins in interneuronal synapse formation. Curr Opin Neurobiol. 2003;13:520–6. https://doi.org/10.1016/j.conb.2003.09.003.

    Article  CAS  PubMed  Google Scholar 

  50. Rougon G, Hobert O. New insights into the diversity and function of neuronal immunoglobulin superfamily molecules. Annu Rev Neurosci. 2003;26:207–38. https://doi.org/10.1146/annurev.neuro.26.041002.131014.

    Article  CAS  PubMed  Google Scholar 

  51. Davis GW, Schuster CM, Goodman CS. Genetic analysis of the mechanisms controlling target selection: target-derived Fasciclin II regulates the pattern of synapse formation. Neuron. 1997;19:561–73. https://doi.org/10.1016/s0896-6273(00)80372-4.

    Article  CAS  PubMed  Google Scholar 

  52. Mayford M, Barzilai A, Keller F, Schacher S, Kandel ER. Modulation of an NCAM-related adhesion molecule with long-term synaptic plasticity in Aplysia. Science. 1992;256:638–44. https://doi.org/10.1126/science.1585176.

    Article  CAS  PubMed  Google Scholar 

  53. Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M, et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell. 2000;101:671–84. https://doi.org/10.1016/s0092-8674(00)80878-8.

    Article  CAS  PubMed  Google Scholar 

  54. Hsueh YP, Sheng M. Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. J Neurosci. 1999;19:7415–25. https://doi.org/10.1523/JNEUROSCI.19-17-07415.1999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Walsh FS, Doherty P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu Rev Cell Dev Biol. 1997;13:425–56. https://doi.org/10.1146/annurev.cellbio.13.1.425.

    Article  CAS  PubMed  Google Scholar 

  56. Chavis P, Westbrook G. Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature. 2001;411:317–21. https://doi.org/10.1038/35077101.

    Article  CAS  PubMed  Google Scholar 

  57. Missler M, Sudhof TC. Neurexins: three genes and 1001 products. Trends Genet. 1998;14:20–6. https://doi.org/10.1016/S0168-9525(97)01324-3.

    Article  CAS  PubMed  Google Scholar 

  58. Yamagata M, Sanes JR, Weiner JA. Synaptic adhesion molecules. Curr Opin Cell Biol. 2003;15:621–32. https://doi.org/10.1016/s0955-0674(03)00107-8.

    Article  CAS  PubMed  Google Scholar 

  59. Yamagata M, Weiner JA, Sanes JR. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell. 2002;110:649–60. https://doi.org/10.1016/s0092-8674(02)00910-8.

    Article  CAS  PubMed  Google Scholar 

  60. Gottardi CJ, Gumbiner BM. Adhesion signaling: how beta-catenin interacts with its partners. Curr Biol. 2001;11:R792–4. https://doi.org/10.1016/s0960-9822(01)00473-0.

    Article  CAS  PubMed  Google Scholar 

  61. Sheng M, Sala C. PDZ domains and the organization of supramolecular complexes. Annu Rev Neurosci. 2001;24:1–29. https://doi.org/10.1146/annurev.neuro.24.1.1.

    Article  CAS  PubMed  Google Scholar 

  62. Packard M, Mathew D, Budnik V. FASt remodeling of synapses in Drosophila. Curr Opin Neurobiol. 2003;13:527–34. https://doi.org/10.1016/j.conb.2003.09.008.

    Article  CAS  PubMed  Google Scholar 

  63. Scheiffele P. Cell-cell signaling during synapse formation in the CNS. Annu Rev Neurosci. 2003;26:485–508. https://doi.org/10.1146/annurev.neuro.26.043002.094940.

    Article  CAS  PubMed  Google Scholar 

  64. Ferreira A, Paganoni S. The formation of synapses in the central nervous system. Mol Neurobiol. 2002;26:69–79. https://doi.org/10.1385/MN:26:1:069.

    Article  CAS  PubMed  Google Scholar 

  65. Bloom FE, Aghajanian GK. Fine structural and cytochemical analysis of the staining of synaptic junctions with phosphotungstic acid. J Ultrastruct Res. 1968;22:361–75. https://doi.org/10.1016/s0022-5320(68)90027-0.

    Article  CAS  PubMed  Google Scholar 

  66. Pfenninger K, Akert K, Moor H, Sandri C. The fine structure of freeze-fractured presynaptic membranes. J Neurocytol. 1972;1:129–49. https://doi.org/10.1007/BF01099180.

    Article  CAS  PubMed  Google Scholar 

  67. Harlow ML, Ress D, Stoschek A, Marshall RM, McMahan UJ. The architecture of active zone material at the frog's neuromuscular junction. Nature. 2001;409:479–84. https://doi.org/10.1038/35054000.

    Article  CAS  PubMed  Google Scholar 

  68. Phillips GR, Huang JK, Wang Y, Tanaka H, Shapiro L, Zhang W, et al. The presynaptic particle web: ultrastructure, composition, dissolution, and reconstitution. Neuron. 2001;32:63–77. https://doi.org/10.1016/s0896-6273(01)00450-0.

    Article  CAS  PubMed  Google Scholar 

  69. Burns ME, Augustine GJ. Synaptic structure and function: dynamic organization yields architectural precision. Cell. 1995;83:187–94. https://doi.org/10.1016/0092-8674(95)90160-4.

    Article  CAS  PubMed  Google Scholar 

  70. Hirokawa N, Sobue K, Kanda K, Harada A, Yorifuji H. The cytoskeletal architecture of the presynaptic terminal and molecular structure of synapsin 1. J Cell Biol. 1989;108:111–26. https://doi.org/10.1083/jcb.108.1.111.

    Article  CAS  PubMed  Google Scholar 

  71. Hata Y, Butz S, Sudhof TC. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci. 1996;16:2488–94. https://doi.org/10.1523/JNEUROSCI.16-08-02488.1996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kistner U, Wenzel BM, Veh RW, Cases-Langhoff C, Garner AM, Appeltauer U, et al. SAP90, a rat presynaptic protein related to the product of the Drosophila tumor suppressor gene dlg-A. J Biol Chem. 1993;268:4580–3. https://doi.org/10.1016/S0021-9258(18)53433-5.

    Article  CAS  PubMed  Google Scholar 

  73. Koulen P, Fletcher EL, Craven SE, Bredt DS, Wassle H. Immunocytochemical localization of the postsynaptic density protein PSD-95 in the mammalian retina. J Neurosci. 1998;18:10136–49. https://doi.org/10.1523/JNEUROSCI.18-23-10136.1998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Muller BM, Kistner U, Veh RW, Cases-Langhoff C, Becker B, Gundelfinger ED, et al. Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein. J Neurosci. 1995;15:2354–66. https://doi.org/10.1523/JNEUROSCI.15-03-02354.1995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fanning AS, Anderson JM. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest. 1999;103:767–72. https://doi.org/10.1172/JCI6509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Garner CC, Nash J, Huganir RL. PDZ domains in synapse assembly and signalling. Trends Cell Biol. 2000;10:274–80. https://doi.org/10.1016/s0962-8924(00)01783-9.

    Article  CAS  PubMed  Google Scholar 

  77. O'Brien RJ, Lau LF, Huganir RL. Molecular mechanisms of glutamate receptor clustering at excitatory synapses. Curr Opin Neurobiol. 1998;8:364–9. https://doi.org/10.1016/s0959-4388(98)80062-7.

    Article  CAS  PubMed  Google Scholar 

  78. Butz S, Okamoto M, Sudhof TC. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell. 1998;94:773–82. https://doi.org/10.1016/s0092-8674(00)81736-5.

    Article  CAS  PubMed  Google Scholar 

  79. Hsueh YP, Yang FC, Kharazia V, Naisbitt S, Cohen AR, Weinberg RJ, et al. Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. J Cell Biol. 1998;142:139–51. https://doi.org/10.1083/jcb.142.1.139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maximov A, Sudhof TC, Bezprozvanny I. Association of neuronal calcium channels with modular adaptor proteins. J Biol Chem. 1999;274:24453–6. https://doi.org/10.1074/jbc.274.35.24453.

    Article  CAS  PubMed  Google Scholar 

  81. tom Dieck S, Sanmarti-Vila L, Langnaese K, Richter K, Kindler S, Soyke A, et al. Bassoon, a novel zinc-finger CAG/glutamine-repeat protein selectively localized at the active zone of presynaptic nerve terminals. J Cell Biol. 1998;142:499–509. https://doi.org/10.1083/jcb.142.2.499.

    Article  CAS  PubMed  Google Scholar 

  82. Fenster SD, Chung WJ, Zhai R, Cases-Langhoff C, Voss B, Garner AM, et al. Piccolo, a presynaptic zinc finger protein structurally related to bassoon. Neuron. 2000;25:203–14. https://doi.org/10.1016/s0896-6273(00)80883-1.

    Article  CAS  PubMed  Google Scholar 

  83. Wang X, Kibschull M, Laue MM, Lichte B, Petrasch-Parwez E, Kilimann MW. Aczonin, a 550-kD putative scaffolding protein of presynaptic active zones, shares homology regions with Rim and Bassoon and binds profilin. J Cell Biol. 1999;147:151–62. https://doi.org/10.1083/jcb.147.1.151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang Y, Liu X, Biederer T, Sudhof TC. A family of RIM-binding proteins regulated by alternative splicing: implications for the genesis of synaptic active zones. Proc Natl Acad Sci U S A. 2002;99:14464–9. https://doi.org/10.1073/pnas.182532999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang Y, Okamoto M, Schmitz F, Hofmann K, Sudhof TC. Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature. 1997;388:593–8. https://doi.org/10.1038/41580.

    Article  CAS  PubMed  Google Scholar 

  86. Brose N, Hofmann K, Hata Y, Sudhof TC. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem. 1995;270:25273–80. https://doi.org/10.1074/jbc.270.42.25273.

    Article  CAS  PubMed  Google Scholar 

  87. Dresbach T, Qualmann B, Kessels MM, Garner CC, Gundelfinger ED. The presynaptic cytomatrix of brain synapses. Cell Mol Life Sci. 2001;58:94–116. https://doi.org/10.1007/PL00000781.

    Article  CAS  PubMed  Google Scholar 

  88. Rosenmund C, Rettig J, Brose N. Molecular mechanisms of active zone function. Curr Opin Neurobiol. 2003;13:509–19. https://doi.org/10.1016/j.conb.2003.09.011.

    Article  CAS  PubMed  Google Scholar 

  89. Takao-Rikitsu E, Mochida S, Inoue E, Deguchi-Tawarada M, Inoue M, Ohtsuka T, et al. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J Cell Biol. 2004;164:301–11. https://doi.org/10.1083/jcb.200307101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lagnado L. Ribbon synapses. Curr Biol. 2003;13:R631. https://doi.org/10.1016/s0960-9822(03)00566-9.

    Article  CAS  PubMed  Google Scholar 

  91. Lenzi D, von Gersdorff H. Structure suggests function: the case for synaptic ribbons as exocytotic nanomachines. BioEssays. 2001;23:831–40. https://doi.org/10.1002/bies.1118.

    Article  CAS  PubMed  Google Scholar 

  92. von Gersdorff H. Synaptic ribbons: versatile signal transducers. Neuron. 2001;29:7–10. https://doi.org/10.1016/s0896-6273(01)00175-1.

    Article  Google Scholar 

  93. Hallam SJ, Goncharov A, McEwen J, Baran R, Jin Y. SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP-like domains, specifies axon identity in C. elegans. Nat Neurosci. 2002;5:1137–46. https://doi.org/10.1038/nn959.

    Article  CAS  PubMed  Google Scholar 

  94. Meinertzhagen IA. Ultrastructure and quantification of synapses in the insect nervous system. J Neurosci Methods. 1996;69:59–73. https://doi.org/10.1016/S0165-0270(96)00021-0.

    Article  CAS  PubMed  Google Scholar 

  95. Yasuyama K, Meinertzhagen IA, Schurmann FW. Synaptic organization of the mushroom body calyx in Drosophila melanogaster. J Comp Neurol. 2002;445:211–26. https://doi.org/10.1002/cne.10155.

    Article  PubMed  Google Scholar 

  96. Govind CK, Meiss DE. Quantitative comparison of low- and high-output neuromuscular synapses from a motoneuron of the lobster (Homarus americanus). Cell Tissue Res. 1979;198:455–63. https://doi.org/10.1007/BF00234190.

    Article  CAS  PubMed  Google Scholar 

  97. Garner CC, Kindler S, Gundelfinger ED. Molecular determinants of presynaptic active zones. Curr Opin Neurobiol. 2000;10:321–7. https://doi.org/10.1016/s0959-4388(00)00093-3.

    Article  CAS  PubMed  Google Scholar 

  98. Muresan V, Lyass A, Schnapp BJ. The kinesin motor KIF3A is a component of the presynaptic ribbon in vertebrate photoreceptors. J Neurosci. 1999;19:1027–37. https://doi.org/10.1523/JNEUROSCI.19-03-01027.1999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hilfiker S, Pieribone VA, Czernik AJ, Kao HT, Augustine GJ, Greengard P. Synapsins as regulators of neurotransmitter release. Philos Trans R Soc Lond Ser B Biol Sci. 1999;354:269–79. https://doi.org/10.1098/rstb.1999.0378.

    Article  CAS  Google Scholar 

  100. Brandstatter JH, Fletcher EL, Garner CC, Gundelfinger ED, Wassle H. Differential expression of the presynaptic cytomatrix protein bassoon among ribbon synapses in the mammalian retina. Eur J Neurosci. 1999;11:3683–93. https://doi.org/10.1046/j.1460-9568.1999.00793.x.

    Article  CAS  PubMed  Google Scholar 

  101. Dick O, tom Dieck S, Altrock WD, Ammermuller J, Weiler R, Garner CC, et al. The presynaptic active zone protein bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron. 2003;37:775–86. https://doi.org/10.1016/s0896-6273(03)00086-2.

    Article  CAS  PubMed  Google Scholar 

  102. Kittel RJ, Wichmann C, Rasse TM, Fouquet W, Schmidt M, Schmid A, et al. Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release. Science. 2006;312:1051–4. https://doi.org/10.1126/science.1126308.

    Article  CAS  PubMed  Google Scholar 

  103. Lenzi D, Crum J, Ellisman MH, Roberts WM. Depolarization redistributes synaptic membrane and creates a gradient of vesicles on the synaptic body at a ribbon synapse. Neuron. 2002;36:649–59. https://doi.org/10.1016/s0896-6273(02)01025-5.

    Article  CAS  PubMed  Google Scholar 

  104. Lenzi D, Runyeon JW, Crum J, Ellisman MH, Roberts WM. Synaptic vesicle populations in saccular hair cells reconstructed by electron tomography. J Neurosci. 1999;19:119–32. https://doi.org/10.1523/JNEUROSCI.19-01-00119.1999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Matthews G. Synaptic mechanisms of bipolar cell terminals. Vis Res. 1999;39:2469–76. https://doi.org/10.1016/s0042-6989(98)00249-1.

    Article  CAS  PubMed  Google Scholar 

  106. Regus-Leidig H, Ott C, Lohner M, Atorf J, Fuchs M, Sedmak T, et al. Identification and immunocytochemical characterization of Piccolino, a novel Piccolo splice variant selectively expressed at sensory ribbon synapses of the eye and ear. PLoS One. 2013;8:e70373. https://doi.org/10.1371/journal.pone.0070373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Regus-Leidig H, Fuchs M, Lohner M, Leist SR, Leal-Ortiz S, Chiodo VA, et al. In vivo knockdown of Piccolino disrupts presynaptic ribbon morphology in mouse photoreceptor synapses. Front Cell Neurosci. 2014;8:259. https://doi.org/10.3389/fncel.2014.00259.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Govind CK, Quigley PA, Pearce J. Synaptic differentiation between two phasic motoneurons to a crayfish fast muscle. Invertebr Neurosci. 2001;4:77–84. https://doi.org/10.1007/s101580100009.

    Article  CAS  Google Scholar 

  109. Ahmari SE, Buchanan J, Smith SJ. Assembly of presynaptic active zones from cytoplasmic transport packets. Nat Neurosci. 2000;3:445–51. https://doi.org/10.1038/74814.

    Article  CAS  PubMed  Google Scholar 

  110. Friedman HV, Bresler T, Garner CC, Ziv NE. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron. 2000;27:57–69. https://doi.org/10.1016/s0896-6273(00)00009-x.

    Article  CAS  PubMed  Google Scholar 

  111. Dresbach T, Torres V, Wittenmayer N, Altrock WD, Zamorano P, Zuschratter W, et al. Assembly of active zone precursor vesicles: obligatory trafficking of presynaptic cytomatrix proteins Bassoon and Piccolo via a trans-Golgi compartment. J Biol Chem. 2006;281:6038–47. https://doi.org/10.1074/jbc.M508784200.

    Article  CAS  PubMed  Google Scholar 

  112. Zhai RG, Vardinon-Friedman H, Cases-Langhoff C, Becker B, Gundelfinger ED, Ziv NE, et al. Assembling the presynaptic active zone: a characterization of an active one precursor vesicle. Neuron. 2001;29:131–43. https://doi.org/10.1016/s0896-6273(01)00185-4.

    Article  CAS  PubMed  Google Scholar 

  113. Shapira M, Zhai RG, Dresbach T, Bresler T, Torres VI, Gundelfinger ED, et al. Unitary assembly of presynaptic active zones from Piccolo-Bassoon transport vesicles. Neuron. 2003;38:237–52. https://doi.org/10.1016/s0896-6273(03)00207-1.

    Article  CAS  PubMed  Google Scholar 

  114. Patel MR, Lehrman EK, Poon VY, Crump JG, Zhen M, Bargmann CI, et al. Hierarchical assembly of presynaptic components in defined C. elegans synapses. Nat Neurosci. 2006;9:1488–98. https://doi.org/10.1038/nn1806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhen M, Jin Y. The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature. 1999;401:371–5. https://doi.org/10.1038/43886.

    Article  CAS  PubMed  Google Scholar 

  116. Serra-Pages C, Medley QG, Tang M, Hart A, Streuli M. Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem. 1998;273:15611–20. https://doi.org/10.1074/jbc.273.25.15611.

    Article  CAS  PubMed  Google Scholar 

  117. Kaufmann N, DeProto J, Ranjan R, Wan H, Van Vactor D. Drosophila liprin-alpha and the receptor phosphatase Dlar control synapse morphogenesis. Neuron. 2002;34:27–38. https://doi.org/10.1016/s0896-6273(02)00643-8.

    Article  CAS  PubMed  Google Scholar 

  118. Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS. Wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron. 2002;33:545–58. https://doi.org/10.1016/s0896-6273(02)00589-5.

    Article  CAS  PubMed  Google Scholar 

  119. Marques G, Bao H, Haerry TE, Shimell MJ, Duchek P, Zhang B, et al. The Drosophila BMP type II receptor Wishful Thinking regulates neuromuscular synapse morphology and function. Neuron. 2002;33:529–43. https://doi.org/10.1016/s0896-6273(02)00595-0.

    Article  CAS  PubMed  Google Scholar 

  120. Chen X, Wu X, Wu H, Zhang M. Phase separation at the synapse. Nat Neurosci. 2020;23:301–10. https://doi.org/10.1038/s41593-019-0579-9.

    Article  CAS  PubMed  Google Scholar 

  121. Wu X, Cai Q, Feng Z, Zhang M. Liquid-liquid phase separation in neuronal development and synaptic signaling. Dev Cell. 2020;55:18–29. https://doi.org/10.1016/j.devcel.2020.06.012.

    Article  CAS  PubMed  Google Scholar 

  122. Wu X, Cai Q, Shen Z, Chen X, Zeng M, Du S, et al. RIM and RIM-BP form presynaptic active-zone-like condensates via phase separation. Mol Cell. 2019;73:971–984 e975. https://doi.org/10.1016/j.molcel.2018.12.007.

    Article  CAS  PubMed  Google Scholar 

  123. Wu X, Ganzella M, Zhou J, Zhu S, Jahn R, Zhang M. Vesicle tethering on the surface of phase-separated active zone condensates. Mol Cell. 2021;81:13–24 e17. https://doi.org/10.1016/j.molcel.2020.10.029.

    Article  CAS  Google Scholar 

  124. McDonald NA, Fetter RD, Shen K. Assembly of synaptic active zones requires phase separation of scaffold molecules. Nature. 2020;588:454–8. https://doi.org/10.1038/s41586-020-2942-0.

    Article  CAS  PubMed  Google Scholar 

  125. Brandstatter JH, Meinertzhagen IA. The rapid assembly of synaptic sites in photoreceptor terminals of the fly's optic lobe recovering from cold shock. Proc Natl Acad Sci U S A. 1995;92:2677–81. https://doi.org/10.1073/pnas.92.7.2677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rybak J, Meinertzhagen IA. The effects of light reversals on photoreceptor synaptogenesis in the fly Musca domestica. Eur J Neurosci. 1997;9:319–33. https://doi.org/10.1111/j.1460-9568.1997.tb01402.x.

    Article  CAS  PubMed  Google Scholar 

  127. Wojtowicz JM, Marin L, Atwood HL. Activity-induced changes in synaptic release sites at the crayfish neuromuscular junction. J Neurosci. 1994;14:3688–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Harris KM, Fiala JC, Ostroff L. Structural changes at dendritic spine synapses during long-term potentiation. Philos Trans R Soc Lond Ser B Biol Sci. 2003;358:745–8. https://doi.org/10.1098/rstb.2002.1254.

    Article  Google Scholar 

  129. Weeks AC, Ivanco TL, Leboutillier JC, Racine RJ, Petit TL. Sequential changes in the synaptic structural profile following long-term potentiation in the rat dentate gyrus. II. Induction/early maintenance phase. Synapse. 2000;36:286–96. https://doi.org/10.1002/(SICI)1098-2396(20000615)36:4<286::AID-SYN5>3.0.CO;2-T.

    Article  CAS  PubMed  Google Scholar 

  130. Reiff DF, Thiel PR, Schuster CM. Differential regulation of active zone density during long-term strengthening of Drosophila neuromuscular junctions. J Neurosci. 2002;22:9399–409. https://doi.org/10.1523/JNEUROSCI.22-21-09399.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Meinertzhagen IA, Govind CK, Stewart BA, Carter JM, Atwood HL. Regulated spacing of synapses and presynaptic active zones at larval neuromuscular junctions in different genotypes of the flies Drosophila and Sarcophaga. J Comp Neurol. 1998;393:482–92. https://doi.org/10.1002/(sici)1096-9861(19980420)393:4<482::aid-cne7>3.0.co;2-x.

    Article  CAS  PubMed  Google Scholar 

  132. Dickman DK, Lu Z, Meinertzhagen IA, Schwarz TL. Altered synaptic development and active zone spacing in endocytosis mutants. Curr Biol. 2006;16:591–8. https://doi.org/10.1016/j.cub.2006.02.058.

    Article  CAS  PubMed  Google Scholar 

  133. Gundelfinger ED, Reissner C, Garner CC. Role of Bassoon and Piccolo in assembly and molecular organization of the active zone. Front Synap Neurosci. 2015;7:19. https://doi.org/10.3389/fnsyn.2015.00019.

    Article  CAS  Google Scholar 

  134. Waites CL, Leal-Ortiz SA, Okerlund N, Dalke H, Fejtova A, Altrock WD, et al. Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation. EMBO J. 2013;32:954–69. https://doi.org/10.1038/emboj.2013.27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Montenegro-Venegas C, Annamneedi A, Hoffmann-Conaway S, Gundelfinger ED, Garner CC. BSN (bassoon) and PRKN/parkin in concert control presynaptic vesicle autophagy. Autophagy. 2020;16:1732–3. https://doi.org/10.1080/15548627.2020.1801259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Okerlund ND, Schneider K, Leal-Ortiz S, Montenegro-Venegas C, Kim SA, Garner LC, et al. Bassoon controls presynaptic autophagy through Atg5. Neuron. 2017;93:897–913 e897. https://doi.org/10.1016/j.neuron.2017.01.026.

    Article  CAS  PubMed  Google Scholar 

  137. Ceccarelli B, Fesce R, Grohovaz F, Haimann C. The effect of potassium on exocytosis of transmitter at the frog neuromuscular junction. J Physiol. 1988;401:163–83. https://doi.org/10.1113/jphysiol.1988.sp017156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zenisek D, Davila V, Wan L, Almers W. Imaging calcium entry sites and ribbon structures in two presynaptic cells. J Neurosci. 2003;23:2538–48. https://doi.org/10.1523/JNEUROSCI.23-07-02538.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zenisek D, Steyer JA, Almers W. Transport, capture and exocytosis of single synaptic vesicles at active zones. Nature. 2000;406:849–54. https://doi.org/10.1038/35022500.

    Article  CAS  PubMed  Google Scholar 

  140. Sudhof TC. The synaptic vesicle cycle. Annu Rev Neurosci. 2004;27:509–47. https://doi.org/10.1146/annurev.neuro.26.041002.131412.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R. Grace Zhai .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zhai, R.G. (2023). The Architecture of the Presynaptic Release Site. In: Wang, ZW. (eds) Molecular Mechanisms of Neurotransmitter Release. Advances in Neurobiology, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-031-34229-5_1

Download citation

Publish with us

Policies and ethics