Molecular Mechanisms Underlying Neurotransmitter Release

Literature Cited

1. 1.

   Acuna C, Guo Q, Burre J, Sharma M, Sun J, Sudhof TC 2014. Microsecond dissection of neurotransmitter release: SNARE-complex assembly dictates speed and Ca²⁺ sensitivity. Neuron 82:1088–100
   [Google Scholar]
2. 2.

   Aeffner S, Reusch T, Weinhausen B, Salditt T 2012. Energetics of stalk intermediates in membrane fusion are controlled by lipid composition. PNAS 109:E1609–18
   [Google Scholar]
3. 3.

   Arac D, Chen X, Khant HA, Ubach J, Ludtke SJ et al. 2006. Close membrane-membrane proximity induced by Ca²⁺-dependent multivalent binding of synaptotagmin-1 to phospholipids. Nat. Struct. Mol. Biol. 13:209–17
   [Google Scholar]
4. 4.

   Aravamudan B, Fergestad T, Davis WS, Rodesch CK, Broadie K. 1999. Drosophila UNC-13 is essential for synaptic transmission. Nat. Neurosci. 2:965–71
   [Google Scholar]
5. 5.

   Bacaj T, Wu D, Yang X, Morishita W, Zhou P et al. 2013. Synaptotagmin-1 and synaptotagmin-7 trigger synchronous and asynchronous phases of neurotransmitter release. Neuron 80:947–59
   [Google Scholar]
6. 6.

   Bai J, Tucker WC, Chapman ER. 2004. PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nat. Struct. Mol. Biol. 11:36–44
   [Google Scholar]
7. 7.

   Baker RW, Jeffrey PD, Zick M, Phillips BP, Wickner WT, Hughson FM. 2015. A direct role for the Sec1/Munc18-family protein Vps33 as a template for SNARE assembly. Science 349:1111–14
   [Google Scholar]
8. 8.

   Banerjee A, Barry VA, DasGupta BR, Martin TF. 1996. N-ethylmaleimide-sensitive factor acts at a prefusion ATP-dependent step in Ca²⁺-activated exocytosis. J. Biol. Chem. 271:20223–26
   [Google Scholar]
9. 9.

   Bao H, Das D, Courtney NA, Jiang Y, Briguglio JS et al. 2018. Dynamics and number of trans-SNARE complexes determine nascent fusion pore properties. Nature 554:260–63
   [Google Scholar]
10. 10.

    Bao H, Goldschen-Ohm M, Jeggle P, Chanda B, Edwardson JM, Chapman ER 2016. Exocytotic fusion pores are composed of both lipids and proteins. Nat. Struct. Mol. Biol. 23:67–73
    [Google Scholar]
11. 11.

    Basu J, Shen N, Dulubova I, Lu J, Guan R et al. 2005. A minimal domain responsible for Munc13 activity. Nat. Struct. Mol. Biol. 12:1017–18
    [Google Scholar]
12. 12.

    Betz A, Thakur P, Junge HJ, Ashery U, Rhee JS et al. 2001. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron 30:183–96
    [Google Scholar]
13. 13.

    Bharat TA, Malsam J, Hagen WJ, Scheutzow A, Sollner TH, Briggs JA. 2014. SNARE and regulatory proteins induce local membrane protrusions to prime docked vesicles for fast calcium-triggered fusion. EMBO Rep 15:308–14
    [Google Scholar]
14. 14.

    Bowers MR, Reist NE. 2020. The C2A domain of synaptotagmin is an essential component of the calcium sensor for synaptic transmission. PLOS ONE 15:e0228348
    [Google Scholar]
15. 15.

    Bowers MR, Reist NE. 2020. Synaptotagmin: mechanisms of an electrostatic switch. Neurosci. Lett. 722:134834
    [Google Scholar]
16. 16.

    Brewer KD, Bacaj T, Cavalli A, Camilloni C, Swarbrick JD et al. 2015. Dynamic binding mode of a synaptotagmin-1-SNARE complex in solution. Nat. Struct. Mol. Biol. 22:555–64
    [Google Scholar]
17. 17.

    Brewer KD, Li W, Horne BE, Rizo J. 2011. Reluctance to membrane binding enables accessibility of the synaptobrevin SNARE motif for SNARE complex formation. PNAS 108:12723–28
    [Google Scholar]
18. 18.

    Brunger AT, Leitz J, Zhou Q, Choi UB, Lai Y. 2018. Ca²⁺-triggered synaptic vesicle fusion initiated by release of inhibition. Trends Cell Biol 28:631–45
    [Google Scholar]
19. 19.

    Burkhardt P, Hattendorf DA, Weis WI, Fasshauer D. 2008. Munc18a controls SNARE assembly through its interaction with the syntaxin N-peptide. EMBO J 27:923–33
    [Google Scholar]
20. 20.

    Camacho M, Basu J, Trimbuch T, Chang S, Pulido-Lozano C et al. 2017. Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming. Nat. Commun. 8:15293
    [Google Scholar]
21. 21.

    Camacho M, Quade B, Trimbuch T, Xu J, Sari L et al. 2022. Control of neurotransmitter release by two distinct membrane-binding faces of the Munc13-1 C₁C₂B region. eLife 10:e72030
    [Google Scholar]
22. 22.

    Carr CM, Rizo J. 2010. At the junction of SNARE and SM protein function. Curr. Opin. Cell Biol. 22:488–95
    [Google Scholar]
23. 23.

    Castillo PE, Janz R, Sudhof TC, Tzounopoulos T, Malenka RC, Nicoll RA. 1997. Rab3A is essential for mossy fibre long-term potentiation in the hippocampus. Nature 388:590–93
    [Google Scholar]
24. 24.

    Castillo PE, Schoch S, Schmitz F, Sudhof TC, Malenka RC. 2002. RIM1alpha is required for presynaptic long-term potentiation. Nature 415:327–30
    [Google Scholar]
25. 25.

    Chan Y-HM, van Lengerich B, Boxer SG. 2009. Effects of linker sequences on vesicle fusion mediated by lipid-anchored DNA oligonucleotides. PNAS 106:979–84
    [Google Scholar]
26. 26.

    Chang LF, Chen S, Liu CC, Pan X, Jiang J et al. 2012. Structural characterization of full-length NSF and 20S particles. Nat. Struct. Mol. Biol. 19:268–75
    [Google Scholar]
27. 27.

    Chang S, Trimbuch T, Rosenmund C. 2018. Synaptotagmin-1 drives synchronous Ca²⁺-triggered fusion by C2B-domain-mediated synaptic-vesicle-membrane attachment. Nat. Neurosci. 21:33–40
    [Google Scholar]
28. 28.

    Chapman ER, Davis AF. 1998. Direct interaction of a Ca²⁺-binding loop of synaptotagmin with lipid bilayers. J. Biol. Chem. 273:13995–4001
    [Google Scholar]
29. 29.

    Chen X, Lu J, Dulubova I, Rizo J 2008. NMR analysis of the closed conformation of syntaxin-1. J. Biomol. NMR 41:43–54
    [Google Scholar]
30. 30.

    Chen X, Tomchick DR, Kovrigin E, Arac D, Machius M et al. 2002. Three-dimensional structure of the complexin/SNARE complex. Neuron 33:397–409
    [Google Scholar]
31. 31.

    Chernomordik LV, Kozlov MM. 2008. Mechanics of membrane fusion. Nat. Struct. Mol. Biol. 15:675–83
    [Google Scholar]
32. 32.

    Choi UB, Zhao M, White KI, Pfuetzner RA, Esquivies L et al. 2018. NSF-mediated disassembly of on and off-pathway SNARE complexes and inhibition by complexin. eLife 7:e36497
    [Google Scholar]
33. 33.

    Cohen FS, Melikyan GB. 2004. The energetics of membrane fusion from binding, through hemifusion, pore formation, and pore enlargement. J. Membr. Biol. 199:1–14
    [Google Scholar]
34. 34.

    Courtney NA, Bao H, Briguglio JS, Chapman ER. 2019. Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin. Nat. Commun. 10:4076
    [Google Scholar]
35. 35.

    Courtney NA, Briguglio JS, Bradberry MM, Greer C, Chapman ER 2018. Excitatory and inhibitory neurons utilize different Ca²⁺ sensors and sources to regulate spontaneous release. Neuron 98:977–91.e5
    [Google Scholar]
36. 36.

    Dai H, Shen N, Arac D, Rizo J 2007. A quaternary SNARE-synaptotagmin-Ca²⁺-phospholipid complex in neurotransmitter release. J. Mol. Biol. 367:848–63
    [Google Scholar]
37. 37.

    Das D, Bao H, Courtney KC, Wu L, Chapman ER. 2020. Resolving kinetic intermediates during the regulated assembly and disassembly of fusion pores. Nat. Commun. 11:231
    [Google Scholar]
38. 38.

    Deng L, Kaeser PS, Xu W, Sudhof TC. 2011. RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13. Neuron 69:317–31
    [Google Scholar]
39. 39.

    Diao J, Grob P, Cipriano DJ, Kyoung M, Zhang Y et al. 2012. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. eLife 1:e00109
    [Google Scholar]
40. 40.

    Diez-Arazola R, Meijer M, Bourgeois-Jaarsma Q, Cornelisse LN, Verhage M, Groffen AJ. 2020. Doc2 proteins are not required for the increased spontaneous release rate in synaptotagmin-1-deficient neurons. J. Neurosci. 40:2606–17
    [Google Scholar]
41. 41.

    Dittman JS. 2019. Unc13: a multifunctional synaptic marvel. Curr. Opin. Neurobiol. 57:17–25
    [Google Scholar]
42. 42.

    Domanska MK, Kiessling V, Stein A, Fasshauer D, Tamm LK. 2009. Single vesicle millisecond fusion kinetics reveals number of SNARE complexes optimal for fast SNARE-mediated membrane fusion. J. Biol. Chem. 284:32158–66
    [Google Scholar]
43. 43.

    Dulubova I, Lou X, Lu J, Huryeva I, Alam A et al. 2005. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity?. EMBO J 24:2839–50
    [Google Scholar]
44. 44.

    Dulubova I, Sugita S, Hill S, Hosaka M, Fernandez I et al. 1999. A conformational switch in syntaxin during exocytosis: role of munc18. EMBO J 18:4372–82
    [Google Scholar]
45. 45.

    Dulubova I, Yamaguchi T, Gao Y, Min SW, Huryeva I et al. 2002. How Tlg2p/syntaxin 16 “snares” Vps45. EMBO J 21:3620–31
    [Google Scholar]
46. 46.

    Dulubova I, Yamaguchi T, Wang Y, Sudhof TC, Rizo J. 2001. Vam3p structure reveals conserved and divergent properties of syntaxins. Nat. Struct. Biol. 8:258–64
    [Google Scholar]
47. 47.

    Fasshauer D, Sutton RB, Brunger AT, Jahn R. 1998. Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. PNAS 95:15781–86
    [Google Scholar]
48. 48.

    Fernandez I, Arac D, Ubach J, Gerber SH, Shin O et al. 2001. Three-dimensional structure of the synaptotagmin 1 c2b-domain: synaptotagmin 1 as a phospholipid binding machine. Neuron 32:1057–69
    [Google Scholar]
49. 49.

    Fernandez I, Ubach J, Dulubova I, Zhang X, Sudhof TC, Rizo J. 1998. Three-dimensional structure of an evolutionarily conserved N-terminal domain of syntaxin 1A. Cell 94:841–49
    [Google Scholar]
50. 50.

    Fernandez-Chacon R, Konigstorfer A, Gerber SH, Garcia J, Matos MF et al. 2001. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410:41–49
    [Google Scholar]
51. 51.

    Gao Y, Zorman S, Gundersen G, Xi Z, Ma L et al. 2012. Single reconstituted neuronal SNARE complexes zipper in three distinct stages. Science 337:1340–43
    [Google Scholar]
52. 52.

    Gerber SH, Rah JC, Min SW, Liu X, de Wit H et al. 2008. Conformational switch of syntaxin-1 controls synaptic vesicle fusion. Science 321:1507–10
    [Google Scholar]
53. 53.

    Gipson P, Fukuda Y, Danev R, Lai Y, Chen DH et al. 2017. Morphologies of synaptic protein membrane fusion interfaces. PNAS 114:9110–15
    [Google Scholar]
54. 54.

    Giraudo CG, Garcia-Diaz A, Eng WS, Chen Y, Hendrickson WA et al. 2009. Alternative zippering as an on-off switch for SNARE-mediated fusion. Science 323:512–16
    [Google Scholar]
55. 55.

    Gong J, Lai Y, Li X, Wang M, Leitz J et al. 2016. C-terminal domain of mammalian complexin-1 localizes to highly curved membranes. PNAS 113:E7590–99
    [Google Scholar]
56. 56.

    Grushin K, Wang J, Coleman J, Rothman JE, Sindelar CV, Krishnakumar SS. 2019. Structural basis for the clamping and Ca²⁺ activation of SNARE-mediated fusion by synaptotagmin. Nat. Commun. 10:2413
    [Google Scholar]
57. 57.

    Guan Z, Bykhovskaia M, Jorquera RA, Sutton RB, Akbergenova Y, Littleton JT. 2017. A synaptotagmin suppressor screen indicates SNARE binding controls the timing and Ca²⁺ cooperativity of vesicle fusion. eLife 6:e28409
    [Google Scholar]
58. 58.

    Hanson PI, Heuser JE, Jahn R. 1997. Neurotransmitter release—four years of SNARE complexes. Curr. Opin. Neurobiol. 7:310–15
    [Google Scholar]
59. 59.

    He E, Wierda K, van Westen R, Broeke JH, Toonen RF et al. 2017. Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles. Nat. Commun. 8:15915
    [Google Scholar]
60. 60.

    Heo P, Coleman J, Fleury JB, Rothman JE, Pincet F. 2021. Nascent fusion pore opening monitored at single-SNAREpin resolution. PNAS 118:e2024922118
    [Google Scholar]
61. 61.

    Hernandez JM, Stein A, Behrmann E, Riedel D, Cypionka A et al. 2012. Membrane fusion intermediates via directional and full assembly of the SNARE complex. Science 336:1581–84
    [Google Scholar]
62. 62.

    Hobson RJ, Liu Q, Watanabe S, Jorgensen EM. 2011. Complexin maintains vesicles in the primed state in C. elegans. Curr. Biol. 21:106–13
    [Google Scholar]
63. 63.

    Hu Y, Zhu L, Ma C 2020. Structural roles for the juxtamembrane linker region and transmembrane region of synaptobrevin 2 in membrane fusion. Front. Cell Dev. Biol. 8:609708
    [Google Scholar]
64. 64.

    Hu Z, Tong XJ, Kaplan JM. 2013. UNC-13L, UNC-13S, and tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans. eLife 2:e00967
    [Google Scholar]
65. 65.

    Huang X, Sun S, Wang X, Fan F, Zhou Q et al. 2019. Mechanistic insights into the SNARE complex disassembly. Sci. Adv. 5:eaau8164
    [Google Scholar]
66. 66.

    Huntwork S, Littleton JT. 2007. A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth. Nat. Neurosci. 10:1235–37
    [Google Scholar]
67. 67.

    Jahn R, Scheller RH. 2006. SNAREs—engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7:631–43
    [Google Scholar]
68. 68.

    Jiao J, He M, Port SA, Baker RW, Xu Y et al. 2018. Munc18-1 catalyzes neuronal SNARE assembly by templating SNARE association. eLife 7:e41771
    [Google Scholar]
69. 69.

    Jorquera RA, Huntwork-Rodriguez S, Akbergenova Y, Cho RW, Littleton JT. 2012. Complexin controls spontaneous and evoked neurotransmitter release by regulating the timing and properties of synaptotagmin activity. J. Neurosci. 32:18234–45
    [Google Scholar]
70. 70.

    Junge HJ, Rhee JS, Jahn O, Varoqueaux F, Spiess J et al. 2004. Calmodulin and Munc13 form a Ca²⁺ sensor/effector complex that controls short-term synaptic plasticity. Cell 118:389–401
    [Google Scholar]
71. 71.

    Kaeser-Woo YJ, Yang X, Sudhof TC 2012. C-terminal complexin sequence is selectively required for clamping and priming but not for Ca²⁺ triggering of synaptic exocytosis. J. Neurosci. 32:2877–85
    [Google Scholar]
72. 72.

    Kalyana Sundaram RV, Jin H, Li F, Shu T, Coleman J et al. 2021. Munc13 binds and recruits SNAP25 to chaperone SNARE complex assembly. FEBS Lett 595:297–309
    [Google Scholar]
73. 73.

    Khvotchev M, Dulubova I, Sun J, Dai H, Rizo J, Sudhof TC 2007. Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminus. J. Neurosci. 27:12147–55
    [Google Scholar]
74. 74.

    Kim J, Shin YK. 2017. Productive and non-productive pathways for synaptotagmin 1 to support Ca²⁺-triggered fast exocytosis. Front. Mol. Neurosci. 10:380
    [Google Scholar]
75. 75.

    Koushika SP, Richmond JE, Hadwiger G, Weimer RM, Jorgensen EM, Nonet ML. 2001. A post-docking role for active zone protein Rim. Nat. Neurosci. 4:997–1005
    [Google Scholar]
76. 76.

    Kuhlmann JW, Junius M, Diederichsen U, Steinem C 2017. SNARE-mediated single-vesicle fusion events with supported and freestanding lipid membranes. Biophys. J. 112:2348–56
    [Google Scholar]
77. 77.

    Kummel D, Krishnakumar SS, Radoff DT, Li F, Giraudo CG et al. 2011. Complexin cross-links prefusion SNAREs into a zigzag array. Nat. Struct. Mol. Biol. 18:927–33
    [Google Scholar]
78. 78.

    Kyoung M, Srivastava A, Zhang Y, Diao J, Vrljic M et al. 2011. In vitro system capable of differentiating fast Ca²⁺-triggered content mixing from lipid exchange for mechanistic studies of neurotransmitter release. PNAS 108:E304–13
    [Google Scholar]
79. 79.

    Lai Y, Choi UB, Leitz J, Rhee HJ, Lee C et al. 2017. Molecular mechanisms of synaptic vesicle priming by Munc13 and Munc18. Neuron 95:591–607.e10
    [Google Scholar]
80. 80.

    Lai Y, Diao J, Cipriano DJ, Zhang Y, Pfuetzner RA et al. 2014. Complexin inhibits spontaneous release and synchronizes Ca²⁺-triggered synaptic vesicle fusion by distinct mechanisms. eLife 3:e03756
    [Google Scholar]
81. 81.

    Lai Y, Diao J, Liu Y, Ishitsuka Y, Su Z et al. 2013. Fusion pore formation and expansion induced by Ca²⁺ and synaptotagmin 1. PNAS 110:1333–38
    [Google Scholar]
82. 82.

    Lee HK, Yang Y, Su Z, Hyeon C, Lee TS et al. 2010. Dynamic Ca²⁺-dependent stimulation of vesicle fusion by membrane-anchored synaptotagmin 1. Science 328:760–63
    [Google Scholar]
83. 83.

    Li F, Pincet F, Perez E, Eng WS, Melia TJ et al. 2007. Energetics and dynamics of SNAREpin folding across lipid bilayers. Nat. Struct. Mol. Biol. 14:890–96
    [Google Scholar]
84. 84.

    Li F, Pincet F, Perez E, Giraudo CG, Tareste D, Rothman JE 2011. Complexin activates and clamps SNAREpins by a common mechanism involving an intermediate energetic state. Nat. Struct. Mol. Biol. 18:941–46
    [Google Scholar]
85. 85.

    Liu X, Seven AB, Camacho M, Esser V, Xu J et al. 2016. Functional synergy between the Munc13 C-terminal C1 and C2 domains. eLife 5:e13696
    [Google Scholar]
86. 86.

    Lu J, Machius M, Dulubova I, Dai H, Sudhof TC et al. 2006. Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLOS Biol 4:e192
    [Google Scholar]
87. 87.

    Ma C, Li W, Xu Y, Rizo J. 2011. Munc13 mediates the transition from the closed syntaxin-Munc18 complex to the SNARE complex. Nat. Struct. Mol. Biol. 18:542–49
    [Google Scholar]
88. 88.

    Ma C, Su L, Seven AB, Xu Y, Rizo J. 2013. Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339:421–25
    [Google Scholar]
89. 89.

    Mackler JM, Drummond JA, Loewen CA, Robinson IM, Reist NE 2002. The C2B Ca²⁺-binding motif of synaptotagmin is required for synaptic transmission in vivo. Nature 418:340–44
    [Google Scholar]
90. 90.

    Magdziarek M, Bolembach AA, Stepien KP, Quade B, Liu X, Rizo J. 2020. Re-examining how Munc13-1 facilitates opening of syntaxin-1. Protein Sci 29:1440–58
    [Google Scholar]
91. 91.

    Malhotra V, Orci L, Glick BS, Block MR, Rothman JE. 1988. Role of an N-ethylmaleimide-sensitive transport component in promoting fusion of transport vesicles with cisternae of the Golgi stack. Cell 54:221–27
    [Google Scholar]
92. 92.

    Malsam J, Barfuss S, Trimbuch T, Zarebidaki F, Sonnen AF et al. 2020. Complexin suppresses spontaneous exocytosis by capturing the membrane-proximal regions of VAMP2 and SNAP25. Cell Rep 32:107926
    [Google Scholar]
93. 93.

    Malsam J, Parisotto D, Bharat TA, Scheutzow A, Krause JM et al. 2012. Complexin arrests a pool of docked vesicles for fast Ca²⁺-dependent release. EMBO J 31:3270–81
    [Google Scholar]
94. 94.

    Martens S, Kozlov MM, McMahon HT. 2007. How synaptotagmin promotes membrane fusion. Science 316:1205–8
    [Google Scholar]
95. 95.

    Martin JA, Hu Z, Fenz KM, Fernandez J, Dittman JS. 2011. Complexin has opposite effects on two modes of synaptic vesicle fusion. Curr. Biol. 21:97–105
    [Google Scholar]
96. 96.

    Maximov A, Tang J, Yang X, Pang ZP, Sudhof TC 2009. Complexin controls the force transfer from SNARE complexes to membranes in fusion. Science 323:516–21
    [Google Scholar]
97. 97.

    Mayer A, Wickner W, Haas A. 1996. Sec18p (NSF)-driven release of Sec17p (alpha-SNAP) can precede docking and fusion of yeast vacuoles. Cell 85:83–94
    [Google Scholar]
98. 98.

    McMahon HT, Missler M, Li C, Sudhof TC. 1995. Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 83:111–19
    [Google Scholar]
99. 99.

    Meijer M, Dorr B, Lammertse HC, Blithikioti C, van Weering JR et al. 2017. Tyrosine phosphorylation of Munc18-1 inhibits synaptic transmission by preventing SNARE assembly. EMBO J 37:300–20
    [Google Scholar]
100. 100.

     Michelassi F, Liu H, Hu Z, Dittman JS. 2017. A C1-C2 module in Munc13 inhibits calcium-dependent neurotransmitter release. Neuron 95:577–90.e5
     [Google Scholar]
101. 101.

     Mima J, Hickey CM, Xu H, Jun Y, Wickner W. 2008. Reconstituted membrane fusion requires regulatory lipids, SNAREs and synergistic SNARE chaperones. EMBO J 27:2031–42
     [Google Scholar]
102. 102.

     Misura KM, Scheller RH, Weis WI. 2000. Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Nature 404:355–62
     [Google Scholar]
103. 103.

     Mohrmann R, de Wit H, Verhage M, Neher E, Sorensen JB 2010. Fast vesicle fusion in living cells requires at least three SNARE complexes. Science 330:502–5
     [Google Scholar]
104. 104.

     Neher E, Brose N. 2018. Dynamically primed synaptic vesicle states: key to understand synaptic short-term plasticity. Neuron 100:1283–91
     [Google Scholar]
105. 105.

     Pabst S, Hazzard JW, Antonin W, Sudhof TC, Jahn R et al. 2000. Selective interaction of complexin with the neuronal SNARE complex: determination of the binding regions. J. Biol. Chem. 275:19808–18
     [Google Scholar]
106. 106.

     Paddock BE, Wang Z, Biela LM, Chen K, Getzy MD et al. 2011. Membrane penetration by synaptotagmin is required for coupling calcium binding to vesicle fusion in vivo. J. Neurosci. 31:2248–57
     [Google Scholar]
107. 107.

     Pang ZP, Bacaj T, Yang X, Zhou P, Xu W, Sudhof TC. 2011. Doc2 supports spontaneous synaptic transmission by a Ca²⁺-independent mechanism. Neuron 70:244–51
     [Google Scholar]
108. 108.

     Parisotto D, Pfau M, Scheutzow A, Wild K, Mayer MP et al. 2014. An extended helical conformation in domain 3a of Munc18-1 provides a template for SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex assembly. J. Biol. Chem. 289:9639–50
     [Google Scholar]
109. 109.

     Park S, Bin NR, Yu B, Wong R, Sitarska E et al. 2017. UNC-18 and tomosyn antagonistically control synaptic vesicle priming downstream of UNC-13 in Caenorhabditis elegans. J. Neurosci. 37:8797–815
     [Google Scholar]
110. 110.

     Park Y, Seo JB, Fraind A, Perez-Lara A, Yavuz H et al. 2015. Synaptotagmin-1 binds to PIP2-containing membrane but not to SNAREs at physiological ionic strength. Nat. Struct. Mol. Biol. 22:815–23
     [Google Scholar]
111. 111.

     Park Y, Vennekate W, Yavuz H, Preobraschenski J, Hernandez JM et al. 2014. α-SNAP interferes with the zippering of the SNARE protein membrane fusion machinery. J. Biol. Chem. 289:16326–35
     [Google Scholar]
112. 112.

     Pei J, Ma C, Rizo J, Grishin NV. 2009. Remote homology between Munc13 MUN domain and vesicle tethering complexes. J. Mol. Biol. 391:509–17
     [Google Scholar]
113. 113.

     Poirier MA, Xiao W, Macosko JC, Chan C, Shin YK, Bennett MK 1998. The synaptic SNARE complex is a parallel four-stranded helical bundle. Nat. Struct. Biol. 5:765–69
     [Google Scholar]
114. 114.

     Prinslow EA, Brautigam CA, Rizo J. 2017. Reconciling isothermal titration calorimetry analyses of interactions between complexin and truncated SNARE complexes. eLife 6:e30286
     [Google Scholar]
115. 115.

     Prinslow EA, Stepien KP, Pan YZ, Xu J, Rizo J. 2019. Multiple factors maintain assembled trans-SNARE complexes in the presence of NSF and αSNAP. eLife 8:e38880
     [Google Scholar]
116. 116.

     Quade B, Camacho M, Zhao X, Orlando M, Trimbuch T et al. 2019. Membrane bridging by Munc13-1 is crucial for neurotransmitter release. eLife 8:e42806
     [Google Scholar]
117. 117.

     Radhakrishnan A, Li X, Grushin K, Krishnakumar SS, Liu J, Rothman JE. 2021. Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals. PNAS 118:e2024029118
     [Google Scholar]
118. 118.

     Radoff DT, Dong Y, Snead D, Bai J, Eliezer D, Dittman JS. 2014. The accessory helix of complexin functions by stabilizing central helix secondary structure. eLife 3:e04553
     [Google Scholar]
119. 119.

     Ramakrishnan S, Bera M, Coleman J, Krishnakumar SS, Pincet F, Rothman JE 2019. Synaptotagmin oligomers are necessary and can be sufficient to form a Ca²⁺-sensitive fusion clamp. FEBS Lett 593:154–62
     [Google Scholar]
120. 120.

     Reddy-Alla S, Bohme MA, Reynolds E, Beis C, Grasskamp AT et al. 2017. Stable positioning of Unc13 restricts synaptic vesicle fusion to defined release sites to promote synchronous neurotransmission. Neuron 95:1350–64.e12
     [Google Scholar]
121. 121.

     Regehr WG. 2012. Short-term presynaptic plasticity. Cold Spring Harb. Perspect. Biol. 4:a005702
     [Google Scholar]
122. 122.

     Rhee JS, Betz A, Pyott S, Reim K, Varoqueaux F et al. 2002. β Phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell 108:121–33
     [Google Scholar]
123. 123.

     Rhee JS, Li LY, Shin OH, Rah JC, Rizo J et al. 2005. Augmenting neurotransmitter release by enhancing the apparent Ca²⁺ affinity of synaptotagmin 1. PNAS 102:18664–69
     [Google Scholar]
124. 124.

     Richmond JE, Davis WS, Jorgensen EM 1999. UNC-13 is required for synaptic vesicle fusion in C. elegans. Nat. Neurosci. 2:959–64
     [Google Scholar]
125. 125.

     Richmond JE, Weimer RM, Jorgensen EM. 2001. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature 412:338–41
     [Google Scholar]
126. 126.

     Rizo J. 2018. Mechanism of neurotransmitter release coming into focus. Protein Sci 27:1364–91
     [Google Scholar]
127. 127.

     Rizo J, Sudhof TC. 1998. C2-domains, structure and function of a universal Ca²⁺-binding domain. J. Biol. Chem. 273:15879–82
     [Google Scholar]
128. 128.

     Rizo J, Sudhof TC. 2012. The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices—guilty as charged?. Annu. Rev. Cell Dev. Biol. 28:279–308
     [Google Scholar]
129. 129.

     Rothman JE, Krishnakumar SS, Grushin K, Pincet F 2017. Hypothesis—buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission. FEBS Lett 591:3459–80
     [Google Scholar]
130. 130.

     Ryu JK, Jahn R, Yoon TY 2016. Progresses in understanding N-ethylmaleimide sensitive factor (NSF) mediated disassembly of SNARE complexes. Biopolymers 105:518–31
     [Google Scholar]
131. 131.

     Sakamoto H, Ariyoshi T, Kimpara N, Sugao K, Taiko I et al. 2018. Synaptic weight set by Munc13-1 supramolecular assemblies. Nat. Neurosci. 21:41–49
     [Google Scholar]
132. 132.

     Schwartz ML, Merz AJ. 2009. Capture and release of partially zipped trans-SNARE complexes on intact organelles. J. Cell Biol. 185:535–49
     [Google Scholar]
133. 133.

     Seiler F, Malsam J, Krause JM, Sollner TH. 2009. A role of complexin-lipid interactions in membrane fusion. FEBS Lett 583:2343–48
     [Google Scholar]
134. 134.

     Shao X, Fernandez I, Sudhof TC, Rizo J. 1998. Solution structures of the Ca²⁺-free and Ca²⁺-bound C2A domain of synaptotagmin I: Does Ca²⁺ induce a conformational change?. Biochemistry 37:16106–15
     [Google Scholar]
135. 135.

     Shao X, Li C, Fernandez I, Zhang X, Sudhof TC, Rizo J. 1997. Synaptotagmin-syntaxin interaction: the C2 domain as a Ca²⁺-dependent electrostatic switch. Neuron 18:133–42
     [Google Scholar]
136. 136.

     Shi L, Shen QT, Kiel A, Wang J, Wang HW et al. 2012. SNARE proteins: one to fuse and three to keep the nascent fusion pore open. Science 335:1355–59
     [Google Scholar]
137. 137.

     Shin OH, Lu J, Rhee JS, Tomchick DR, Pang ZP et al. 2010. Munc13 C2B domain is an activity-dependent Ca²⁺ regulator of synaptic exocytosis. Nat. Struct. Mol. Biol. 17:280–88
     [Google Scholar]
138. 138.

     Shu T, Jin H, Rothman JE, Zhang Y 2020. Munc13-1 MUN domain and Munc18-1 cooperatively chaperone SNARE assembly through a tetrameric complex. PNAS 117:1036–41
     [Google Scholar]
139. 139.

     Sinha R, Ahmed S, Jahn R, Klingauf J 2011. Two synaptobrevin molecules are sufficient for vesicle fusion in central nervous system synapses. PNAS 108:14318–23
     [Google Scholar]
140. 140.

     Sitarska E, Xu J, Park S, Liu X, Quade B et al. 2017. Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion. eLife 6:e24278
     [Google Scholar]
141. 141.

     Sollner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE. 1993. A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75:409–18
     [Google Scholar]
142. 142.

     Sollner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S et al. 1993. SNAP receptors implicated in vesicle targeting and fusion. Nature 362:318–24
     [Google Scholar]
143. 143.

     Song H, Torng TL, Orr AS, Brunger AT, Wickner WT. 2021. Sec17/Sec18 can support membrane fusion without help from completion of SNARE zippering. eLife 10:e67578
     [Google Scholar]
144. 144.

     Stepien KP, Prinslow EA, Rizo J. 2019. Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP. Nat. Commun. 10:4326
     [Google Scholar]
145. 145.

     Stepien KP, Rizo J. 2021. Synaptotagmin-1-, Munc18-1-, and Munc13-1-dependent liposome fusion with a few neuronal SNAREs. PNAS 118:e2019314118
     [Google Scholar]
146. 146.

     Striegel AR, Biela LM, Evans CS, Wang Z, Delehoy JB et al. 2012. Calcium binding by synaptotagmin's C2A domain is an essential element of the electrostatic switch that triggers synchronous synaptic transmission. J. Neurosci. 32:1253–60
     [Google Scholar]
147. 147.

     Sudhof TC. 2013. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80:675–90
     [Google Scholar]
148. 148.

     Sudhof TC, Rothman JE. 2009. Membrane fusion: grappling with SNARE and SM proteins. Science 323:474–77
     [Google Scholar]
149. 149.

     Sutton RB, Davletov BA, Berghuis AM, Sudhof TC, Sprang SR. 1995. Structure of the first C2 domain of synaptotagmin I: a novel Ca²⁺/phospholipid-binding fold. Cell 80:929–38
     [Google Scholar]
150. 150.

     Sutton RB, Fasshauer D, Jahn R, Brunger AT 1998. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395:347–53
     [Google Scholar]
151. 151.

     Tagliatti E, Bello OD, Mendonca PRF, Kotzadimitriou D, Nicholson E et al. 2020. Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release. PNAS 117:3819–27
     [Google Scholar]
152. 152.

     Tang J, Maximov A, Shin OH, Dai H, Rizo J, Sudhof TC. 2006. A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis. Cell 126:1175–87
     [Google Scholar]
153. 153.

     Tien CW, Yu B, Huang M, Stepien KP, Sugita K et al. 2020. Open syntaxin overcomes exocytosis defects of diverse mutants in C. elegans. Nat. Commun. 11:5516
     [Google Scholar]
154. 154.

     Trimbuch T, Xu J, Flaherty D, Tomchick DR, Rizo J, Rosenmund C. 2014. Re-examining how complexin inhibits neurotransmitter release. eLife 3:e02391
     [Google Scholar]
155. 155.

     Tucker WC, Weber T, Chapman ER 2004. Reconstitution of Ca²⁺-regulated membrane fusion by synaptotagmin and SNAREs. Science 304:435–38
     [Google Scholar]
156. 156.

     Ubach J, Zhang X, Shao X, Sudhof TC, Rizo J. 1998. Ca²⁺ binding to synaptotagmin: How many Ca²⁺ ions bind to the tip of a C2-domain?. EMBO J 17:3921–30
     [Google Scholar]
157. 157.

     van den Bogaart G, Thutupalli S, Risselada JH, Meyenberg K, Holt M et al. 2011. Synaptotagmin-1 may be a distance regulator acting upstream of SNARE nucleation. Nat. Struct. Mol. Biol. 18:805–12
     [Google Scholar]
158. 158.

     Varoqueaux F, Sigler A, Rhee JS, Brose N, Enk C et al. 2002. Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. PNAS 99:9037–42
     [Google Scholar]
159. 159.

     Verhage M, Maia AS, Plomp JJ, Brussaard AB, Heeroma JH et al. 2000. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287:864–69
     [Google Scholar]
160. 160.

     Voleti R, Jaczynska K, Rizo J. 2020. Ca²⁺-dependent release of synaptotagmin-1 from the SNARE complex on phosphatidylinositol 4,5-bisphosphate-containing membranes. eLife 9:e57154
     [Google Scholar]
161. 161.

     Wang J, Bello O, Auclair SM, Wang J, Coleman J et al. 2014. Calcium sensitive ring-like oligomers formed by synaptotagmin. PNAS 111:13966–71
     [Google Scholar]
162. 162.

     Wang S, Choi UB, Gong J, Yang X, Li Y et al. 2017. Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis. EMBO J 36:816–29
     [Google Scholar]
163. 163.

     Wang S, Li Y, Gong J, Ye S, Yang X et al. 2019. Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly. Nat. Commun. 10:69
     [Google Scholar]
164. 164.

     Wang X, Gong J, Zhu L, Wang S, Yang X et al. 2020. Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly. EMBO J 39:e103631
     [Google Scholar]
165. 165.

     Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M et al. 1998. SNAREpins: minimal machinery for membrane fusion. Cell 92:759–72
     [Google Scholar]
166. 166.

     White KI, Zhao M, Choi UB, Pfuetzner RA, Brunger AT. 2018. Structural principles of SNARE complex recognition by the AAA+ protein NSF. eLife 7:e38888
     [Google Scholar]
167. 167.

     Whiteheart SW, Brunner M, Wilson DW, Wiedmann M, Rothman JE 1992. Soluble N-ethylmaleimide-sensitive fusion attachment proteins (SNAPs) bind to a multi-SNAP receptor complex in Golgi membranes. J. Biol. Chem. 267:12239–43
     [Google Scholar]
168. 168.

     Wickner W. 2010. Membrane fusion: five lipids, four SNAREs, three chaperones, two nucleotides, and a Rab, all dancing in a ring on yeast vacuoles. Annu. Rev. Cell Dev. Biol. 26:115–36
     [Google Scholar]
169. 169.

     Wickner W, Rizo J. 2017. A cascade of multiple proteins and lipids catalyzes membrane fusion. Mol. Biol. Cell 28:707–11
     [Google Scholar]
170. 170.

     Winter U, Chen X, Fasshauer D 2009. A conserved membrane attachment site in α-SNAP facilitates N-ethylmaleimide-sensitive factor (NSF)-driven SNARE complex disassembly. J. Biol. Chem. 284:31817–26
     [Google Scholar]
171. 171.

     Witkowska A, Heinz LP, Grubmuller H, Jahn R. 2021. Tight docking of membranes before fusion represents a metastable state with unique properties. Nat. Commun. 12:3606
     [Google Scholar]
172. 172.

     Wolfes AC, Dean C. 2020. The diversity of synaptotagmin isoforms. Curr. Opin. Neurobiol. 63:198–209
     [Google Scholar]
173. 173.

     Wragg RT, Snead D, Dong Y, Ramlall TF, Menon I et al. 2013. Synaptic vesicles position complexin to block spontaneous fusion. Neuron 77:323–34
     [Google Scholar]
174. 174.

     Wu Z, Auclair SM, Bello O, Vennekate W, Dudzinski NR et al. 2016. Nanodisc-cell fusion: control of fusion pore nucleation and lifetimes by SNARE protein transmembrane domains. Sci. Rep. 6:27287
     [Google Scholar]
175. 175.

     Xu H, Jun Y, Thompson J, Yates J, Wickner W. 2010. HOPS prevents the disassembly of trans-SNARE complexes by Sec17p/Sec18p during membrane fusion. EMBO J 29:1948–60
     [Google Scholar]
176. 176.

     Xu J, Brewer KD, Perez-Castillejos R, Rizo J. 2013. Subtle interplay between synaptotagmin and complexin binding to the SNARE complex. J. Mol. Biol. 425:3461–75
     [Google Scholar]
177. 177.

     Xu J, Camacho M, Xu Y, Esser V, Liu X et al. 2017. Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. eLife 6:e22567
     [Google Scholar]
178. 178.

     Xu Y, Su L, Rizo J 2010. Binding of Munc18-1 to synaptobrevin and to the SNARE four-helix bundle. Biochemistry 49:1568–76
     [Google Scholar]
179. 179.

     Xue M, Craig TK, Xu J, Chao HT, Rizo J, Rosenmund C 2010. Binding of the complexin N terminus to the SNARE complex potentiates synaptic-vesicle fusogenicity. Nat. Struct. Mol. Biol. 17:568–75
     [Google Scholar]
180. 180.

     Xue M, Lin YQ, Pan H, Reim K, Deng H et al. 2009. Tilting the balance between facilitatory and inhibitory functions of mammalian and Drosophila complexins orchestrates synaptic vesicle exocytosis. Neuron 64:367–80
     [Google Scholar]
181. 181.

     Xue M, Ma C, Craig TK, Rosenmund C, Rizo J 2008. The Janus-faced nature of the C2B domain is fundamental for synaptotagmin-1 function. Nat. Struct. Mol. Biol. 15:1160–68
     [Google Scholar]
182. 182.

     Xue M, Reim K, Chen X, Chao HT, Deng H et al. 2007. Distinct domains of complexin I differentially regulate neurotransmitter release. Nat. Struct. Mol. Biol. 14:949–58
     [Google Scholar]
183. 183.

     Xue M, Stradomska A, Chen H, Brose N, Zhang W et al. 2008. Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system. PNAS 105:7875–80
     [Google Scholar]
184. 184.

     Yang X, Wang S, Sheng Y, Zhang M, Zou W et al. 2015. Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat. Struct. Mol. Biol. 22:547–54
     [Google Scholar]
185. 185.

     Yavuz H, Kattan I, Hernandez JM, Hofnagel O, Witkowska A et al. 2018. Arrest of trans-SNARE zippering uncovers loosely and tightly docked intermediates in membrane fusion. J. Biol. Chem. 293:8645–55
     [Google Scholar]
186. 186.

     Yin L, Kim J, Shin YK 2016. Complexin splits the membrane-proximal region of a single SNAREpin. Biochem. J. 473:2219–24
     [Google Scholar]
187. 187.

     Yoon T-Y, Okumus B, Zhang F, Shin YK, Ha T. 2006. Multiple intermediates in SNARE-induced membrane fusion. PNAS 103:19731–36
     [Google Scholar]
188. 188.

     Zhang X, Rizo J, Sudhof TC 1998. Mechanism of phospholipid binding by the C2A-domain of synaptotagmin I. Biochemistry 37:12395–403
     [Google Scholar]
189. 189.

     Zhang Y, Hughson FM. 2021. Chaperoning SNARE folding and assembly. Annu. Rev. Biochem. 90:581–603
     [Google Scholar]
190. 190.

     Zhao M, Wu S, Zhou Q, Vivona S, Cipriano DJ et al. 2015. Mechanistic insights into the recycling machine of the SNARE complex. Nature 518:61–67
     [Google Scholar]
191. 191.

     Zhou K, Stawicki TM, Goncharov A, Jin Y. 2013. Position of UNC-13 in the active zone regulates synaptic vesicle release probability and release kinetics. eLife 2:e01180
     [Google Scholar]
192. 192.

     Zhou P, Pang ZP, Yang X, Zhang Y, Rosenmund C et al. 2013. Syntaxin-1 N-peptide and Habc-domain perform distinct essential functions in synaptic vesicle fusion. EMBO J 32:159–71
     [Google Scholar]
193. 193.

     Zhou Q, Lai Y, Bacaj T, Zhao M, Lyubimov AY et al. 2015. Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis. Nature 525:62–67
     [Google Scholar]
194. 194.

     Zhou Q, Zhou P, Wang AL, Wu D, Zhao M et al. 2017. The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. Nature 548:420–25
     [Google Scholar]
195. 195.

     Zick M, Wickner W. 2016. Improved reconstitution of yeast vacuole fusion with physiological SNARE concentrations reveals an asymmetric Rab(GTP) requirement. Mol. Biol. Cell 27:2590–97
     [Google Scholar]
196. 196.

     Zick M, Wickner WT. 2014. A distinct tethering step is vital for vacuole membrane fusion. eLife 3:e03251
     [Google Scholar]