Zilkha Virtual Seminar Series - Zhitao Hu PhD: Molecular Basis for Ca2+-Dependent Neurotransmitter Release

Wednesday, June 16 at 4:00pm to 5:00pm

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Ca2+-dependent neurotransmitter release requires synaptotagmins as Ca2+ sensors to trigger synaptic vesicle (SV) exocytosis through binding of their tandem C2 domains (C2A and C2B) to Ca2+. We have previously demonstrated that SNT-1, a mouse synaptotagmin-1 (Syt1) homolog, functions as the fast Ca2+ sensor in C. elegans. Here we report a new Ca2+ sensor, SNT-3, which triggers slow Ca2+-dependent neurotransmitter release. snt-1;snt-3 double mutants abolish evoked synaptic transmission, demonstrating that C. elegans NMJs use a dual Ca2+ sensor system. SNT-3 possesses canonical aspartate residues in both C2 domains, but lacks an N-terminal transmembrane (TM) domain. Biochemical evidence demonstrates that SNT-3 binds both Ca2+ and the plasma membrane. Functional analysis shows that SNT-3 is activated when SNT-1 function is impaired, triggering SV release that is loosely coupled to Ca2+ entry. Compared to SNT-1 which is tethered to SVs, SNT-3 is not SV associated. Eliminating the SV tethering of SNT-1 by removing the TM domain or the whole N terminus rescues fast release kinetics demonstrating that cytoplasmic SNT-1 is still functional and triggers fast neurotransmitter release, but exhibits decreased evoked amplitude and release probability. These results suggest that the fast and slow properties of SV release are determined by the intrinsically different C2 domains of the fast and slow Ca2+ sensors, rather than their N termini-mediated membrane tethering. Our findings therefore reveal a novel dual-Ca2+ sensor system in C. elegans and provide significant insights into Ca2+-regulated exocytosis.


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Health Sciences Campus



Keck School of Medicine
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