Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling
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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.
Original language | English |
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Journal | Nature Neuroscience |
Volume | 19 |
Issue number | 10 |
Pages (from-to) | 1311-1320 |
Number of pages | 10 |
ISSN | 1097-6256 |
DOIs | |
Publication status | Published - 2016 |
Externally published | Yes |
- Animals, Calcium Channels/metabolism, Carrier Proteins/genetics, Drosophila Proteins/metabolism, Drosophila melanogaster/genetics, Female, GTPase-Activating Proteins/metabolism, Intracellular Signaling Peptides and Proteins, Male, Models, Neurological, Mutation, Phosphoproteins/metabolism, Presynaptic Terminals/metabolism, Protein Isoforms, Synaptic Vesicles/metabolism, rab3 GTP-Binding Proteins/metabolism
Research areas
ID: 334035442