Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ 
channel–vesicle.

Böhme, A.; Beis, C.; Reddy-Alla, S.; Reynolds, E.; Mampell, M. M.; Grasskamp, A. T.; Lützkendorf, J.; Dufour Bergeron, D.; Driller, J. H.; Babikir, H.; Göttfert, F.; Robinson, I. M.; O’Kane, C. J.; Hell, S. W.; Wahl, M. C.; Stelzl, U.; Loll, B.; Walter, A. M.; Sigrist, S. J.

doi:10.1038/nn.4364

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Journal Article

Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca²⁺ channel–vesicle.

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Göttfert, F.
Department of NanoBiophotonics, MPI for Biophysical Chemistry, Max Planck Society;

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Hell, S. W.
Department of NanoBiophotonics, MPI for Biophysical Chemistry, Max Planck Society;

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Citation

Böhme, A., Beis, C., Reddy-Alla, S., Reynolds, E., Mampell, M. M., Grasskamp, A. T., et al. (2016). Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca²⁺ channel–vesicle. Nature Neuroscience, 19(10), 1311-1320. doi:10.1038/nn.4364.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002B-2236-2

Abstract

Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca2+ channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca2+ channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13Anull mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca2+-channel topology whose developmental tightening optimizes synaptic transmission.