Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling - PubMed (original) (raw)

. 2016 Oct;19(10):1311-20.

doi: 10.1038/nn.4364. Epub 2016 Aug 15.

Christina Beis 1, Suneel Reddy-Alla 1, Eric Reynolds 1, Malou M Mampell 1, Andreas T Grasskamp 2 3, Janine Lützkendorf 1, Dominique Dufour Bergeron 1, Jan H Driller 4, Husam Babikir 1, Fabian Göttfert 5, Iain M Robinson 6, Cahir J O'Kane 7, Stefan W Hell 5, Markus C Wahl 4, Ulrich Stelzl 8, Bernhard Loll 4, Alexander M Walter 3, Stephan J Sigrist 1 2

Affiliations

Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling

Mathias A Böhme et al. Nat Neurosci. 2016 Oct.

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 Ca(2+) 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 Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) 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-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.

PubMed Disclaimer

Similar articles

Cited by

References

    1. J Neurosci. 2005 Mar 23;25(12):3209-18 - PubMed
    1. Neuron. 2002 Feb 14;33(4):545-58 - PubMed
    1. Neuron. 2015 Jan 7;85(1):145-58 - PubMed
    1. PLoS Comput Biol. 2015 May 07;11(5):e1004253 - PubMed
    1. Nat Struct Mol Biol. 2011 May;18(5):542-9 - PubMed

MeSH terms

Substances

LinkOut - more resources