Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Should I stop or should I go? The role of complexin in neurotransmitter release

Nature Reviews Neuroscience volume 17, pages 118–125 (2016)Cite this article

Subjects

Abstract

When it comes to fusion with the neuronal cell membrane, does a synaptic vesicle have a choice whether to stop or to go? Recent work suggests that complexin, a tiny protein found within the synaptic terminal, contributes to the mechanism through which this choice is made. How complexin plays this consulting part and which synaptic vesicle proteins it interacts with remain open questions. Indeed, studies in mice and flies have led to the proposal of different models of complexin function. We suggest that understanding the modular nature of complexin will help us to unpick its role in synaptic vesicle release.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Models of complexin function.
Figure 2: Models of the inhibitory activity of the complexin accessory alpha helix.
Figure 3: Different functions for different species?

Similar content being viewed by others

References

  1. McMahon, H. T., Missler, M., Li, C. & Sudhof, T. C. Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 83, 111–119 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi, S. et al. Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses. FEBS Lett. 368, 455–460 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Ishizuka, T., Saisu, H., Odani, S. & Abe, T. Synaphin: a protein associated with the docking/fusion complex in presynaptic terminals. Biochem. Biophys. Res. Commun. 213, 1107–1114 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Reim, K. et al. Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell 104, 71–81 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Xue, M. et al. Complexins facilitate neurotransmitter release at excitatory and inhibitory synapses in mammalian central nervous system. Proc. Natl Acad. Sci. USA 105, 7875–7880 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Xue, M. et al. Binding of the complexin N terminus to the SNARE complex potentiates synaptic-vesicle fusogenicity. Nat. Struct. Mol. Biol. 17, 568–575 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chang, S. et al. Complexin stabilizes newly primed synaptic vesicles and prevents their premature fusion at the mouse calyx of held synapse. J. Neurosci. 35, 8272–8290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Strenzke, N. et al. Complexin-I is required for high-fidelity transmission at the endbulb of Held auditory synapse. J. Neurosci. 29, 7991–8004 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martin, J. A., Hu, Z., Fenz, K. M., Fernandez, J. & Dittman, J. S. Complexin has opposite effects on two modes of synaptic vesicle fusion. Curr. Biol. 21, 97–105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huntwork, S. & Littleton, J. T. A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth. Nat. Neurosci. 10, 1235–1237 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Maximov, A., Tang, J., Yang, X., Pang, Z. P. & Sudhof, T. C. Complexin controls the force transfer from SNARE complexes to membranes in fusion. Science 323, 516–521 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Giraudo, C. G., Eng, W. S., Melia, T. J. & Rothman, J. E. A clamping mechanism involved in SNARE-dependent exocytosis. Science 313, 676–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Lai, Y. et al. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms. eLife 3, e03756 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Malsam, J. et al. The carboxy-terminal domain of complexin I stimulates liposome fusion. Proc. Natl Acad. Sci. USA 106, 2001–2006 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Lin, M. Y. et al. Complexin facilitates exocytosis and synchronizes vesicle release in two secretory model systems. J. Physiol. 591, 2463–2473 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. An, S. J., Grabner, C. P. & Zenisek, D. Real-time visualization of complexin during single exocytic events. Nat. Neurosci. 13, 577–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tang, J. et al. A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis. Cell 126, 1175–1187 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Schaub, J. R., Lu, X., Doneske, B., Shin, Y. K. & McNew, J. A. Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nat. Struct. Mol. Biol. 13, 748–750 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Xue, M. et al. Tilting the balance between facilitatory and inhibitory functions of mammalian and Drosophila complexins orchestrates synaptic vesicle exocytosis. Neuron 64, 367–380 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cho, R. W., Song, Y. & Littleton, J. T. Comparative analysis of Drosophila and mammalian complexins as fusion clamps and facilitators of neurotransmitter release. Mol. Cell Neurosci. 45, 389–397 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosenmund, C. & Stevens, C. F. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron 16, 1197–1207 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Basu, J., Betz, A., Brose, N. & Rosenmund, C. Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. J. Neurosci. 27, 1200–1210 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schotten, S. et al. Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate. eLife 4, e05531 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xue, M. et al. Distinct domains of complexin I differentially regulate neurotransmitter release. Nat. Struct. Mol. Biol. 14, 949–958 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang, X., Cao, P. & Sudhof, T. C. Deconstructing complexin function in activating and clamping Ca2+-triggered exocytosis by comparing knockout and knockdown phenotypes. Proc. Natl Acad. Sci. USA 110, 20777–20782 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Kaeser-Woo, Y. J., Yang, X. & Sudhof, T. C. C-terminal complexin sequence is selectively required for clamping and priming but not for Ca2+ triggering of synaptic exocytosis. J. Neurosci. 32, 2877–2885 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang, X., Kaeser-Woo, Y. J., Pang, Z. P., Xu, W. & Sudhof, T. C. Complexin clamps asynchronous release by blocking a secondary Ca2+ sensor via its accessory alpha helix. Neuron 68, 907–920 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Giraudo, C. G. et al. Distinct domains of complexins bind SNARE complexes and clamp fusion in vitro. J. Biol. Chem. 283, 21211–21219 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu, J., Pang, Z. P., Shin, O. H. & Sudhof, T. C. Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release. Nat. Neurosci. 12, 759–766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pang, Z. P. et al. Synaptotagmin-2 is essential for survival and contributes to Ca2+ triggering of neurotransmitter release in central and neuromuscular synapses. J. Neurosci. 26, 13493–13504 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xu, J., Brewer, K. D., Perez-Castillejos, R. & Rizo, J. Subtle Interplay between synaptotagmin and complexin binding to the SNARE complex. J. Mol. Biol. 425, 3461–3475 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chicka, M. C. & Chapman, E. R. Concurrent binding of complexin and synaptotagmin to liposome-embedded SNARE complexes. Biochemistry 48, 657–659 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brewer, K. D. et al. Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nat. Struct. Mol. Biol. 22, 555–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, X. et al. Three-dimensional structure of the complexin/SNARE complex. Neuron 33, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Bracher, A., Kadlec, J., Betz, H. & Weissenhorn, W. X-ray structure of a neuronal complexin-SNARE complex from squid. J. Biol. Chem. 277, 26517–26523 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Giraudo, C. G. et al. Alternative zippering as an on-off switch for SNARE-mediated fusion. Science 323, 512–516 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kummel, D. et al. Complexin cross-links prefusion SNAREs into a zigzag array. Nat. Struct. Mol. Biol. 18, 927–933 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Cho, R. W. et al. Genetic analysis of the complexin trans-clamping model for cross-linking SNARE complexes in vivo. Proc. Natl Acad. Sci. USA 111, 10317–10322 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Trimbuch, T. et al. Re-examining how complexin inhibits neurotransmitter release. eLife 3, e02391 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Radoff, D. T. et al. The accessory helix of complexin functions by stabilizing central helix secondary structure. eLife 3, e04553 (2014).

    Article  PubMed Central  Google Scholar 

  41. Krishnakumar, S. S. et al. Re-visiting the trans insertion model for complexin clamping. eLife 4, e04463 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hobson, R. J., Liu, Q., Watanabe, S. & Jorgensen, E. M. Complexin maintains vesicles in the primed state in C. elegans. Curr. Biol. 21, 106–113 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wragg, R. T. et al. Synaptic vesicles position complexin to block spontaneous fusion. Neuron 77, 323–334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Snead, D., Wragg, R. T., Dittman, J. S. & Eliezer, D. Membrane curvature sensing by the C-terminal domain of complexin. Nat. Commun. 5, 4955 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reim, K. et al. Structurally and functionally unique complexins at retinal ribbon synapses. J. Cell Biol. 169, 669–680 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Seiler, F., Malsam, J., Krause, J. M. & Sollner, T. H. A role of complexin-lipid interactions in membrane fusion. FEBS Lett. 583, 2343–2348 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Buhl, L. K. et al. Differential regulation of evoked and spontaneous neurotransmitter release by C-terminal modifications of complexin. Mol. Cell Neurosci. 52, 161–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Diao, J. et al. Complexin-1 enhances the on-rate of vesicle docking via simultaneous SNARE and membrane interactions. J. Am. Chem. Soc. 135, 15274–15277 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Malsam, J. et al. Complexin arrests a pool of docked vesicles for fast Ca2+-dependent release. EMBO J. 31, 3270–3281 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Diao, J. et al. Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion. eLife 1, e00109 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Schuske, K., Beg, A. A. & Jorgensen, E. M. The GABA nervous system in C. elegans. Trends Neurosci. 27, 407–414 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank M. Herman, J. Rizo and T. Littleton for helpful discussions. This work was supported by the German Research Council (DFG Collaborative Research Grants SFB665 and SFB958 to T.T. and C.R.), the European Research Foundation (Grant SynVglut to C.R.), and the Excellence Cluster Neurocure Exc257 (to C.R.).

Author information

Authors and Affiliations

  1. Neuroscience Research Center, Charité Universitätsmedizin Berlin, Chariteplatz 1, Berlin, 10117, Germany

    Thorsten Trimbuch & Christian Rosenmund

Authors
  1. Thorsten Trimbuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Rosenmund
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Rosenmund.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trimbuch, T., Rosenmund, C. Should I stop or should I go? The role of complexin in neurotransmitter release. Nat Rev Neurosci 17, 118–125 (2016). https://doi.org/10.1038/nrn.2015.16

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn.2015.16

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing