Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ channel-vesicle coupling

作者：Boehme Mathias A; Beis Christina; Reddy Alla Suneel; Reynolds Eric; Mampell Malou M; Grasskamp Andreas T; Luetzkendorf Janine; Bergeron Dominique Dufour; Driller Jan H; Babikir Husam; Goettfert Fabian; Robinson Iain M; O' Kane Cahir J; Hell Stefan W; Wahl Markus C; Stelzl Ulrich; Loll Bernhard; Walter Alexander M; Sigrist Stephan J

来源：Nature Neuroscience, 2016, 19(10): 1311-+.

DOI：10.1038/nn.4364

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-alpha, 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. 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-Ca2+-channel topology whose developmental tightening optimizes synaptic transmission.

• 出版日期2016-10