Encyclopedia of Computational Neuroscience

Living Edition
| Editors: Dieter Jaeger, Ranu Jung

Calcium-Dependent Exocytosis, Biophysical Models of

Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-7320-6_178-1



Calcium-dependent exocytosis is the biochemically controlled fusion of the bilipid secretory vesicle membrane with the bilipid cell membrane, triggered by the binding of several Ca2+ ions to control proteins such as synaptotagmins anchored at the interface between these two membranes. Exocytosis results in the release of vesicle contents into the extracellular space, namely, the release of neurotransmitter into the synaptic cleft in the case of neuronal synapses and neuromuscular junctions or the secretion of hormone into the bloodstream in the case of endocrine cells. Exocytosis also allows the transmembrane proteins contained in the vesicle membrane to be incorporated into the cell membrane, although such membrane protein trafficking is more characteristic of Ca2+-independent, constitutive exocytosis.

Detailed Description

In synapses, neuromuscular junctions, and endocrine cells, fast Ca2+-triggered exocytosis of...


Vesicle Fusion Ribbon Synapse Vesicle Release Vesicle Pool Vesicle Priming 
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.
This is a preview of subscription content, log in to check access.


  1. Barg S, Ma X, Eliasson L, Galvanovskis J, Gopel SO, Obermuller S, Platzer J, Renstrom E, Trus M, Atlas D, Striessnig J, Rorsman P (2001) Fast exocytosis with few Ca(2+) channels in insulin-secreting mouse pancreatic B cells. Biophys J 81:3308–3323PubMedCrossRefPubMedCentralGoogle Scholar
  2. Bennett MR, Farnell L, Gibson WG (2004) The facilitated probability of quantal secretion within an array of calcium channels of an active zone at the amphibian neuromuscular junction. Biophys J 86:2674–2690PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bertram R, Sherman A, Stanley EF (1996) Single-domain/bound calcium hypothesis of transmitter release and facilitation. J Neurophysiol 75:1919–1931PubMedGoogle Scholar
  4. Bertram R, Smith GD, Sherman A (1999) Modeling study of the effects of overlapping Ca2+ microdomains on neurotransmitter release. Biophys J 76:735–750PubMedCrossRefPubMedCentralGoogle Scholar
  5. Bollmann JH, Sakmann B (2005) Control of synaptic strength and timing by the release-site Ca2+ signal. Nat Neurosci 8:426–434PubMedGoogle Scholar
  6. Bollmann JH, Sakmann B, Borst JG (2000) Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289:953–957PubMedCrossRefGoogle Scholar
  7. Bornschein G, Arendt O, Hallermann S, Brachtendorf S, Eilers J, Schmidt H (2013) Paired-pulse facilitation at recurrent Purkinje neuron synapses is independent of calbindin and parvalbumin during high-frequency activation. J Physiol 591:3355–3370PubMedPubMedCentralGoogle Scholar
  8. Bucurenciu I, Kulik A, Schwaller B, Frotscher M, Jonas P (2008) Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse. Neuron 57:536–545PubMedCrossRefGoogle Scholar
  9. Chapman ER (2002) Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nat Rev Mol Cell Biol 3:498–508PubMedCrossRefGoogle Scholar
  10. Chen YD, Wang S, Sherman A (2008) Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis. Biophys J 95:2226–2241PubMedCrossRefPubMedCentralGoogle Scholar
  11. Cho S, von Gersdorff H (2012) Ca(2+) influx and neurotransmitter release at ribbon synapses. Cell Calcium 52:208–216PubMedCrossRefPubMedCentralGoogle Scholar
  12. Chow RH, Lv R, Neher E (1992) Delay in vesicle fusion revealed by electrochemical monitoring of single secretory events in adrenal chromaffin cells. Nature 356:60–63PubMedCrossRefGoogle Scholar
  13. Chung C, Raingo J (2013) Vesicle dynamics: how synaptic proteins regulate different modes of neurotransmission. J Neurochem 126:146–154PubMedCrossRefGoogle Scholar
  14. Coggins M, Zenisek D (2009) Evidence that exocytosis is driven by calcium entry through multiple calcium channels in goldfish retinal bipolar cells. J Neurophysiol 101:2601–2619PubMedCrossRefPubMedCentralGoogle Scholar
  15. Dittman JS, Regehr WG (1998) Calcium dependence and recovery kinetics of presynaptic depression at the climbing fiber to Purkinje cell synapse. J Neurosci 18:6147–6162PubMedGoogle Scholar
  16. Dittman JS, Kreitzer AC, Regehr WG (2000) Interplay between facilitation, depression, and residual calcium at three presynaptic terminals. J Neurosci 20:1374–1385PubMedGoogle Scholar
  17. Dittrich M, Pattillo JM, King JD, Cho S, Stiles JR, Meriney SD (2013) An excess-calcium-binding-site model predicts neurotransmitter release at the neuromuscular junction. Biophys J 104:2751–2763PubMedCrossRefPubMedCentralGoogle Scholar
  18. Dodge FA, Rahamimoff R (1967) Cooperative action of calcium ions in transmitter release at the neuromuscular junction. J Physiol 193:419–432PubMedPubMedCentralGoogle Scholar
  19. Eggermann E, Bucurenciu I, Goswami SP, Jonas P (2012) Nanodomain coupling between Ca(2)(+) channels and sensors of exocytosis at fast mammalian synapses. Nat Rev Neurosci 13:7–21CrossRefGoogle Scholar
  20. Ermolyuk YS, Adler FG, Surges R, Pavlov IY, Timofeeva Y, Kullman DM, Volynski KE (2013) Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels. Nature Neurosci 16:1754–1763PubMedCrossRefGoogle Scholar
  21. Felmy F, Neher E, Schneggenburger R (2003) Probing the intracellular calcium sensitivity of transmitter release during synaptic facilitation. Neuron 37:801–811PubMedCrossRefGoogle Scholar
  22. Gentile L, Stanley EF (2005) A unified model of presynaptic release site gating by calcium channel domains. Eur J Neurosci 21:278–282PubMedCrossRefGoogle Scholar
  23. Glavinovic MI, Rabie HR (2001) Monte Carlo evaluation of quantal analysis in the light of Ca2+ dynamics and the geometry of secretion. Pflugers Arch 443:132–145PubMedCrossRefGoogle Scholar
  24. Han X, Wang CT, Bai J, Chapman ER, Jackson MB (2004) Transmembrane segments of syntaxin line the fusion pore of Ca2+-triggered exocytosis. Science 304:289–292PubMedCrossRefGoogle Scholar
  25. Heidelberger R, Heinemann C, Neher E, Matthews G (1994) Calcium dependence of the rate of exocytosis in a synaptic terminal. Nature 371:513–515PubMedCrossRefGoogle Scholar
  26. Heil P, Neubauer H (2010) Summing across different active zones can explain the quasi-linear Ca-dependencies of exocytosis by receptor cells. Front Synaptic Neurosci 2:148PubMedCrossRefPubMedCentralGoogle Scholar
  27. Heinemann C, von Ruden L, Chow RH, Neher E (1993) A two-step model of secretion control in neuroendocrine cells. Pflugers Arch 424:105–112PubMedCrossRefGoogle Scholar
  28. Hosoi N, Sakaba T, Neher E (2007) Quantitative analysis of calcium-dependent vesicle recruitment and its functional role at the calyx of Held synapse. J Neurosci 27:14286–14298PubMedCrossRefGoogle Scholar
  29. Jahn R, Fasshauer D (2012) Molecular machines governing exocytosis of synaptic vesicles. Nature 490:201–207PubMedCrossRefGoogle Scholar
  30. Johnson SL, Franz C, Kuhn S, Furness DN, Ruttiger L, Munkner S, Rivolta MN, Seward EP, Herschman HR, Engel J, Knipper M, Marcotti W (2010) Synaptotagmin IV determines the linear Ca2+ dependence of vesicle fusion at auditory ribbon synapses. Nat Neurosci 13:45–52PubMedCrossRefPubMedCentralGoogle Scholar
  31. Kaeser PS, Regehr WG (2014) Molecular mechanisms for synchronous, asynchronous, and spontaneous neurotransmitter release. Annu Rev Physiol 76:333–363Google Scholar
  32. Lee JS, Ho WK, Neher E, Lee SH (2013) Superpriming of synaptic vesicles after their recruitment to the readily releasable pool. Proc Natl Acad Sci USA 110:15079–15084PubMedCrossRefPubMedCentralGoogle Scholar
  33. Lou X, Scheuss V, Schneggenburger R (2005) Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature 435:497–501PubMedCrossRefGoogle Scholar
  34. Matveev V, Bertram R, Sherman A (2006) Residual bound Ca2+ can account for the effects of Ca2+ buffers on synaptic facilitation. J Neurophysiol 96:3389–3397PubMedCrossRefGoogle Scholar
  35. Matveev V, Bertram R, Sherman A (2009) Ca2+ current versus Ca2+ channel cooperativity of exocytosis. J Neurosci 29:12196–12209PubMedCrossRefPubMedCentralGoogle Scholar
  36. Matveev V, Bertram R, Sherman A (2011) Calcium cooperativity of exocytosis as a measure of Ca(2)+ channel domain overlap. Brain Res 1398:126–138PubMedCrossRefPubMedCentralGoogle Scholar
  37. Meinrenken CJ, Borst JG, Sakmann B (2002) Calcium secretion coupling at calyx of held governed by nonuniform channel-vesicle topography. J Neurosci 22:1648–1667PubMedGoogle Scholar
  38. Meinrenken CJ, Borst JG, Sakmann B (2003) Local routes revisited: the space and time dependence of the Ca2+ signal for phasic transmitter release at the rat calyx of Held. J Physiol 547:665–689PubMedPubMedCentralGoogle Scholar
  39. Millar AG, Zucker RS, Ellis-Davies GC, Charlton MP, Atwood HL (2005) Calcium sensitivity of neurotransmitter release differs at phasic and tonic synapses. J Neurosci 25:3113–3125PubMedCrossRefGoogle Scholar
  40. Moser T, Neef A, Khimich D (2006) Mechanisms underlying the temporal precision of sound coding at the inner hair cell ribbon synapse. J Physiol 576:55–62PubMedCrossRefPubMedCentralGoogle Scholar
  41. Mutch SA, Kensel-Hammes P, Gadd JC, Fujimoto BS, Allen RW, Schiro PG, Lorenz RM, Kuyper CL, Kuo JS, Bajjalieh SM, Chiu DT (2011) Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. J Neurosci 31:1461–1470PubMedCrossRefPubMedCentralGoogle Scholar
  42. Nadkarni S, Bartol TM, Stevens CF, Sejnowski TJ, Levine H (2012) Short-term plasticity constrains spatial organization of a hippocampal presynaptic terminal. Proc Natl Acad Sci USA 109:14657–14662PubMedCrossRefPubMedCentralGoogle Scholar
  43. Neher E (2012) Introduction: regulated exocytosis. Cell Calcium 52:196–198PubMedCrossRefGoogle Scholar
  44. Neher E, Sakaba T (2008) Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59:861–872PubMedCrossRefGoogle Scholar
  45. Nouvian R, Neef J, Bulankina AV, Reisinger E, Pangrsic T, Frank T, Sikorra S, Brose N, Binz T, Moser T (2011) Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins. Nat Neurosci 14:411–413PubMedCrossRefGoogle Scholar
  46. Oheim M, Kirchhoff F, Stuhmer W (2006) Calcium microdomains in regulated exocytosis. Cell Calcium 40:423–439PubMedCrossRefGoogle Scholar
  47. Pan B, Zucker RS (2009) A general model of synaptic transmission and short-term plasticity. Neuron 62:539–554PubMedCrossRefPubMedCentralGoogle Scholar
  48. Pangrsic T, Reisinger E, Moser T (2012) Otoferlin: a multi-C2 domain protein essential for hearing. Trends Neurosci 35:671–680PubMedCrossRefGoogle Scholar
  49. Pedersen MG, Sherman A (2009) Newcomer insulin secretory granules as a highly calcium-sensitive pool. Proc Natl Acad Sci USA 106:7432–7436PubMedCrossRefPubMedCentralGoogle Scholar
  50. Quastel DM, Guan YY, Saint DA (1992) The relation between transmitter release and Ca2+ entry at the mouse motor nerve terminal: role of stochastic factors causing heterogeneity. Neuroscience 51:657–671PubMedCrossRefGoogle Scholar
  51. Raingo J, Khvotchev M, Liu P, Darios F, Li YC, Ramirez DM, Adachi M, Lemieux P, Toth K, Davletov B, Kavalali ET (2012) VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission. Nat Neurosci 15:738–745PubMedCrossRefPubMedCentralGoogle Scholar
  52. Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C (2006) Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127:277–289PubMedCrossRefGoogle Scholar
  53. Sakaba T (2008) Two Ca(2+)-dependent steps controlling synaptic vesicle fusion and replenishment at the cerebellar basket cell terminal. Neuron 57:406–419PubMedCrossRefGoogle Scholar
  54. Schmidt H, Brachtendorf S, Arendt O, Hallermann S, Ishiyama S, Bornschein G, Gall D, Schiffmann SN, Heckmann M, Eilers J (2013) Nanodomain coupling at an excitatory cortical synapse. Curr Biol 23:244–249PubMedCrossRefGoogle Scholar
  55. Schneggenburger R, Neher E (2000) Intracellular calcium dependence of transmitter release rates at a fast central synapse. Nature 406:889–893PubMedCrossRefGoogle Scholar
  56. Scimemi A, Diamond JS (2012) The number and organization of Ca2+ channels in the active zone shapes neurotransmitter release from Schaffer collateral synapses. J Neurosci 32:18157–18176PubMedCrossRefPubMedCentralGoogle Scholar
  57. Shahrezaei V, Delaney KR (2005) Brevity of the Ca2+ microdomain and active zone geometry prevent Ca2+-sensor saturation for neurotransmitter release. J Neurophysiol 94:1912–1919PubMedCrossRefGoogle Scholar
  58. Shahrezaei V, Cao A, Delaney KR (2006) Ca2+ from one or two channels controls fusion of a single vesicle at the frog neuromuscular junction. J Neurosci 26:13240–13249PubMedCrossRefGoogle Scholar
  59. Smith SM, Chen W, Vyleta NP, Williams C, Lee CH, Phillips C, Andresen MC (2012) Calcium regulation of spontaneous and asynchronous neurotransmitter release. Cell Calcium 52:226–233PubMedCrossRefPubMedCentralGoogle Scholar
  60. Sorensen JB (2004) Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles. Pflugers Arch 448:347–362PubMedCrossRefGoogle Scholar
  61. Stanley EF (1997) The calcium channel and the organization of the presynaptic transmitter release face. Trends Neurosci 20:404–409PubMedCrossRefGoogle Scholar
  62. Sterling P, Matthews G (2005) Structure and function of ribbon synapses. Trends Neurosci 28:20–29PubMedCrossRefGoogle Scholar
  63. Stevens CF, Wesseling JF (1998) Activity-dependent modulation of the rate at which synaptic vesicles become available to undergo exocytosis. Neuron 21:415–424PubMedCrossRefGoogle Scholar
  64. Sun J, Pang ZP, Qin D, Fahim AT, Adachi R, Sudhof TC (2007) A dual-Ca2+-sensor model for neurotransmitter release in a central synapse. Nature 450:676–682PubMedCrossRefPubMedCentralGoogle Scholar
  65. Thoreson WB, Rabl K, Townes-Anderson E, Heidelberger R (2004) A highly Ca2+-sensitive pool of vesicles contributes to linearity at the rod photoreceptor ribbon synapse. Neuron 42:595–605PubMedCrossRefPubMedCentralGoogle Scholar
  66. Verhage M, Toonen RF (2007) Regulated exocytosis: merging ideas on fusing membranes. Curr Opin Cell Biol 19:402–408PubMedCrossRefGoogle Scholar
  67. Voets T (2000) Dissection of three Ca2+-dependent steps leading to secretion in chromaffin cells from mouse adrenal slices. Neuron 28:537–545PubMedCrossRefGoogle Scholar
  68. Voets T, Neher E, Moser T (1999) Mechanisms underlying phasic and sustained secretion in chromaffin cells from mouse adrenal slices. Neuron 23:607–615PubMedCrossRefGoogle Scholar
  69. von Ruden L, Neher E (1993) A Ca-dependent early step in the release of catecholamines from adrenal chromaffin cells. Science 262:1061–1065CrossRefGoogle Scholar
  70. Wadel K, Neher E, Sakaba T (2007) The coupling between synaptic vesicles and Ca2+ channels determines fast neurotransmitter release. Neuron 53:563–575PubMedCrossRefGoogle Scholar
  71. Wang LY, Kaczmarek LK (1998) High-frequency firing helps replenish the readily releasable pool of synaptic vesicles. Nature 394:384–388PubMedCrossRefGoogle Scholar
  72. Weiss JN (1997) The Hill equation revisited: uses and misuses. FASEB J 11:835–841PubMedGoogle Scholar
  73. Wolfel M, Schneggenburger R (2003) Presynaptic capacitance measurements and Ca2+ uncaging reveal submillisecond exocytosis kinetics and characterize the Ca2+ sensitivity of vesicle pool depletion at a fast CNS synapse. J Neurosci 23:7059–7068PubMedGoogle Scholar
  74. Wolfel M, Lou X, Schneggenburger R (2007) A mechanism intrinsic to the vesicle fusion machinery determines fast and slow transmitter release at a large CNS synapse. J Neurosci 27:3198–3210PubMedCrossRefGoogle Scholar
  75. Worden MK, Bykhovskaia M, Hackett JT (1997) Facilitation at the lobster neuromuscular junction: a stimulus-dependent mobilization model. J Neurophysiol 78:417–428PubMedGoogle Scholar
  76. Wu MM, Llobet A, Lagnado L (2009) Loose coupling between calcium channels and sites of exocytosis in chromaffin cells. J Physiol 587:5377–5391PubMedCrossRefPubMedCentralGoogle Scholar
  77. Yamada MW, Zucker RS (1992) Time course of transmitter release calculated from stimulations of a calcium diffusion model. Biophys J 61:671–682PubMedCrossRefPubMedCentralGoogle Scholar
  78. Yang Y, Gillis KD (2004) A highly Ca2+-sensitive pool of granules is regulated by glucose and protein kinases in insulin-secreting INS-1 cells. J Gen Physiol 124:641–651PubMedCrossRefPubMedCentralGoogle Scholar
  79. Yang Y, Udayasankar S, Dunning J, Chen P, Gillis KD (2002) A highly Ca2+-sensitive pool of vesicles is regulated by protein kinase C in adrenal chromaffin cells. Proc Natl Acad Sci USA 99:17060–17065PubMedCrossRefPubMedCentralGoogle Scholar
  80. Yao J, Gaffaney JD, Kwon SE, Chapman ER (2011) Doc2 is a Ca2+ sensor required for asynchronous neurotransmitter release. Cell 147:666–677PubMedCrossRefPubMedCentralGoogle Scholar
  81. Zucker RS, Fogelson AL (1986) Relationship between transmitter release and presynaptic calcium influx when calcium enters through discrete channels. Proc Natl Acad Sci USA 83:3032–3036PubMedCrossRefPubMedCentralGoogle Scholar
  82. Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Mathematical SciencesNew Jersey Institute of TechnologyNewarkUSA