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Distinct domains of complexin I differentially regulate neurotransmitter release

Nature Structural & Molecular Biology volume 14, pages 949–958 (2007)Cite this article

Abstract

Complexins constitute a family of four synaptic high-affinity SNARE complex–binding proteins. They positively regulate a late, post-priming step in Ca2+-triggered synchronous neurotransmitter release, but the underlying molecular mechanisms are unclear. We show here that SNARE complex binding of complexin I (CplxI) via its central α-helix is necessary but, unexpectedly, not sufficient for its key function in promoting neurotransmitter release. An accessory α-helix on the N-terminal side of the SNARE complex–binding region has an inhibitory effect on fast synaptic exocytosis, whereas sequences N-terminally adjacent to this helix facilitate Ca2+-triggered release even in the absence of the Ca2+ sensor synaptotagmin-1. Our results indicate that distinct functional domains of CplxI differentially regulate synaptic exocytosis and that, through the interplay between these domains, CplxI carries out a crucial role in fine-tuning Ca2+-triggered fast neurotransmitter release.

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Figure 1: Overexpression of CplxI rescues CplxI/II DKO neurons.
Figure 2: Synaptic function is not sensitive to CplxI abundance.
Figure 3: Identification of mutations in CplxI that block SNARE complex binding.
Figure 4: Rescue of CplxI/II DKO neurons with SNARE complex binding–deficient CplxI mutants.
Figure 5: SNARE complex binding and function of CplxI N-terminal mutants.
Figure 6: Overexpression of CplxI N-terminal mutants in WT neurons.
Figure 7: Effects of overexpression of WT CplxI and CplxI27–134 in Syt1 KO neurons.
Figure 8: Model for complexin function in Ca2+-triggered neurotransmitter release.

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Acknowledgements

We thank H. Chen, T. Hellmann, I. Herfort, D. Reuter, S. Wenger and A. Zeuch for excellent technical assistance; F. Benseler, D. Schwerdtfeger and I. Thanhäuser for DNA sequencing and oligonucleotide synthesis; R. Nehring and R. Atkinson for technical advice; H. Bellen for comments on the manuscript and E. Neher for continuous support and advice. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 523/B9 to N.B. and C.R.), a Heisenberg Fellowship (to C.R.), the Brown Foundation (to C.R.), the US National Institutes of Health (NS50655 to C.R., NS37200 to J.R.) and Baylor Research Advocates for Student Scientists and a McNair Fellowship (both to H.-T.C.).

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Author notes

  1. Mingshan Xue and Kerstin Reim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, Texas, USA

    Mingshan Xue, Hsiao-Tuan Chao, Hui Deng & Christian Rosenmund

  2. Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, D-37075, Germany

    Kerstin Reim & Nils Brose

  3. Department of Biochemistry and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Xiaocheng Chen & Josep Rizo

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Correspondence to Nils Brose or Christian Rosenmund.

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Xue, M., Reim, K., Chen, X. et al. Distinct domains of complexin I differentially regulate neurotransmitter release. Nat Struct Mol Biol 14, 949–958 (2007). https://doi.org/10.1038/nsmb1292

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