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Cited by 218Cellular transport and secretionNeuroscience and Neuropharmacology ResearchCalcium signaling and nucleotide metabolism

Doc2 Is a Ca2+ Sensor Required for Asynchronous Neurotransmitter Release

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Yao, Jun, Gaffaney, Jon D., Kwon, Sung E., Chapman, Edwin R.·2011·Cell
DOI 10.1016/j.cell.2011.09.046PMC PMC3220409
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Abstract

Synaptic transmission involves a fast synchronous phase and a slower asynchronous phase of neurotransmitter release that are regulated by distinct Ca(2+) sensors. Though the Ca(2+) sensor for rapid exocytosis, synaptotagmin I, has been studied in depth, the sensor for asynchronous release remains unknown. In a screen for neuronal Ca(2+) sensors that respond to changes in [Ca(2+)] with markedly slower kinetics than synaptotagmin I, we observed that Doc2--another Ca(2+), SNARE, and lipid-binding protein--operates on timescales consistent with asynchronous release. Moreover, up- and downregulation of Doc2 expression levels in hippocampal neurons increased or decreased, respectively, the slow phase of synaptic transmission. Synchronous release, when triggered by single action potentials, was unaffected by manipulation of Doc2 but was enhanced during repetitive stimulation in Doc2 knockdown neurons, potentially due to greater vesicle availability. In summary, we propose that Doc2 is a Ca(2+) sensor that is kinetically tuned to regulate asynchronous neurotransmitter release.

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  • In excitatory mouse hippocampal neurons, the calcium sensor Doc2α drives the majority of asynchronous release after a single action potential.

    “In excitatory mouse hippocampal neurons, the calcium sensor Doc2α drives the majority of asynchronous release after a single action potential66,67.”

    From Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis (2023) · cites this paper as [67]

    The Results section on single-action-potential responses reports that Doc2α knockdown clearly reduced the slow asynchronous component in cultured hippocampal neurons, and the Discussion identifies Doc2 as a sensor for asynchronous release in excitatory hippocampal neurons. Our copy does not establish that Doc2α drives the majority of that release after a single action potential. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 58

  1. Best AR Regehr WG 2009 Inhibitory regulation of electrically coupled neurons in the inferior olive is mediated by asynchronous release of GABA Neuron 62 555 565 19477156 PMC3261724
  2. Bhalla A Chicka MC Tucker WC Chapman ER 2006 Ca(2+)-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion Nat Struct Mol Biol 13 323 330 16565726
  3. Bhalla A Tucker WC Chapman ER 2005 Synaptotagmin isoforms couple distinct ranges of Ca2+, Ba2+, and Sr2+ concentration to SNARE-mediated membrane fusion Mol Biol Cell 16 4755 4764 16093350 PMC1237081
  4. Burgalossi A Jung S Meyer G Jockusch WJ Jahn O Taschenberger H O’Connor VM Nishiki T Takahashi M Brose N 2010 SNARE protein recycling by alphaSNAP and betaSNAP supports synaptic vesicle priming Neuron 68 473 487 21040848
  5. Chapman ER 2008 How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem 77 615 641 18275379
  6. Chicka MC Hui E Liu H Chapman ER 2008 Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca(2+) Nat Struct Mol Biol 15 827 835 18622390 PMC2570314
  7. Dean C Liu H Dunning FM Chang PY Jackson MB Chapman ER 2009 Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release Nat Neurosci 12 767 776 19448629 PMC2846764
  8. Duncan RR Betz A Shipston MJ Brose N Chow RH 1999 Transient, phorbol ester-induced DOC2-Munc13 interactions in vivo J Biol Chem 274 27347 27350 10488064
  9. Friedrich R Groffen AJ Connell E van Weering JR Gutman O Henis YI Davletov B Ashery U 2008 DOC2B acts as a calcium switch and enhances vesicle fusion J Neurosci 28 6794 6806 18596155 PMC2673511
  10. Fukuda M Mikoshiba K 2000 Doc2gamma, a third isoform of double C2 protein, lacking calcium-dependent phospholipid binding activity Biochem Biophys Res Commun 276 626 632 11027523
  11. Gaffaney JD Dunning FM Wang Z Hui E Chapman ER 2008 Synaptotagmin C2B domain regulates Ca2+-triggered fusion in vitro: critical residues revealed by scanning alanine mutagenesis J Biol Chem 283 31763 31775 18784080 PMC2581593
  12. Galvin JE Palamand D Strider J Milone M Pestronk A 2006 The muscle protein dysferlin accumulates in the Alzheimer brain Acta Neuropathol 112 665 671 17024495 PMC1705477
  13. Groffen AJ Brian EC Dudok JJ Kampmeijer J Toonen RF Verhage M 2004 Ca(2+)-induced recruitment of the secretory vesicle protein DOC2B to the target membrane J Biol Chem 279 23740 23747 15033971
  14. Groffen AJ Friedrich R Brian EC Ashery U Verhage M 2006 DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties J Neuroche 97 818 833 16515538
  15. Groffen AJ Martens S Diez Arazola R Cornelisse LN Lozovaya N de Jong AP Goriounova NA Habets RL Takai Y Borst JG 2010 Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release Science 327 1614 1618 20150444 PMC2846320
  16. Hagler DJ Jr Goda Y 2001 Properties of synchronous and asynchronous release during pulse train depression in cultured hippocampal neurons J Neurophysiol 85 2324 2334 11387379
  17. Higashio H Nishimura N Ishizaki H Miyoshi J Orita S Sakane A Sasaki T 2008 Doc2 alpha and Munc13-4 regulate Ca(2+) -dependent secretory lysosome exocytosis in mast cells J Immunol 180 4774 4784 18354201
  18. Hjelmstad GO 2006 Interactions between asynchronous release and short-term plasticity in the nucleus accumbens slice J Neurophysiol 95 2020 2023 16338991
  19. Hui E Bai J Wang P Sugimori M Llinas RR Chapman ER 2005 Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis Proc Natl Acad Sci USA 102 5210 5214 15793006 PMC556003
  20. Hui E Gaffaney JD Wang Z Johnson CP Evans CS Chapman ER 2011 Mechanism and function of synaptotagmin-mediated membrane apposition Nat Struct Mol Biol 18 813 821 21642967 PMC3130839
  21. Iremonger KJ Bains JS 2007 Integration of asynchronously released quanta prolongs the postsynaptic spike window J Neurosci 27 6684 6691 17581955 PMC6672686
  22. Johnson CP Chapman ER 2010 Otoferlin is a calcium sensor that directly regulates SNARE-mediated membrane fusion J Cell Biol 191 187 197 20921140 PMC2953437
  23. Koh TW Bellen HJ 2003 Synaptotagmin I, a Ca2+ sensor for neurotransmitter release Trends Neurosci 26 413 422 12900172
  24. Kojima T Fukuda M Aruga J Mikoshiba K 1996 Calcium-dependent phospholipid binding to the C2A domain of a ubiquitous form of double C2 protein (Doc2 beta) J Biochem 120 671 676 8902635
  25. Korteweg N Denekamp FA Verhage M Burbach JP 2000 Different spatiotemporal expression of DOC2 genes in the developing rat brain argues for an additional, nonsynaptic role of DOC2B in early development Eur J Neurosci 12 165 171 10651871
  26. Kullmann DM Asztely F 1998 Extrasynaptic glutamate spillover in the hippocampus: evidence and implications Trends Neurosci 21 8 14 9464678
  27. Lau PM Bi GQ 2005 Synaptic mechanisms of persistent reverberatory activity in neuronal networks Proc Natl Acad Sci USA 102 10333 10338 16006530 PMC1177363
  28. Lewis JL Dong M Earles CA Chapman ER 2001 The transmembrane domain of syntaxin 1A is critical for cytoplasmic domain protein-protein interactions J Biol Chem 276 15458 15465 11278966
  29. Liu H Dean C Arthur CP Dong M Chapman ER 2009 Autapses and networks of hippocampal neurons exhibit distinct synaptic transmission phenotypes in the absence of synaptotagmin I J Neurosci 29 7395 7403 19515907 PMC2723061
  30. Lu T Trussell LO 2000 Inhibitory transmission mediated by asynchronous transmitter release Neuron 26 683 694 10896163
  31. Mackler JM Drummond JA Loewen CA Robinson IM Reist NE 2002 The C(2)B Ca(2+)-binding motif of synaptotagmin is required for synaptic transmission in vivo Nature 418 340 344 12110842
  32. Maximov A Lao Y Li H Chen X Rizo J Sorensen JB Sudhof TC 2008 Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis Proc Natl Acad Sci USA 105 3986 3991 18308933 PMC2268828
  33. Maximov A Sudhof TC 2005 Autonomous function of synaptotagmin 1 in triggering synchronous release independent of asynchronous release Neuron 48 547 554 16301172
  34. Mochida S Orita S Sakaguchi G Sasaki T Takai Y 1998 Role of the Doc2 alpha-Munc13–1 interaction in the neurotransmitter release process Proc Natl Acad Sci USA 95 11418 11422 9736751 PMC21657
  35. Naito A Orita S Wanaka A Sasaki T Sakaguchi G Maeda M Igarashi H Tohyama M Takai Y 1997 Molecular cloning of mouse Doc2alpha and distribution of its mRNA in adult mouse brain Brain Res Mol Brain Res 44 198 204 9073161
  36. Nishiki T Augustine GJ 2004a Dual roles of the C2B domain of synaptotagmin I in synchronizing Ca2+-dependent neurotransmitter release J Neurosci 24 8542 8550 15456828 PMC6729890
  37. Nishiki T Augustine GJ 2004b Synaptotagmin I synchronizes transmitter release in mouse hippocampal neurons J Neurosci 24 6127 6132 15240804 PMC6729667
  38. Orita S Naito A Sakaguchi G Maeda M Igarashi H Sasaki T Takai Y 1997 Physical and functional interactions of Doc2 and Munc13 in Ca2+-dependent exocytotic machinery J Biol Chem 272 16081 16084 9195900
  39. Orita S Sasaki T Komuro R Sakaguchi G Maeda M Igarashi H Takai Y 1996 Doc2 enhances Ca2+-dependent exocytosis from PC12 cells J Biol Chem 271 7257 7260 8631736
  40. Orita S Sasaki T Naito A Komuro R Ohtsuka T Maeda M Suzuki H Igarashi H Takai Y 1995 Doc2: a novel brain protein having two repeated C2-like domains Biochem Biophys Res Commu 206 439 448 7826360
  41. Otsu Y Shahrezaei V Li B Raymond LA Delaney KR Murphy TH 2004 Competition between phasic and asynchronous release for recovered synaptic vesicles at developing hippocampal autaptic synapses J Neurosci 24 420 433 14724240 PMC6729994
  42. Pang ZP Bacaj T Yang X Zhou P Xu W Sudhof TC 2011 Doc2 supports spontaneous synaptic transmission by a Ca(2+)-independent mechanism Neuron 70 244 251 21521611 PMC3102832
  43. Peters JH McDougall SJ Fawley JA Smith SM Andresen MC 2010 Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons Neuron 65 657 669 20223201 PMC2837850
  44. Robinson IM Ranjan R Schwarz TL 2002 Synaptotagmins I and IV promote transmitter release independently of Ca(2+) binding in the C(2)A domain Nature 418 336 340 12110845
  45. Roux I Safieddine S Nouvian R Grati M Simmler MC Bahloul A Perfettini I Le Gall M Rostaing P Hamard G 2006 Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse Cell 127 277 289 17055430
  46. Sakaguchi G Manabe T Kobayashi K Orita S Sasaki T Naito A Maeda M Igarashi H Katsuura G Nishioka H 1999 Doc2alpha is an activity-dependent modulator of excitatory synaptic transmission Eur J Neurosci 11 4262 4268 10594652
  47. Sakaguchi G Orita S Maeda M Igarashi H Takai Y 1995 Molecular cloning of an isoform of Doc2 having two C2-like domains Biochem Biophys Res Commu 217 1053 1061 8554557
  48. Sato M Mori Y Matsui T Aoki R Oya M Yanagihara Y Fukuda M Tsuboi T 2010 Role of the polybasic sequence in the Doc2alpha C2B domain in dense-core vesicle exocytosis in PC12 cells J Neurochem 114 171 181 20403080
  49. 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 1919 15888526
  50. 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 450 676 682 18046404 PMC3536472
  51. Thomson AM 2000 Molecular frequency filters at central synapses Progress Neurobiol 62 159 196 10828382
  52. Tong G Jahr CE 1994 Multivesicular release from excitatory synapses of cultured hippocampal neurons Neuron 12 51 59 7507341
  53. Tucker WC Weber T Chapman ER 2004 Reconstitution of Ca2+-regulated membrane fusion by synaptotagmin and SNAREs Science 304 435 438 15044754
  54. Verhage M de Vries KJ Roshol H Burbach JP Gispen WH Sudhof TC 1997 DOC2 proteins in rat brain: complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion Neuron 18 453 461 9115738
  55. Volman V Gerkin RC Lau PM Ben-Jacob E Bi GQ 2007 Calcium and synaptic dynamics underlying reverberatory activity in neuronal networks Phys Biol 4 91 103 17664654
  56. Wang P Chicka MC Bhalla A Richards DA Chapman ER 2005 Synaptotagmin VII is targeted to secretory organelles in PC12 cells, where it functions as a high-affinity calcium sensor Mol Cell Biol 25 8693 8702 16166648 PMC1265757
  57. Wen H Linhoff MW McGinley MJ Li GL Corson GM Mandel G Brehm P 2010 Distinct roles for two synaptotagmin isoforms in synchronous and asynchronous transmitter release at zebrafish neuromuscular junction Proc Natl Acad Sci USA 107 13906 13911 20643933 PMC2922265
  58. Young SM Jr Neher E 2009 Synaptotagmin has an essential function in synaptic vesicle positioning for synchronous release in addition to its role as a calcium sensor Neuron 63 482 496 19709630

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Authors
Yao, J., Gaffaney, J. D., Kwon, S. E., & Chapman, E. R.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Chapman, Edwin R.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2011-10
Volume
147
Issue
3
Pages
666-677
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2011.09.046
PMC
PMC3220409
OpenAlex
W2015894821
Cited by
218
References
2
Citations by year
2026: 10 · 2025: 11 · 2024: 10 · 2023: 10 · 2022: 12 · 2021: 11 · 2020: 15 · 2019: 18 · 2018: 9 · 2017: 12 · 2016: 8 · 2015: 19 · 2014: 27 · 2013: 25 · 2012: 17
FWCI
11.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • American Heart Association
  • National Institutes of Health
  • National Institute of Mental Health (MH61876, R01MH061876)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
calcium sensor, asynchronous neurotransmitter release, synaptic transmission, synaptotagmin-1, SNARE proteins, hippocampal neurons, repetitive stimulation
MeSH terms
Action Potentials, Animals, Calcium, Calcium-Binding Proteins, Cells, Cultured, Hippocampus, Humans, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Synaptic Vesicles, Neurotransmitter Agents, Lipid Metabolism, SNARE Proteins, Synaptotagmin I, Mice, Rats, Gene Knockdown Techniques

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