Journal
JOURNAL OF CELL BIOLOGY
Volume 216, Issue 4, Pages 1143-1161Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201606086
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Funding
- Deutsche Forschungsgemeinschaft [DFG-CNM PB FZT103, SPP1365/KA3423/1-1, KA3423/3-1, SFB958/A5]
- European Union (EUROSPIN)
- European Union (SynSys)
- European Union (European Research Council Advanced Grant SYNPRIME)
- National Institutes of Health [NS051262, R01NS083898]
- Fritz Thyssen Foundation
- Japan Society for the Promotion of Science
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
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Presynaptic active zones (AZs) are unique subcellular structures at neuronal synapses, which contain a network of specific proteins that control synaptic vesicle (SV) tethering, priming, and fusion. Munc13s are core AZ proteins with an essential function in SV priming. In hippocampal neurons, two different Munc13s-Munc13-1 and bMunc13-2-mediate opposite forms of presynaptic short-term plasticity and thus differentially affect neuronal network characteristics. We found that most presynapses of cortical and hippocampal neurons contain only Munc13-1, whereas similar to 10% contain both Munc13-1 and bMunc13-2. Whereas the presynaptic recruitment and activation of Munc13-1 depends on Rab3-interacting proteins (RIMs), we demonstrate here that bMunc13-2 is recruited to synapses by the AZ protein ELKS1, but not ELKS2, and that this recruitment determines basal SV priming and short-term plasticity. Thus, synapse-specific interactions of different Munc13 isoforms with ELKS1 or RIMs are key determinants of the molecular and functional heterogeneity of presynaptic AZs.
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